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ABSTRACT |
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ABSTRACT
INTRODUCTION
CASE REPORT
DISCUSSION
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
CASE REPORT
DISCUSSION
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The Centers for Disease Control (CDC) clinical case definition requires a febrile illness in a previously healthy person with the development of bilateral interstitial pulmonary edema or infiltrates with hypoxemia requiring supplemental oxygen within 72 hours of hospitalization.4 The case definition also includes an unexplained respiratory illness resulting in death, with an autopsy examination showing noncardiogenic pulmonary edema without an identifiable cause. Clinically compatible cases are laboratory confirmed by detection of hantavirus IgM or rising titers of hantavirus IgG, detection of hantavirus RNA by polymerase chain reaction (PCR), or detection of hantavirus antigen by immunohistochemistry.4,5
SNV infection has rarely been found in family clusters, and young children seem to be less commonly affected. Few pediatric cases were observed in the original outbreaks, leading some to hypothesize that children may be better protected from pulmonary involvement.6 In North America, hantavirus infections have been rarely recognized in children < 10 years of age.7 Ramos and others8 described the clinical outcomes of North American pediatric cases from 1993 to 2000. Among 13 patients, 10–16 years of age, there was a 31% mortality rate. Although pediatric hantavirus infections are frequently mild, the mortality rate reported by Ramos and others is only marginally below that of the cumulative US mortality rate of 36%.9
Interesting differences between hantaviruses have been noted comparing the South American Andes virus (ANDV) and the North American SNV in the pediatric setting.10 The ANDV cases have involved children as young as 1.4 years of age. In comparison, the youngest case reported up to this time of SNV infection meeting the CDC clinical case definition of HPS involved a 10-year-old child. Furthermore, one half of the ANDV pediatric HPS cases have involved case clusters, whereas this phenomenon is rare in the setting of pediatric SNV infections.
As of November 1, 2006, there had been 64 laboratory-confirmed cases of HPS in Canada. In total, 34 of 64 (53%) of these cases have been reported from the western province of Alberta (unpublished data). The first pediatric case of HPS in Canada involved a 16-year-old boy in Alberta in 1997,11 although a cluster of HPS cases has not been previously reported in Canada. In May 2005, a cluster of four cases of HPS was confirmed in Alberta. Three of these cases involved three generations of a single family: a 7-year-old boy, his 26-year-old mother, and his 51-year-old grandmother. A fourth case involving a related man from the same community was later identified. In this paper, we report the first family cluster of HPS in Canada and one of the youngest identified cases of HPS in North America.
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CASE REPORT
DISCUSSION
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Just before the grandmother’s death, the mother (Case 2) became increasingly unwell during the early morning of May 7 and left the grandmother’s bedside to receive medical attention in the emergency department. Bloodwork revealed a hemoglobin of 151 g/L with a hematocrit of 0.44 and platelets of 71 x 109/L. Although her leukocyte count was only 4.3 x109/L, she was noted to have 49% bands. Within hours, she developed severe respiratory distress requiring intubation and intensive care unit (ICU) admission. She was treated supportively with vasoactive drugs, corticosteroids, and empirical cefotaxime and azithromycin.
That same day, May 7, her 7-year-old son (Case 3) was brought to the emergency department by his father with a 5-day history of fevers, dry cough, increasing dyspnea, nausea, and emesis. On history, the son had spent time at his mother’s home around April 23 and had noted deer mice at that time. Deer mice had also been observed around a storage trailer on his father’s property, and it was felt that the boy may have been exposed to deer mice and excreta in either setting. On examination, he was noted to have a fever of 39.5°C. Although he initially maintained an oxygen saturation of 97% on room air, he was noted to be tachypneic with a respiratory rate > 40 breaths/min, and his chest radiograph showed severe pulmonary edema. Initial laboratory studies included an elevated hematocrit of 0.41 with a platelet count of 125 x 109/L. Although his leukocyte count was within normal limits measuring 5.0 x 109/L, he showed 34% bands. Renal function was normal with a creatinine of 51 µmol/L. He was admitted to the pediatric ICU and treated empirically with cloxacillin, cefotaxime, and azithromycin. Despite intermittent fevers and the need for 2 L/min supplemental oxygen, he remained stable with milder illness. He did not require hemodynamic support and was transferred to a pediatric ward on May 9.
