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Hantavirus infection in North America: a clinical review
American Journal of Emergency Medicine 31 (2013) 978–982
Contents lists available at SciVerse ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Review
Hantavirus infection in North America: a clinical review☆,☆☆,★ James Hartline MD ⁎, Chris Mierek MD, Tristan Knutson MD, Christopher Kang MD Madigan Army Medical Center, Department of Emergency Medicine, Fort Lewis (Tacoma), WA
a r t i c l e
i n f o
Article history: Received 7 December 2012 Accepted 1 February 2013
a b s t r a c t The recent outbreak of hantavirus in Yosemite National Park has attracted national attention, with 10 confirmed cases of hantavirus cardiopulmonary syndrome and thousands of more people exposed. This article will review the epidemiology, presentation, workup, and treatment for this rare but potentially lethal illness. The possibility of infection with hantavirus deserves consideration in patients with severe respiratory symptoms with rodent exposure or rural/wilderness travel. Accurate diagnosis requires a high index of suspicion. Hantavirus cardiopulmonary syndrome presents as a vague prodrome of fever, cough, myalgias, chills, and nausea followed by a rapidly worsening respiratory phase. Presumptive diagnosis can be made based on pulmonary interstitial edema on chest radiographs in association with leukocytosis, thrombocytopenia, and hemoconcentration. Suspected cases should be confirmed with a reference laboratory and reported to the appropriate public health authorities. Although treatment is primarily supportive, aggressive fluid administration should be avoided due to the risk of pulmonary edema. The cardiopulmonary phase of the disease can progress rapidly with catastrophic decompensation in as little as a few hours. Patients require rapid intensive care unit admission for monitoring, mechanical ventilation, vasoactive agents, and possibly extracorporeal mechanical ventilation. Emergency physicians should be aware of outbreaks and vigilant for hantavirus exposures, especially during the summer and early fall months. Published by Elsevier Inc.
1. Introduction Hantavirus, the cause of an uncommon but lethal disease known as hantavirus cardiopulmonary syndrome (HCPS), has drawn renewed attention after a recent outbreak in Yosemite National Park, CA. As of November 1 2012 (most recent data available), there have been 10 confirmed cases of HCPS, 3 of which were fatal [1]. Of the 10 cases, 9 occurred in people known to have stayed in tent cabins in a single campsite known as Curry Village [1]. It is estimated that more than 3100 visitors to the same campground were directly exposed to the virus. State of California officials subsequently warned an additional 230 000 people who may also have been exposed this summer [2,3]. In late October, a nonfatal case of hantavirus occurring after a rodent bite in the Adirondacks was confirmed [4]. Because of the recent reemergence of HCPS and the ubiquitous nature of the hantavirus, emergency physicians should be familiar with the incidence, clinical manifestations, and treatment of this disease.
☆ The views expressed are those of the author(s) and do not reflect the official policy of the Department of the Army, the Department of Defense, or the US Government. ☆☆ Source of support: No financial support was obtained for this manuscript. ★ Prior presentation: This article has not been previously presented or published. ⁎ Corresponding author. Madigan Healthcare System, ATTN: MCHJ-EM, Tacoma, WA 98431, USA. E-mail address: [email protected] (J. Hartline). 0735-6757/$ – see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ajem.2013.02.001
The hantaviruses are a genus of more than 21 enveloped singlestranded negative-sense RNA viruses belonging to the Bunyaviridae family [5]. The hantavirus causes 2 distinct febrile illnesses in humans involving an element of vascular leak resulting in end-organ damage ranging from proteinuria to severe pulmonary edema [6–8]. Hantavirus cardiopulmonary syndrome (also known as hantavirus pulmonary syndrome) is seen in North and South America and caused by the “New World” viruses. Hantavirus cardiopulmonary syndrome is characterized by a nonspecific viral prodrome followed by rapidly worsening respiratory distress, noncardiogenic pulmonary edema, and hemodynamic compromise [6,9]. Hemorrhagic fever with renal syndrome (HFRS) is seen in Asia and Europe and is caused by the “Old World” viruses. Hemorrhagic fever with renal syndrome was first recognized as the cause of illness in roughly 3200 US and UN military personnel during the Korean War in the early 1950s [8,10]. Originally known as “Korean Hemorrhagic Fever,” HFRS involves the acute onset of fever, headache, hypotension, and renal failure [11]. The high incidence of HFRS during the Korean War is thought to have been caused by soldiers living the fields having significant contact with carrier rodents [12]. An estimated 150 000 to 200 000 cases of HFRS occur annually worldwide, primarily in China, Russia, and Korea [13]. In China, more than 1.5 million cases of HFRS were reported between 1950 and 2007, resulting in more than 46 000 deaths [14]. Mortality rates are estimated to be as high as 60% in HCPS and 12% in HFRS [8].
J. Hartline et al. / American Journal of Emergency Medicine 31 (2013) 978–982
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Fig. 1. Centers for Disease Control and Prevention map of HCPS cases by state of exposure, updated 14 December 2012 [19].
