Radiographic Findings in 20 Patients with Hantavirus Pulmonary Syndrome Correlated with Clinical Outcome

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1 M. oroja 1 J. R. arrie G. S. Raymond Received pril 27, 2001; accepted after revision ugust 2, Department of Radiology and Diagnostic Imaging, Thoracic Division, University of lberta Hospital, WMC 22.41, th St., Edmonton, lberta T6G 27, Canada. ddress correspondence to G. S. Raymond. JR 2002;178: X/02/ merican Roentgen Ray Society Radiographic Findings in 20 Patients with Hantavirus Pulmonary Syndrome Correlated with Clinical Outcome OJECTIVE. Hantavirus is a rare rodent-borne pathogen responsible for the Hantavirus pulmonary syndrome. The objective of this study was to review the clinical and radiographic findings of patients presenting with Hantavirus pulmonary syndrome in northern lberta, Canada. MTERILS ND METHODS. We retrospectively reviewed the cases of 20 patients who presented with Hantavirus pulmonary syndrome from 1989 to RESULTS. Two patterns of presentation were identified. One group (13/20 patients) presented with fulminant clinical and radiographic findings and required intensive care support. Six (46%) of the 13 died within a few days of presentation. Some presented in respiratory failure with bilateral parenchymal infiltrates or a rapid progression from mild bilateral interstitial changes to bilateral interstitial and alveolar infiltrates with pleural effusions. The radiographic findings paralleled these clinical symptoms. The second group (7/20) consisted of patients whose clinical course was more limited, as were their corresponding radiographic findings. These patients had a limited hospital stay, and only minimal changes were identified on radiographs. None of the second group of patients died. CONCLUSION. Clearly, in our study, the patients with Hantavirus pulmonary syndrome presented as two groups: those with the fulminant form of the illness and those with the limited type. Of the patients we studied, the group with the fulminant form presented with severe clinical symptoms and radiographic signs of pulmonary disease and had a 46% mortality rate. The group with the limited form presented with mild clinical symptoms and minimal radiographic changes and had no mortalities. H antavirus pulmonary syndrome was first recognized in 1993 when an epidemic illness occurred in the Four Corners region of the southwestern United States, which encompasses the states of Utah, rizona, Colorado, and New Mexico [1, 2]. Patients presented with a rapid onset of respiratory distress of unknown origin. The high mortality rate prompted a search for the responsible pathogen, which was eventually identified as Hantavirus [1 4]. s of December 1999, 32 cases of Hantavirus pulmonary syndrome had been reported in Canada, predominantly in western Canada, with ritish Columbia and lberta reporting the largest numbers of cases [5, 6]. t the University of lberta Hospital, 20 patients with Hantavirus pulmonary syndrome presented from 1989 to Verity et al. [7] described the clinical and laboratory findings of 19 of the 20 patients. We performed a retrospective case review, including review of the pertinent radiographic studies, and identified two broad categories of Hantavirus pulmonary syndrome clinically and radiologically: a rapidly progressive, fulminant, and often fatal clinical form with radiographic features of rapidly progressive alveolar pulmonary edema, air-space consolidation, and pleural effusions; and a limited, less severe clinical form usually associated with radiographic features of mild interstitial edema and minimal air-space disease. ll patients with the limited form of Hantavirus pulmonary syndrome survived the illness, whereas 46% of those with the fulminant form died. Materials and Methods Twenty recorded cases of Hantavirus pulmonary syndrome presented in northern lberta between 1989 and The medical records and radiographic data from each patient were reviewed, with the exception of four patients whose radiographs had been destroyed. However, the radiologic reports from these four patients were reviewed. In one patient, a CT scan of the chest had JR:178, January

2 oroja et al. been obtained using a protocol of 7-mm collimation at 10-mm intervals. The diagnosis of Hantavirus pulmonary syndrome was established in each patient by serologic testing performed at the University of Ottawa or the University of New Mexico. The presence of IgM or IgG antibodies specific to the Sin Nombre virus confirmed Hantavirus pulmonary syndrome in our series of patients, who ranged in age from 15 to 65 years (mean age, 41.4 years). Twelve (60%) of the patients were men. Two were children. The chest radiographs were reviewed by two thoracic radiologists in our institution for the presence of interstitial changes, alveolar opacities, consolidation, and pleural effusions. The progression and distribution of the findings were recorded. rapid progression of findings was defined as diffuse interstitial and parenchymal opacities (involving more than one third of the lung fields) seen within 48 hr of admission, with clinical deterioration resulting in transfer to the intensive care unit or in death. limited presentation