Hantaviruses are considered a potential bioterrorism agent, currently listed as a category C pathogen by the Centers for Disease Control and Prevention (CDC), which include those emerging pathogens considered to be at risk for bioterrorism engineering because of “availability, ease of production and dissemination, and potential for high morbidity and mortality rates and major health impact” [15]. Hantaviruses have previously been considered category A gents, indicating the uncertain estimation of the treat they pose as potential biowarfare agents [8,16]. The hantaviruses are listed as category-A pathogens by the National Institute of Allergy and Infectious Disease priority list of pathogens, which includes those organisms and agents that pose the highest risk to national security because of their ease of dissemination or transmission, high mortality rates, potential for major public health impact, risk of public panic and social disruption, and require special action for public health preparedness [17]. 2. Epidemiology To date, more than 2000 cases of HCPS have been identified in small clusters and individual cases throughout North and South America, with a total of 616 cases occurring in the United States (between 11 and 48 cases annually; see Fig. 1) [8,18,19]. More than half of the North American hantavirus cases occur in the Four Corners area of the Southwest, but infections have been reported in 34 US states. Although generally occurring in rural areas, up to 25% of cases occur in urban and suburban areas [18]. Although reporting of the disease appears relatively sparse, the actual incidence may be somewhat higher due to asymptomatic infections. In a study performed in Baltimore (an area with very few reported cases of HCPS), 44% of mice and 0.74% (9 patients) were serologically positive for hantavirus despite being otherwise healthy and asymptomatic [20]. Although there appears to be a significant spectrum of disease, the case fatality rate for symptomatic HCPS patients in the United States is 38% [20]. Most cases occur during the late spring and early summer months, which may allow clinicians to distinguish the disease from influenza, which has a similar presentation [21]. Cases almost exclusively occur in people who sleep or work in areas where they may be exposed to
rodents. Transmission of the virus occurs predominately through inhalation of aerosolized rodent urine, feces, or saliva; exposure may also occur through food contaminated by rodent saliva and excreta and through rodent bites [8,13]. Although human-to-human transmission has not been observed in North America, there have been a few documented cases of such transmission in South America [8]. The largest risk factor is entering closed buildings with rodent infestations [22]. There is no known arthropod vector [13]. Given the close association with these risk factors, prevention of exposure to rodents or rodent droppings is essential. Those living in areas with known populations of carrier rodents should minimize contact by eliminating hospitable rodent environments, sealing gaps in homes and outbuildings, placing traps to discourage rodent infestation, removing potential nesting sites, and promptly disposing of leftover food and garbage [23]. Furthermore, in light of anticipated trends toward warmer weather, additional and possibly larger exposures to hantavirus are likely. As a result, especially with the ease and frequency of rapid long-distance travel, emergency physicians should be cognizant of local and distant outbreaks and regularly take a travel history, exposure history, and inquire about sick contacts when appropriate. 3. Pathophysiology Hantavirus infection is typically transmitted to humans via the inhalation of aerosolized rodent urine, feces, or saliva. Infection from animal bites has also been reported. No person-to-person transmission of hantavirus has been reported in North America. The average time between exposure and symptomatic illness is 1 to 5 weeks with a median incubation time of 18 days [24,25]. The primary site of hantavirus infection is the lung, where the virus elicits an inflammatory response enabling widespread dissemination to the vascular endothelial cells, culminating in subsequent severe vascular permeability, capillary leak, noncardiogenic pulmonary edema, hypoxia, lactic acidosis, elevated systemic vascular resistance, and myocardial depression [26,27]. As cardiac output decreases, systemic vascular resistance increases, and lactic acidosis develops [25,27]. Although the proximate cause of death is usually cardiogenic shock rather than respiratory failure, there is debate in the literature as to whether the
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cardiogenic shock is caused by a functional cardiac depression or by a typical myocarditis [24,28,29]. 4. Clinical presentation Hantavirus cardiopulmonary syndrome is characterized by a lengthy incubation period followed by a rapid onset of severe pulmonary disease. Patients with HCPS initially present with a vague viral prodrome, almost indistinguishable from influenza, lasting 3 to 5 days, with nonspecific complaints including, fatigue, fever, chills, malaise, nausea, myalgias, headache, and dizziness [25,27,30]. Headache and abdominal pain may be quite prominent and can complicate the workup by masquerading as other illnesses. Symptoms progress over the next 7 to 10 days and include nonproductive cough, tachypnea, and dyspnea. Patients will be febrile, tachycardic, tachypneic (generally 26 to 30 breaths per minute), and hypoxic. These changes herald the development of worsening cardiopulmonary disease, which can worsen catastrophically, requiring hospitalization and mechanical ventilation in as little as 24 hours [30]. However, if patients survive the acute period of the disease, they progress to the diuretic phase followed by rapid improvement, often permitting extubation in 1 to 2 days. The subsequent convalescent phase is characterized by prolonged weakness and fatigue with an abnormal diffusion capacity of the lungs that may require months to years to fully normalize [12,24]. 5. Workup Timely identification of recent travel or exposure to rodents and their habitats is imperative. Initial chest radiographs will reveal evidence of pulmonary edema in roughly one-third of patients with HCPS. Within 48 hours, nearly all patients will have interstitial edema, many will have pleural effusions, and two-thirds of them will display extensive bibasilar or perihilar airspace disease [30]. The presence of interstitial edema is seen much more frequently in HCPS than acute respiratory distress syndrome (ARDS) (88% vs 5%, respectively) and may assist with differentiating the two syndromes [31]. Thrombocytopenia is one of the earliest and most sensitive laboratory findings, occurring as early as the prodromal phase and seen in more than 80% of patients [30,32]. The CDC recommends drawing a complete blood count and serum chemistry panels every 8 to 12 hours in patients with suspected HCPS [33]. Laboratory findings commonly seen in HCPS include: [35] • Leukocytosis with neutrophilia, a left shift (possibly as high as 50%), and atypical lymphocytes; • Platelet count less than 150 000; • Elevated serum creatinine levels (reported in approximately 15% of all patients); • Proteinuria; • Mild elevations of transaminases, CPK, and amylase have been reported; and • CDC: “The combination of atypical lymphocytes, a significant bandemia, and thrombocytopenia in the setting of pulmonary edema is strongly suggestive of a hantavirus infection.” HCPS poor prognostic indicators: • Falling serum albumin, hemoconcentration, and a significant decline in the platelet count suggest a fluid shift from the systemic circulation to the lungs. • Metabolic acidosis in combination with rising serum lactate (N 4.0 mmol/L) and prolonged PT and PTT. • Cardiac index of less than 2.2 L/min per square meter. • Disseminated intravascular coagulation may rarely occur in severe cases of HCPS; however, this is much less common than in hemorrhagic fever with renal syndrome.
Because HCPS and ARDS share many overlapping characteristics, formal hantavirus testing at a reference laboratory is only recommended for previously healthy patients without predisposing medical conditions such as chronic obstructive pulmonary disease, malignancy, trauma, burns, and surgery [34]. Laboratory criteria for diagnosis of HCPS include detection of hantavirus-specific immunoglobulin M, rising titers of hantavirus-specific immunoglobulin G, detection of Hantavirus RNA by PCR, or detection of hantavirus antigen by immunohistochemistry [33]. In response to last summer's outbreak, the California Department of Public Health recommended formal testing only in patients who presented within 6 weeks of their visit to Yosemite [35]. Suspected cases of HCPS should be promptly reported to local, state, and national public health agencies. The CDC Clinical Case definition for HCPS requires meeting one or more of the following criteria: [34] • A febrile illness (ie, temperature N 101.0° F (N38.3° C) characterized by bilateral diffuse interstitial edema that may radiographically resemble ARDS, with respiratory compromise requiring supplemental oxygen, developing within 72 hours of hospitalization, and occurring in a previously healthy person. • An unexplained respiratory illness resulting in death, with an autopsy examination demonstrating noncardiogenic pulmonary edema without an identifiable cause. Because confirmatory testing is often not immediately available, a peripheral blood smear may facilitate a more timely diagnosis. If pulmonary edema is evident radiographically in a previously healthy patient with a suspected exposure or travel history, the presence of 4 of 5 of the following criteria was shown to be 96% sensitive and 99% specific for Hantavirus: myelocytosis, greater than 10% immunoblasts, hemoconcentration, thrombocytopenia, and the absence of toxic granulations in neutrophils [32]. 6. Treatment To date, no specific therapy for hantavirus has been shown to be effective for HCPS. Thus, the treatment for HCPS is predominately supportive in nature [12,24,36]. Patients should receive intravenous fluids, supplemental oxygen and ventilator support, antipyretics, and analgesia as needed. Because HCPS can overlap significantly with other infectious etiologies, appropriate broad-spectrum antibiotics should be considered in situations where HCPS is suspected but not yet confirmed. Judicious intravenous fluids should be administered given the widespread capillary leak and risk of worsening pulmonary edema. Because shock in HCPS is cardiogenic rather than distributive in nature, the lack of improvement in response to a fluid challenge is characteristic of HCPS [24,25]. The administration of excessive intravenous fluids may actually precipitate the development of hypoxemia by causing a refractory pulmonary edema [24]. Because fluid overload risks accelerating the progression to fulminant respiratory failure, aggressive fluid administration is strongly discouraged [12,24,23]. Electrolytes should be closely monitored. Once the cardiopulmonary phase evolves, patients with HCPS can decline precipitously and should be rapidly admitted to the intensive care unit for close monitoring and support of volume status and cardiopulmonary function, including intubation and the use of inotropes and vasopressors as needed. Extracorporeal membrane oxygenation (ECMO) has been successfully used in patients with refractory HCPS [37]. A study evaluating ECMO in 51 patients with a predicted mortality of 100% demonstrated a dramatic reduction in mortality, with an overall survival rate of 66.6% [37]. If available, the appropriate service should be consulted and ECMO initiated as soon as advanced shock or respiratory failure is recognized. The University of New Mexico has developed an institutional protocol for the prophylactic placement of femoral
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vascular access catheters in anticipation of possible rapid decompensation to allow for emergent initiation of ECMO [38]. The phase of severe cardiopulmonary dysfunction appears to be self-limited and last 2 to 4 days, making ECMO an ideal therapy for hantavirus patients unresponsive to other preliminary therapies. Extracorporeal membrane oxygenation is indicated for patients with advanced HCPS who would not be expected to survive without it. Inclusion criteria used include known HCPS with a cardiac index of less than 2.3 L/min per square meter, an arterial oxygen tensionfractional inspired oxygen (PaO2/FIO2) ratio of less than 50 [23]. Exclusion criteria include age over 70 years, severe preexisting disease, and neurologic impairment [23]. Extracorporeal membrane oxygenation may also be considered in patients with severe cardiopulmonary failure who continue to worsen despite aggressive critical care support, even if the above criteria absent [37]. Some authors have reported that intubation and the accompanying loss of adrenergic drive carry a risk of abrupt hemodynamic collapse and cardiac arrest and recommend that intubation should be avoided as long as possible for patients who are ECMO candidates [23]. Noninvasive ventilation such as bilevel positive airway pressure is contraindicated because of the profound pulmonary edema [23]. If intubation is required, both inotropic and vasoactive agents, such as a combination of dobutamine (5-15 μg/kg per minute) and norepinephrine (1-4 μg/min), have been used successfully and should be available at the bedside [23]. As a treatment for HFRS, when given early in the course of the disease, intravenous ribavirin has demonstrated efficacy at reducing mortality, decreasing the occurrence of progression to the oliguric phase, a decreased severity of renal insufficiency, and a decreased requirement for dialysis [39,40]. The Viral Special Pathogens Branch of the CDC has been testing several drugs in animal models and recently reported preliminary success with vandetanib, an antithyroid cancer drug that blocks the vascular endothelial growth factor (VEGF) receptor and appears to reduce vascular leakage and modestly improved survival in hamsters [41]. Infectious disease researchers at the University for Development in Santiago, Chile, have reported improved survival in patients using plasma from HCPS survivors believed to contain significant amounts of antihantavirus antibodies, finding a 23% absolute decrease in mortality (unpublished results communicated in Nature Medicine) [41]. Vaccines for HFRS have been developed and are routinely given in China and South Korea, contributing to the reduction from 150 000 to less than 20 000 annual cases in China with a similar decrease in South Korea [14,42]. These vaccines use killed virus and are derived from either rodent brains or cell cultures. There is currently no Food and Drug Administration–approved vaccine for the New World Hantaviruses; however, investigation into the use of viral antigens is currently underway [43,44]. Inactivated virus vaccines like those used in Asia are generally not being pursued for HCPS because of inadequate efficacy and concerns about the risks of mass production of a high-containment virus [12]. Given the possible use of hantavirus as a bioterrorism agent and its endemic status across the globe, it is clear that the development of effective hantavirus countermeasures is necessary. 