of Hantavirus pulmonary syndrome was defined as mild interstitial and parenchymal opacities (involving less than one third of the lung fields). Pleural effusions were categorized as small, moderate, or large. Results Sixty-five percent of the patients presented with a rapid progression to respiratory failure that required the support of the intensive care unit. The initial radiographic findings in each patient were similar and consisted of interstitial edema with rapid progression to bilateral airspace consolidation (Figs. 1 and 2). The mortality rate of the patients presenting with rapid progression was high, with six (46%) of the 13 patients dying. mong the six patients who died, the mean time to death after hospitalization was 1.8 days; the remainder of the seven patients had a mean hospital stay of 10.8 days. oth of the pediatric patients presented with rapid progression. One patient died within a day of presentation, and the second was discharged from hospital after 6 days. One patient was treated with extracorporeal membrane oxygenation but subsequently died. utopsies were performed on two patients and revealed diffuse alveolar damage in one patient and congested, stiff, heavy lungs in the second patient. The autopsy results in these two patients are similar to those described in other cases of Hantavirus pulmonary syndrome [3, 8, 9]. Thirty-five percent (7/20) of patients presented with limited radiographic findings. ll patients in this category presented with interstitial edema and minimal air-space opacities that resolved in a mean time of 7.7 days (Figs. 3 and 4). These patients did not require intensive care support, and no deaths occurred in this group. Seventy-five percent (15/20) of the patients had small bilateral pleural effusions. One patient had a small right-sided pleural effusion, and three patients had no pleural effusion. The radiographic reports for one of the four patients whose radiographs had been destroyed makes no mention of pleural effusions, although pleural effusions are noted in the reports for the other three patients. CT scan obtained in one patient reveals small bilateral pleural effusions, mild left-sided paratracheal lymphadenopathy, and mild cardiomegaly. In our series, 95% (19/20) of patients with Hantavirus pulmonary syndrome lived or worked in rural communities or had contact with deer mice or deer mice droppings, a known risk factor. The largest number of patients (n = 7) presented in Three patients each presented in the years 1994 and The most common months of presentation were June (six patients) and October (five patients). Discussion Hantavirus, a single-stranded RN virus, is a rodent-borne pathogen of the family unyaviridae that causes Hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome [1 4]. Hantavirus is not a new pathogen; it has been known to the medical community since the 1950s [2]. However, the epidemic in 1993 has led to further investigation of this virus. The species of Hantavirus identified in the 1993 epidemic was the Sin Nombre virus [1]. Research since then has identified three additional Fig year-old man who presented with shortness of breath and flulike symptoms. Within 24 hr, patient died, and serologic tests subsequently confirmed that he had Hantavirus pulmonary syndrome., Initial posteroanterior radiograph shows basilar and perihilar interstitial pattern., Follow-up chest radiograph obtained (with portable equipment) 24 hr after patient s marked clinical deterioration shows progression to extensive perihilar and upper lung zone consolidation with associated air bronchograms. 160 JR:178, January 2002

3 Radiography of Hantavirus Pulmonary Syndrome types of Hantavirus: the lack Creek Canal, ayou, and New York viruses, all of which cause an illness similar to Hantavirus pulmonary syndrome [2, 3, 5, 10]. nother virus, the El Moro Canyon virus, is prevalent among harvest mice (Reithrodontomys megalotis) and genetically is very similar to the other strains. Thus, this virus should also be considered a potential pathogen [2]. Fig year-old woman who presented to emergency department in respiratory distress after camping trip. Patient died 24 hr later. Serologic tests subsequently confirmed Hantavirus pulmonary syndrome. Initial radiograph (obtained with portable equipment) shows normally sized heart and diffuse alveolar air-space pattern that is more predominant centrally and in mid and lower lung zones. The primary reservoir of the Hantavirus, specifically the Sin Nombre virus, is the deer mouse (Peromyscus maniculatus) [1 3]. Hantavirus is transmitted via inhalation of aerosolized virus particles from rodent urine, saliva, or dried excreta. Cases of direct inoculation through rodent bites have also been documented. However, no human-to-human transmission has been recorded. Recently, a suggestion of human-to-human transmission of ndes virus infection, which causes an illness in rgentina similar to Hantavirus pulmonary syndrome, was made, but no conclusive evidence was provided [11]. lthough there have also been five documented cases of Hantavirus pulmonary syndrome in pregnant women, no vertical transmission has been observed [12]. Certain patient populations may have a greater risk for