7. Conclusion Hantavirus and HCPS should be suspected in patients with a prodrome of fever, cough, myalgias, chills, nausea, and vomiting from rural areas or with possible rodent exposure within the last 6 weeks. Timely diagnosis requires a high index of suspicion. The cardiopulmonary phase of the disease can cause a precipitous decline in as little as 24 hours. Treatment is primarily supportive and will likely require intensive care unit monitoring, mechanical ventilation, and vasoactive agents. Aggressive fluid administration should be avoided due to the risk of increasing pulmonary edema and accelerating the
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progression to respiratory failure. Extracorporeal membrane oxygenation may increase survival in severe cases. Because no specific therapy, including antivirals, has been shown to be effective for HCPS, emergency physicians should be vigilant for hantavirus exposures during the summer and early fall months to facilitate time-sensitive diagnosis and supportive care and alert the appropriate public health authorities. References [1] Hantavirus: “Outbreak of Hantavirus Infection in Yosemite National Park”. Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/hantavirus/ outbreaks/yosemite-national-park-2012.html. Updated 1 November 2012. Accessed 31 January 2013. [2] Jaret P. “Long Wait and Worry for a Visitor to Yosemite.” The New York Times. http://www.nytimes.com/2012/09/18/health/waiting-and-worrying-afteryosemite-hantavirus-outbreak.html. Updated 17 September 2012. Accessed 17 September 2012. [3] Mather K. “Hantavirus in Yosemite: New batch of park visitors notified.” The Los Angeles Times. http://latimesblogs.latimes.com/lanow/2012/09/hantavirus.html. Updated 14 September 2012. Accessed 17 September 2012. [4] “Tests confirm NY professor contracted Hantavirus.” The Wall Street Journal. http://online.wsj.com/article/AP50025f0449824e5f848157b38937d672.html. Updated 22 October 2012. Accessed 30 October 2012. [5] Plyusnin A, Morzunov SP. Virus evolution and genetic diversity of hantaviruses and their rodent hosts. Curr Top Microbiol Immunol 2001;256:47–75. [6] Peters CJ, Khan AS. Hantavirus pulmonary syndrome: the new American hemorrhagic fever. Clin Infect Dis 2002;34:1224–31. [7] Khan A, Khan AS. Hantaviruses: a tale of two hemispheres. Panminerva Med 2003;45(1):43–51. [8] Jonsson C, et al. Global perspective on hantavirus ecology, epidemiology, and disease. Clin Microbiol Rev 2010 April;23(2):412–41. [9] Enria DA, Briggiler AM, Pini N, Levis S. Clinical manifestations of New World hantaviruses. Curr Top Microbiol Immunol 2001;256:117–34. [10] Lee HW, Lee P-W, Johnson KM. Isolation of the etiologic agent of Korean hemorrhagic fever. J Infect Dis 1978;137:298–308. [11] Peters CJ, Simpson GL, Levy H. Spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Annu Rev Med 1999;50:531–45. [12] Jonsson CB, Hooper J, Mertz G. Treatment of Hantavirus pulmonary syndrome. Antiviral Res 2008;78:162–9http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2810485/. [13] Schmaljohn C, Hjelle B. Hantaviruses: a global disease problem. Emerg Infect Dis 1997;3(2):95–104. [14] Zhang YZ, Zou Y, Fu ZF, Plyusnin A. Hantavirus infections in humans and animals, China. Emerg Infect Dis 2010;16(8):1195–203. [15] CDC Emergency Preparedness and Response: Bioterrorism Agents/Diseases. http:// emergency.cdc.gov/agent/agentlist-category.asp. Accessed 25 January 2013. [16] Bronze MS, Huycke MM, Machado LJ, Voskuhl GW, Greenfield RA. Viral agents as biological weapons and agents of bioterrorism. Am J Med Sci 2002;323:316–25. [17] “NIAID Category A, B, and C Priority Pathogens.” National Institute of Allergy and Infectious Disease. Last Updated February 27, 2012http://www.niaid.nih.gov/ topics/biodefenserelated/biodefense/pages/cata.aspx. Accessed 27 January 2013. [18] “Reported Cases of HPS.” Centers for Disease Control and Prevention (CDC). http:// www.cdc.gov/hantavirus/surveillance/index.html. Updated 29 August 2012. Accessed 31 January 2013. [19] “US HCPS cases by state of exposure.” Centers for Disease Control and Prevention. http://www.cdc.gov/hantavirus/surveillance/state-of-exposure.html. Updated 14 December 2012. Accessed 25 January 2013. [20] Zaki SR, Khan AS, Goodman RA, Armstrong LR, Greer PW, Coffield LM, et al. Retrospective diagnosis of Hantavirus pulmonary syndrome, 1978-1993: implications for emerging infectious diseases. Arch Pathol Lab Med 1996 Feb;120(2): 134–9. [21] “Hantavirus infection - southwestern United States: Interim recommendations for risk reduction.” Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1993;42(RR-11):i-13. [22] Armstrong LR, Zaki SR, et al. Hantavirus pulmonary syndrome associated with entering or cleaning rarely used, rodent-infested structures. J Infect Dis 1995;172: 1166. [23] Chang B, Crowley M, Campen M, Koster F. Hantavirus cardiopulmonary syndrome. Semin Respir Crit Care Med 2007;28:193–200. [24] Mertz GJ, Hjelle B, Crowley M, Iwamoto G, Tomicic V, Vial PA. Diagnosis and treatment of new world hantavirus infections. Curr Opin Infect Dis 2006;19:437–42. [25] “Hantavirus Technical/Clinical Information.” Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/hantavirus/technical/index.html. Updated 29 August 2012. Accessed 17 October 2012. [26] Gavrilovskaya I, Gorbunova E, Koster F, Mackow E. Elevated VEGF levels in pulmonary edema fluid and PBMCs from patients with acute hantavirus pulmonary syndrome. Adv Virol 2012;2012:674360. [27] Hallin GW, Simpson SQ, et al. Cardiopulmonary manifestations of hantavirus pulmonary syndrome. Crit Care Med 1996 Feb;24(2):252–8. [28] Saggioro FP, Rossi MA, 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;195(10):1541–9.
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[29] Abel Borges A, Figueiredo LT. Mechanisms of shock in hantavirus pulmonary syndrome. Curr Opin Infect Dis 2008;21(3):293–7. [30] “Hantavirus Technical/Clinical Information: Clinical Manifestation.” Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/hantavirus/technical/ hps/clinical-manifestation.html. Updated 29 August 2012. Accessed 17 October 2012. [31] Ketai LH, Williamson MR, Telepak RJ, Levy H, Koster FT, Nolte KB, et al. Hantavirus pulmonary syndrome: radiographic findings in 16 patients. Radiology 1994;191:665–8. [32] 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;116:665–72. [33] “Diagnostics.” Centers for Disease Control and Prevention (CDC). http://www.cdc. gov/hantavirus/technical/hps/diagnostics.html. Updated 29 August 2012. Accessed 17 October 2012. [34] “Hantavirus Case Definition.” Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/hantavirus/health-care-workers/hps-case-definition.html. Updated 29 August 2012. Accessed 17 October 2012. [35] “Alert and Guidance for Physicians with Patients Presenting with Concerns or Symptoms of Hantavirus Pulmonary Syndrome after Visit to Yosemite National Park.” California Department of Public Health. http://www.cdph.ca.gov/ HealthInfo/discond/Documents/HANTAGuidanceForClinicians9-12.pdf. 5 September 2012.
[36] “Hantavirus Technical/Clinical Information: Treatment.” Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/hantavirus/technical/hps/ treatment.html. Updated 29 August 2012. Accessed31 January 2013. [37] Wernly JA, Dietl CA, Tabe CE, et al. Extracorporeal membrane oxygenation support improves survival of patients with Hantavirus cardiopulmonary syndrome refractory to medical treatment. Eur J Cardiothorac Surg 2011;40:1334–40. [38] Frizzell JD, Boivin MA. Correspondence: breathtaking journey. N Engl J Med 2012;367:1473–4. [39] Huggins JW, Hsiang CM, et al. Prospective, double-blind, concurrent, placebocontrolled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis 1991;164:1119–27. [40] Rusnak JM, Byrne WR, et al. Experience with intravenous ribavirin in the treatment of hemorrhagic fever with renal syndrome in Korea. Antiviral Res 2009;81(1):68–76. [41] Dolgin E. Hantavirus treatments advance amidst outbreak in US park. Nat Med 2012;18(10):1448. [42] Cho HW, Howard CR, Lee HW. Review of an inactivated vaccine against hantaviruses. Intervirology 2002;45(4–6):328–33. [43] Schmaljohn CS. Vaccines for hantaviruses: progress and issues. Expert Rev Vaccines 2012;11(5):511–3. [44] Schmaljohn C. Vaccines for hantaviruses. Vaccine 2009 Nov 5;27(Suppl 4):D61–4.
Contents lists available at SciVerse ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Review
Hantavirus infection in North America: a clinical review☆,☆☆,★ James Hartline MD ⁎, Chris Mierek MD, Tristan Knutson MD, Christopher Kang MD Madigan Army Medical Center, Department of Emergency Medicine, Fort Lewis (Tacoma), WA
a r t i c l e
i n f o
Article history: Received 7 December 2012 Accepted 1 February 2013
a b s t r a c t The recent outbreak of hantavirus in Yosemite National Park has attracted national attention, with 10 confirmed cases of hantavirus cardiopulmonary syndrome and thousands of more people exposed. This article will review the epidemiology, presentation, workup, and treatment for this rare but potentially lethal illness. The possibility of infection with hantavirus deserves consideration in patients with severe respiratory symptoms with rodent exposure or rural/wilderness travel. Accurate diagnosis requires a high index of suspicion. Hantavirus cardiopulmonary syndrome presents as a vague prodrome of fever, cough, myalgias, chills, and nausea followed by a rapidly worsening respiratory phase. Presumptive diagnosis can be made based on pulmonary interstitial edema on chest radiographs in association with leukocytosis, thrombocytopenia, and hemoconcentration. Suspected cases should be confirmed with a reference laboratory and reported to the appropriate public health authorities. Although treatment is primarily supportive, aggressive fluid administration should be avoided due to the risk of pulmonary edema. The cardiopulmonary phase of the disease can progress rapidly with catastrophic decompensation in as little as a few hours. Patients require rapid intensive care unit admission for monitoring, mechanical ventilation, vasoactive agents, and possibly extracorporeal mechanical ventilation. Emergency physicians should be aware of outbreaks and vigilant for hantavirus exposures, especially during the summer and early fall months. Published by Elsevier Inc.
1. Introduction Hantavirus, the cause of an uncommon but lethal disease known as hantavirus cardiopulmonary syndrome (HCPS), has drawn renewed attention after a recent outbreak in Yosemite National Park, CA. As of November 1 2012 (most recent data available), there have been 10 confirmed cases of HCPS, 3 of which were fatal [1]. Of the 10 cases, 9 occurred in people known to have stayed in tent cabins in a single campsite known as Curry Village [1]. It is estimated that more than 3100 visitors to the same campground were directly exposed to the virus. State of California officials subsequently warned an additional 230 000 people who may also have been exposed this summer [2,3]. In late October, a nonfatal case of hantavirus occurring after a rodent bite in the Adirondacks was confirmed [4]. Because of the recent reemergence of HCPS and the ubiquitous nature of the hantavirus, emergency physicians should be familiar with the incidence, clinical manifestations, and treatment of this disease.