contracting Hantavirus pulmonary syndrome. In addition to the appropriate clinical findings, a history of residence in a rural area; recent travel to rural areas; an occupational history of performing agricultural work, handling animals, or cleaning areas where animals are kept; or living in a home known to have rodent infestation should cause the clinician to consider Hantavirus pulmonary syndrome in the differential diagnosis [5, 7, 13]. fter the 1993 outbreak, a spring summer seasonality of Hantavirus pulmonary syndrome was established [1, 14]. However, in our series, an additional cluster of cases was found in September and October, a finding that may be partly related to farming activities. It is also believed that the El Niño weather pattern played a role in the 1993 Hantavirus pulmonary syndrome outbreak: the increased precipitation led to an increase Fig year-old male oil-field worker who presented with 5-day history of dyspnea and flulike symptoms. Serologic tests confirmed Hantavirus pulmonary syndrome., Posteroanterior chest radiograph obtained at presentation shows interstitial edema, Kerley lines, pulmonary vascular congestion, and mild consolidation of perihilium and lower lung area., Posteroanterior chest radiograph obtained 1 week later shows resolution of pulmonary edema and of perihilar and lower lung consolidation. JR:178, January

4 oroja et al. in rodent populations and thus may have increased the risk of exposure to Sin Nombre virus [14]. Most of the Hantavirus pulmonary syndrome cases in our series occurred later than the initial outbreak in the Four Corners region, but we may have experienced delayed effects of the El Niños of and Hantavirus pulmonary syndrome characteristically presents as respiratory distress from noncardiogenic edema. fter an incubation period of approximately 9 35 days, the syndrome begins to progress through its three stages [1, 2, 5, 12, 15]. The initial stage is the prodromal phase, which is followed by the cardiopulmonary and convalescent phases [3]. The prodromal phase consists of a multitude of nonspecific symptoms such as myalgia, fever, headache, cough, shortness of breath, nausea, vomiting, and diarrhea [1, 7, 12, 16]. Symptoms of an upper respiratory tract infection, such as rhinorrhea, sore throat, or nasal congestion, are uncommon in Hantavirus pulmonary syndrome [3]. The prodromal stage usually lasts 3 6 days, and the physical findings may be unremarkable during this period [3, 4]. Most cases of Hantavirus pulmonary syndrome progress rapidly to the second stage, the cardiopulmonary phase. The features of this stage include a rapid clinical decompensation with hypotension and respiratory insufficiency Fig year-old woman who lives on farm presented with 6-day history of fevers, chills, cough, and night sweats. Patient was discharged 8 days later with serologically confirmed Hantavirus pulmonary syndrome., Posteroanterior radiograph obtained at presentation reveals subtle interstitial edema and normally sized heart., Posteroanterior radiograph obtained 8 days later shows complete resolution of interstitial edema. followed by respiratory failure and shock; death occurs in approximately 50% of patients [1 3, 13, 16]. Many of these patients require support in the intensive care unit; intravascular monitoring shows a low capillary wedge pressure, an elevated systemic vascular resistance, and a decreased cardiac index [2, 13, 16]. These findings are supportive of noncardiogenic edema and contrast to findings that would be found in sepsis typically an elevated cardiac output and low systemic vascular resistance [2, 13, 16]. If the patient survives the cardiopulmonary stage, he or she enters the convalescent phase, which is characterized by rapidly improving oxygenation, hemodynamic stabilization, and diuresis [16]. Extracorporeal membrane oxygenation has been shown to benefit a limited number of patients [17]. Thus, early recognition of Hantavirus pulmonary syndrome is important so that the appropriate supportive measures can be undertaken, providing a better chance of survival. Patients with Hantavirus pulmonary syndrome are extubated quicker than those with adult respiratory distress syndrome, and no long-term sequelae have been identified in a small number of survivors of Hantavirus pulmonary syndrome who have received follow-up for a year [2, 13]. In patients with Hantavirus pulmonary syndrome, the clinical history, symptoms, and physical examination, along with the laboratory findings, may suggest the diagnosis. However, to confirm the diagnosis, a viral-specific diagnostic test is required. nalysis of the antibody response during the early and convalescent phases of Hantavirus pulmonary syndrome reveals IgM and Ig antibodies specific to the Sin Nombre virus in the early phase [18]. Thus, an IgM capture enzyme-linked immunosorbent assay is most often used; results of the assay may be positive in the prodromal phase or at admission of the patient to the hospital [2, 13]. Other tests that can be and have been used are the IgM Western blot assay and reverse transcriptase polymerase chain reaction [2, 13]. Tissue specimens can be used to look for Hantavirus antigens via immunohistochemistry [2, 13]. Radiographically, Hantavirus pulmonary syndrome presents with interstitial edema with or without rapid progression to airspace disease [1, 3, 19, 20]. We consistently found this pattern in our study. If the airspace disease does emerge, it is usually central or basilar [19, 20]. This finding contrasts with the pattern of adult respiratory distress syndrome, which tends to present with peripheral air-space disease without a preceding interstitial disease [19, 20]. lso, pleural effusions are a common finding in Hantavirus pulmonary syndrome. The characteristics of the fluid vary depending on the stage of 162 JR:178, January 2002