☆ The views expressed are those of the author(s) and do not reflect the official policy of the Department of the Army, the Department of Defense, or the US Government. ☆☆ Source of support: No financial support was obtained for this manuscript. ★ Prior presentation: This article has not been previously presented or published. ⁎ Corresponding author. Madigan Healthcare System, ATTN: MCHJ-EM, Tacoma, WA 98431, USA. E-mail address: [email protected] (J. Hartline). 0735-6757/$ – see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ajem.2013.02.001
The hantaviruses are a genus of more than 21 enveloped singlestranded negative-sense RNA viruses belonging to the Bunyaviridae family [5]. The hantavirus causes 2 distinct febrile illnesses in humans involving an element of vascular leak resulting in end-organ damage ranging from proteinuria to severe pulmonary edema [6–8]. Hantavirus cardiopulmonary syndrome (also known as hantavirus pulmonary syndrome) is seen in North and South America and caused by the “New World” viruses. Hantavirus cardiopulmonary syndrome is characterized by a nonspecific viral prodrome followed by rapidly worsening respiratory distress, noncardiogenic pulmonary edema, and hemodynamic compromise [6,9]. Hemorrhagic fever with renal syndrome (HFRS) is seen in Asia and Europe and is caused by the “Old World” viruses. Hemorrhagic fever with renal syndrome was first recognized as the cause of illness in roughly 3200 US and UN military personnel during the Korean War in the early 1950s [8,10]. Originally known as “Korean Hemorrhagic Fever,” HFRS involves the acute onset of fever, headache, hypotension, and renal failure [11]. The high incidence of HFRS during the Korean War is thought to have been caused by soldiers living the fields having significant contact with carrier rodents [12]. An estimated 150 000 to 200 000 cases of HFRS occur annually worldwide, primarily in China, Russia, and Korea [13]. In China, more than 1.5 million cases of HFRS were reported between 1950 and 2007, resulting in more than 46 000 deaths [14]. Mortality rates are estimated to be as high as 60% in HCPS and 12% in HFRS [8].
J. Hartline et al. / American Journal of Emergency Medicine 31 (2013) 978–982
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Fig. 1. Centers for Disease Control and Prevention map of HCPS cases by state of exposure, updated 14 December 2012 [19].
Hantaviruses are considered a potential bioterrorism agent, currently listed as a category C pathogen by the Centers for Disease Control and Prevention (CDC), which include those emerging pathogens considered to be at risk for bioterrorism engineering because of “availability, ease of production and dissemination, and potential for high morbidity and mortality rates and major health impact” [15]. Hantaviruses have previously been considered category A gents, indicating the uncertain estimation of the treat they pose as potential biowarfare agents [8,16]. The hantaviruses are listed as category-A pathogens by the National Institute of Allergy and Infectious Disease priority list of pathogens, which includes those organisms and agents that pose the highest risk to national security because of their ease of dissemination or transmission, high mortality rates, potential for major public health impact, risk of public panic and social disruption, and require special action for public health preparedness [17]. 2. Epidemiology To date, more than 2000 cases of HCPS have been identified in small clusters and individual cases throughout North and South America, with a total of 616 cases occurring in the United States (between 11 and 48 cases annually; see Fig. 1) [8,18,19]. More than half of the North American hantavirus cases occur in the Four Corners area of the Southwest, but infections have been reported in 34 US states. Although generally occurring in rural areas, up to 25% of cases occur in urban and suburban areas [18]. Although reporting of the disease appears relatively sparse, the actual incidence may be somewhat higher due to asymptomatic infections. In a study performed in Baltimore (an area with very few reported cases of HCPS), 44% of mice and 0.74% (9 patients) were serologically positive for hantavirus despite being otherwise healthy and asymptomatic [20]. Although there appears to be a significant spectrum of disease, the case fatality rate for symptomatic HCPS patients in the United States is 38% [20]. Most cases occur during the late spring and early summer months, which may allow clinicians to distinguish the disease from influenza, which has a similar presentation [21]. Cases almost exclusively occur in people who sleep or work in areas where they may be exposed to
rodents. Transmission of the virus occurs predominately through inhalation of aerosolized rodent urine, feces, or saliva; exposure may also occur through food contaminated by rodent saliva and excreta and through rodent bites [8,13]. Although human-to-human transmission has not been observed in North America, there have been a few documented cases of such transmission in South America [8]. The largest risk factor is entering closed buildings with rodent infestations [22]. There is no known arthropod vector [13]. Given the close association with these risk factors, prevention of exposure to rodents or rodent droppings is essential. Those living in areas with known populations of carrier rodents should minimize contact by eliminating hospitable rodent environments, sealing gaps in homes and outbuildings, placing traps to discourage rodent infestation, removing potential nesting sites, and promptly disposing of leftover food and garbage [23]. Furthermore, in light of anticipated trends toward warmer weather, additional and possibly larger exposures to hantavirus are likely. As a result, especially with the ease and frequency of rapid long-distance travel, emergency physicians should be cognizant of local and distant outbreaks and regularly take a travel history, exposure history, and inquire about sick contacts when appropriate. 3. Pathophysiology Hantavirus infection is typically transmitted to humans via the inhalation of aerosolized rodent urine, feces, or saliva. Infection from animal bites has also been reported. No person-to-person transmission of hantavirus has been reported in North America. The average time between exposure and symptomatic illness is 1 to 5 weeks with a median incubation time of 18 days [24,25]. The primary site of hantavirus infection is the lung, where the virus elicits an inflammatory response enabling widespread dissemination to the vascular endothelial cells, culminating in subsequent severe vascular permeability, capillary leak, noncardiogenic pulmonary edema, hypoxia, lactic acidosis, elevated systemic vascular resistance, and myocardial depression [26,27]. As cardiac output decreases, systemic vascular resistance increases, and lactic acidosis develops [25,27]. Although the proximate cause of death is usually cardiogenic shock rather than respiratory failure, there is debate in the literature as to whether the
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cardiogenic shock is caused by a functional cardiac depression or by a typical myocarditis [24,28,29]. 4. Clinical presentation Hantavirus cardiopulmonary syndrome is characterized by a lengthy incubation period followed by a rapid onset of severe pulmonary disease. Patients with HCPS initially present with a vague viral prodrome, almost indistinguishable from influenza, lasting 3 to 5 days, with nonspecific complaints including, fatigue, fever, chills, malaise, nausea, myalgias, headache, and dizziness [25,27,30]. Headache and abdominal pain may be quite prominent and can complicate the workup by masquerading as other illnesses. Symptoms progress over the next 7 to 10 days and include nonproductive cough, tachypnea, and dyspnea. Patients will be febrile, tachycardic, tachypneic (generally 26 to 30 breaths per minute), and hypoxic. These changes herald the development of worsening cardiopulmonary disease, which can worsen catastrophically, requiring hospitalization and mechanical ventilation in as little as 24 hours [30]. However, if patients survive the acute period of the disease, they progress to the diuretic phase followed by rapid improvement, often permitting extubation in 1 to 2 days. The subsequent convalescent phase is characterized by prolonged weakness and fatigue with an abnormal diffusion capacity of the lungs that may require months to years to fully normalize [12,24]. 5. Workup Timely identification of recent travel or exposure to rodents and their habitats is imperative. Initial chest radiographs will reveal evidence of pulmonary edema in roughly one-third of patients with HCPS. Within 48 hours, nearly all patients will have interstitial edema, many will have pleural effusions, and two-thirds of them will display extensive bibasilar or perihilar airspace disease [30]. The presence of interstitial edema is seen much more frequently in HCPS than acute respiratory distress syndrome (ARDS) (88% vs 5%, respectively) and may assist with differentiating the two syndromes [31]. Thrombocytopenia is one of the earliest and most sensitive laboratory findings, occurring as early as the prodromal phase and seen in more than 80% of patients [30,32]. The CDC recommends drawing a complete blood count and serum chemistry panels every 8 to 12 hours in patients with suspected HCPS [33]. Laboratory findings commonly seen in HCPS include: [35] • Leukocytosis with neutrophilia, a left shift (possibly as high as 50%), and atypical lymphocytes; • Platelet count less than 150 000; • Elevated serum creatinine levels (reported in approximately 15% of all patients); • Proteinuria; • Mild elevations of transaminases, CPK, and amylase have been reported; and • CDC: “The combination of atypical lymphocytes, a significant bandemia, and thrombocytopenia in the setting of pulmonary edema is strongly suggestive of a hantavirus infection.” HCPS poor prognostic indicators: • Falling serum albumin, hemoconcentration, and a significant decline in the platelet count suggest a fluid shift from the systemic circulation to the lungs. • Metabolic acidosis in combination with rising serum lactate (N 4.0 mmol/L) and prolonged PT and PTT. • Cardiac index of less than 2.2 L/min per square meter. • Disseminated intravascular coagulation may rarely occur in severe cases of HCPS; however, this is much less common than in hemorrhagic fever with renal syndrome.
Because HCPS and ARDS share many overlapping characteristics, formal hantavirus testing at a reference laboratory is only recommended for previously healthy patients without predisposing medical conditions such as chronic obstructive pulmonary disease, malignancy, trauma, burns, and surgery [34]. Laboratory criteria for diagnosis of HCPS include detection of hantavirus-specific immunoglobulin M, rising titers of hantavirus-specific immunoglobulin G, detection of Hantavirus RNA by PCR, or detection of hantavirus antigen by immunohistochemistry [33]. In response to last summer's outbreak, the California Department of Public Health recommended formal testing only in patients who presented within 6 weeks of their visit to Yosemite [35]. Suspected cases of HCPS should be promptly reported to local, state, and national public health agencies. The CDC Clinical Case definition for HCPS requires meeting one or more of the following criteria: [34] • A febrile illness (ie, temperature N 101.0° F (N38.3° C) characterized by bilateral diffuse interstitial edema that may radiographically resemble ARDS, with respiratory compromise requiring supplemental oxygen, developing within 72 hours of hospitalization, and occurring in a previously healthy person. • An unexplained respiratory illness resulting in death, with an autopsy examination demonstrating noncardiogenic pulmonary edema without an identifiable cause. Because confirmatory testing is often not immediately available, a peripheral blood smear may facilitate a more timely diagnosis. If pulmonary edema is evident radiographically in a previously healthy patient with a suspected exposure or travel history, the presence of 4 of 5 of the following criteria was shown to be 96% sensitive and 99% specific for Hantavirus: myelocytosis, greater than 10% immunoblasts, hemoconcentration, thrombocytopenia, and the absence of toxic granulations in neutrophils [32]. 6. Treatment To date, no specific therapy for hantavirus has been shown to be effective for HCPS. Thus, the treatment for HCPS is predominately supportive in nature [12,24,36]. Patients should receive intravenous fluids, supplemental oxygen and ventilator support, antipyretics, and analgesia as needed. Because HCPS can overlap significantly with other infectious etiologies, appropriate broad-spectrum antibiotics should be considered in situations where HCPS is suspected but not yet confirmed. Judicious intravenous fluids should be administered given the widespread capillary leak and risk of worsening pulmonary edema. Because shock in HCPS is cardiogenic rather than distributive in nature, the lack of improvement in response to a fluid challenge is characteristic of HCPS [24,25]. The administration of excessive intravenous fluids may actually precipitate the development of hypoxemia by causing a refractory pulmonary edema [24]. Because fluid overload risks accelerating the progression to fulminant respiratory failure, aggressive fluid administration is strongly discouraged [12,24,23]. Electrolytes should be closely monitored. Once the cardiopulmonary phase evolves, patients with HCPS can decline precipitously and should be rapidly admitted to the intensive care unit for close monitoring and support of volume status and cardiopulmonary function, including intubation and the use of inotropes and vasopressors as needed. Extracorporeal membrane oxygenation (ECMO) has been successfully used in patients with refractory HCPS [37]. A study evaluating ECMO in 51 patients with a predicted mortality of 100% demonstrated a dramatic reduction in mortality, with an overall survival rate of 66.6% [37]. If available, the appropriate service should be consulted and ECMO initiated as soon as advanced shock or respiratory failure is recognized. The University of New Mexico has developed an institutional protocol for the prophylactic placement of femoral