5 Radiography of Hantavirus Pulmonary Syndrome the disease [15]. The pleural fluid is transudative during the period of maximal cardiopulmonary dysfunction, but during recovery, the pleural fluid may take on the characteristics of exudates [15]. lthough there is multiorgan involvement in Hantavirus pulmonary syndrome, the lungs are the target organs. The radiographic findings in Hantavirus pulmonary syndrome are consistent with a pulmonary capillary leak [19, 20]. The exact mechanism resulting in the dysfunctional vascular endothelium is not entirely known. Electron microscopic examination reveals enlarged but intact capillary endothelial cells, a further suggestion of a capillary leak syndrome [7, 8]. The activation of T lymphocytes and monocytes within the lung and local production of inflammatory cytokines play a role in the development of pulmonary edema in patients with Hantavirus pulmonary syndrome [4]. Increased cytokines produced in the lungs of Hantavirus pulmonary syndrome patients have been found, and cytokines are thought to play a role in capillary leakage [4]. Histologically, an interstitial pneumonitis is present with varying amounts of mononuclear cell infiltration, congestion, and both interstitial and intraalveolar edema [7, 8]. Hyaline membranes are present but are focal and composed mainly of fibrin with little cellular debris [7, 8]. Type I pneumocyte processes are intact, but scant type II pneumocyte activation and no neutrophilic infiltrate are seen [7, 8]. Diffuse alveolar damage may appear to be similar to Hantavirus pulmonary syndrome. However, certain distinguishing features in alveolar damage exist extensive cellular debris, destruction of type I cells, the prominence of type II cells, a neutrophilic infiltrate, and fibrosing alveolitis [7, 8]. However, it is possible that these two entities represent different points on a spectrum of a disease process. In conclusion, we have reviewed the radiographic findings in 20 patients with Hantavirus pulmonary syndrome and have correlated them with the clinical outcome in the each case. Our experience is similar to that of Ketai et al. [21]. However, we have further characterized the presentations of Hantavirus pulmonary syndrome into two distinct clinical and radiographic patient groups: fulminant and limited. To our knowledge, we are the first to classify Hantavirus pulmonary syndrome into two distinct radiographic categories. Patients with fulminant Hantavirus pulmonary syndrome present with severe respiratory distress that often progresses to respiratory failure and death; this form of the syndrome is associated with radiographic findings of diffuse alveolar edema mimicking adult respiratory distress syndrome. Patients with limited Hantavirus pulmonary syndrome present with mild systemic clinical symptoms and radiographic findings of both noncardiogenic interstitial pulmonary edema and minimal air-space infiltrates. It is apparent from our review of 20 patients that if the disease did not progress rapidly in the initial stages, it was unlikely to do so later in the course of the illness. In patients in whom the disease course was rapid from the outset, the mortality rate was high. Most patients presented with fulminant Hantavirus pulmonary syndrome, but milder forms were identified in our patient population. lthough serologic testing is required to make a definitive diagnosis, radiologists, particularly those in areas in which the disease is endemic, should be familiar with the radiographic findings associated with this fascinating illness. Early detection and treatment may lead to more favorable outcomes. cknowledgments We thank ob Verity of the Medical Microbiology Department at the University of lberta Hospital for providing the cohort of patients and Jan Dawson for assisting in the preparation of our manuscript. References 1. Khan S, Khabhaz RF, rmstrong LR, et al. Hantavirus pulmonary syndrome: the first 100 U.S. cases. J Infect Dis 1997;12: Mertz GJ, Hjelle L, ryan RT. Hantavirus infection. dv Intern Med 1997;42: Moolenaar RL, reiman RF, Peters CJ. Hantavirus pulmonary syndrome. Semin Respir Infect 1997;12: Mori M, Rothman l, Kurane I, et al. High levels of cytokine producing cells in the lung tissue of patients with fatal hantavirus pulmonary syndrome. J Infect Dis 1999;179: Drebot M, rtsob H, Werker D. Hantavirus pulmonary syndrome in Canada, Can Commun Dis Rep 2000;26: Werker DH, rtsob H. Of mice and mostly men: hantavirus pulmonary syndrome. Can Med ssoc J 1998;158: Verity R, Prasad E, Grimsrud K, et al. 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