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vascular access catheters in anticipation of possible rapid decompensation to allow for emergent initiation of ECMO [38]. The phase of severe cardiopulmonary dysfunction appears to be self-limited and last 2 to 4 days, making ECMO an ideal therapy for hantavirus patients unresponsive to other preliminary therapies. Extracorporeal membrane oxygenation is indicated for patients with advanced HCPS who would not be expected to survive without it. Inclusion criteria used include known HCPS with a cardiac index of less than 2.3 L/min per square meter, an arterial oxygen tensionfractional inspired oxygen (PaO2/FIO2) ratio of less than 50 [23]. Exclusion criteria include age over 70 years, severe preexisting disease, and neurologic impairment [23]. Extracorporeal membrane oxygenation may also be considered in patients with severe cardiopulmonary failure who continue to worsen despite aggressive critical care support, even if the above criteria absent [37]. Some authors have reported that intubation and the accompanying loss of adrenergic drive carry a risk of abrupt hemodynamic collapse and cardiac arrest and recommend that intubation should be avoided as long as possible for patients who are ECMO candidates [23]. Noninvasive ventilation such as bilevel positive airway pressure is contraindicated because of the profound pulmonary edema [23]. If intubation is required, both inotropic and vasoactive agents, such as a combination of dobutamine (5-15 μg/kg per minute) and norepinephrine (1-4 μg/min), have been used successfully and should be available at the bedside [23]. As a treatment for HFRS, when given early in the course of the disease, intravenous ribavirin has demonstrated efficacy at reducing mortality, decreasing the occurrence of progression to the oliguric phase, a decreased severity of renal insufficiency, and a decreased requirement for dialysis [39,40]. The Viral Special Pathogens Branch of the CDC has been testing several drugs in animal models and recently reported preliminary success with vandetanib, an antithyroid cancer drug that blocks the vascular endothelial growth factor (VEGF) receptor and appears to reduce vascular leakage and modestly improved survival in hamsters [41]. Infectious disease researchers at the University for Development in Santiago, Chile, have reported improved survival in patients using plasma from HCPS survivors believed to contain significant amounts of antihantavirus antibodies, finding a 23% absolute decrease in mortality (unpublished results communicated in Nature Medicine) [41]. Vaccines for HFRS have been developed and are routinely given in China and South Korea, contributing to the reduction from 150 000 to less than 20 000 annual cases in China with a similar decrease in South Korea [14,42]. These vaccines use killed virus and are derived from either rodent brains or cell cultures. There is currently no Food and Drug Administration–approved vaccine for the New World Hantaviruses; however, investigation into the use of viral antigens is currently underway [43,44]. Inactivated virus vaccines like those used in Asia are generally not being pursued for HCPS because of inadequate efficacy and concerns about the risks of mass production of a high-containment virus [12]. Given the possible use of hantavirus as a bioterrorism agent and its endemic status across the globe, it is clear that the development of effective hantavirus countermeasures is necessary. 7. Conclusion Hantavirus and HCPS should be suspected in patients with a prodrome of fever, cough, myalgias, chills, nausea, and vomiting from rural areas or with possible rodent exposure within the last 6 weeks. Timely diagnosis requires a high index of suspicion. The cardiopulmonary phase of the disease can cause a precipitous decline in as little as 24 hours. Treatment is primarily supportive and will likely require intensive care unit monitoring, mechanical ventilation, and vasoactive agents. Aggressive fluid administration should be avoided due to the risk of increasing pulmonary edema and accelerating the
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progression to respiratory failure. Extracorporeal membrane oxygenation may increase survival in severe cases. Because no specific therapy, including antivirals, has been shown to be effective for HCPS, emergency physicians should be vigilant for hantavirus exposures during the summer and early fall months to facilitate time-sensitive diagnosis and supportive care and alert the appropriate public health authorities. References [1] Hantavirus: “Outbreak of Hantavirus Infection in Yosemite National Park”. Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/hantavirus/ outbreaks/yosemite-national-park-2012.html. Updated 1 November 2012. Accessed 31 January 2013. [2] Jaret P. “Long Wait and Worry for a Visitor to Yosemite.” The New York Times. http://www.nytimes.com/2012/09/18/health/waiting-and-worrying-afteryosemite-hantavirus-outbreak.html. Updated 17 September 2012. Accessed 17 September 2012. 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Clinical manifestations of New World hantaviruses. Curr Top Microbiol Immunol 2001;256:117–34. [10] Lee HW, Lee P-W, Johnson KM. Isolation of the etiologic agent of Korean hemorrhagic fever. J Infect Dis 1978;137:298–308. [11] Peters CJ, Simpson GL, Levy H. Spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Annu Rev Med 1999;50:531–45. [12] Jonsson CB, Hooper J, Mertz G. Treatment of Hantavirus pulmonary syndrome. Antiviral Res 2008;78:162–9http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2810485/. [13] Schmaljohn C, Hjelle B. Hantaviruses: a global disease problem. Emerg Infect Dis 1997;3(2):95–104. [14] Zhang YZ, Zou Y, Fu ZF, Plyusnin A. Hantavirus infections in humans and animals, China. Emerg Infect Dis 2010;16(8):1195–203. [15] CDC Emergency Preparedness and Response: Bioterrorism Agents/Diseases. http:// emergency.cdc.gov/agent/agentlist-category.asp. Accessed 25 January 2013. 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[36] “Hantavirus Technical/Clinical Information: Treatment.” Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/hantavirus/technical/hps/ treatment.html. Updated 29 August 2012. Accessed31 January 2013. [37] Wernly JA, Dietl CA, Tabe CE, et al. Extracorporeal membrane oxygenation support improves survival of patients with Hantavirus cardiopulmonary syndrome refractory to medical treatment. Eur J Cardiothorac Surg 2011;40:1334–40. [38] Frizzell JD, Boivin MA. Correspondence: breathtaking journey. N Engl J Med 2012;367:1473–4. [39] Huggins JW, Hsiang CM, et al. Prospective, double-blind, concurrent, placebocontrolled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis 1991;164:1119–27. [40] Rusnak JM, Byrne WR, et al. Experience with intravenous ribavirin in the treatment of hemorrhagic fever with renal syndrome in Korea. Antiviral Res 2009;81(1):68–76. [41] Dolgin E. Hantavirus treatments advance amidst outbreak in US park. Nat Med 2012;18(10):1448. [42] Cho HW, Howard CR, Lee HW. Review of an inactivated vaccine against hantaviruses. Intervirology 2002;45(4–6):328–33. [43] Schmaljohn CS. Vaccines for hantaviruses: progress and issues. Expert Rev Vaccines 2012;11(5):511–3. [44] Schmaljohn C. Vaccines for hantaviruses. Vaccine 2009 Nov 5;27(Suppl 4):D61–4.