The son’s hospital course was generally uncomplicated. His platelet count nadir was 75 x 109/L on May 8 before improving to 96 x 109/L on May 11. By May 12, after a 6-day admission, the son was discharged home in good health. The mother remained intubated in the ICU for a total of 5 days. However, she was eventually extubated and discharged home on May 14 after an 8-day admission.
Serologic testing and RT-PCR were performed on blood samples (serum and EDTA blood) from each patient collected between Days 3 and 10 after the onset of symptoms. Hantavirus-specific IgM serology was performed using an IgM capture-ELISA test based on antigen prepared from Black Creek Canal virus–infected Vero E6 cells according to a previously published protocol.12 IgG-specific antibodies were determined by a previously described ELISA using an in-house, purified Black Creek Canal IgG lysate. Antibody titration was done in 4-fold dilutions of patient serum starting with 1:100. Test results were interpreted as positive where titers 
400 were obtained. RNA was isolated from whole blood (EDTA blood) using the Viral RNA Mini kit from Qiagen (Mississauga, Ontario, Canada) and was analyzed by RT-PCR using the One-Step RT-PCR kit (Qiagen) and the primers SN5F 5'-gtttattgtttattgttatctgtt and SN5R 5'-tagtagtatgctccttgaaaa. The PCR targets the nucleoprotein gene (S segment) of SNV and amplifies a 427-bp fragment (unpublished data).
All three cases were PCR-positive on the initial EDTA blood sample, indicating a recently acquired hantavirus infection. All amplicons were sequence-confirmed and aligned with published hantavirus sequences deposited into GenBank. The alignment revealed SNV sequences in all three cases with identical sequences for Cases 1 and 2 and a single mutation (G to A) for Case 3. The single serum sample from Case 1 was equivocal for IgM but showed a titer of 6,400 in IgG, supporting the diagnosis of an SNV infection. Cases 2 and 3 were IgM-positive on the initial serum sample and seroconverted in regard to IgG on the follow-up samples, also confirming a SNV infection in these cases. A summary of the results of diagnostic testing is shown in Table 1
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On arrival in Edmonton, examination revealed a temperature of 38.0°C and heart rate of 106 beats/min. Faint crackles were heard diffusely on pulmonary auscultation. Initial bloodwork revealed a leukocyte count of 10.3 x 109/L with 30% bands and 13% myeloids. His hemoglobin measured 149 g/L with a hematocrit of 0.41, platelets of 32 x 109/L, alanine transaminase of 55 U/L, and lactate dehydrogenase of 630 U/L. His arterial pO2 was 62 mm of Hg on room air, although he maintained adequate oxygenation of 97% on 5 L by nasal prongs. He was admitted to the general medical service, managed supportively with oxygen and intravenous fluids, and treated empirically with cefotaxime and azithromycin. He remained stable on the ward and did not require intubation or hemodynamic support. SNV-specific IgM and IgG antibodies and PCR testing were subsequently reported as positive, confirming a recently acquired SNV infection (Table 1
). Sequence analysis and alignments confirmed SNV sequences with two-point mutations compared with Cases 1 and 2. Mycoplasma IgM was also positive. He improved daily and was discharged on May 18 after 7 days of hospitalization with complete resolution of symptoms.
In the setting of this cluster of HPS cases and the excessive number of deer mice noted around the community that spring, a number of control measures were implemented. The homes associated with cases underwent thorough decontamination, and intensive trapping was performed inside and surrounding these homes. Heavy rodent infestation had been noted within the home associated with the first three cases and the house was completely stripped and renovated. The drywall and insulation were removed throughout the house, and all items such as furniture and clothing were removed and discarded. The garage was also cleared, and the area was sprayed with a bleach solution. On a community level, rodent control strategies included provision of cleaning and disinfection supplies and large garbage bins for removal of accumulated refuse and debris from homes in neighboring areas. Recommendations were made for weather stripping and covering exterior vents and ducts with mesh to prevent the entry of mice into homes. Extensive education on clean-up and prevention was provided through information sessions and an informational brochure was developed and widely distributed throughout the community.
Because this was the first time that a cluster of HPS cases had been reported in Canada, personnel from the Public Health Agency of Canada conducted a serologic survey of deer mouse populations within the affected community. In brief, deer mice were collected over six nights from May 16 to 21, 2005 using 225 Sherman live traps. Traps were operated in and around the patient’s residence and at 24 other localities within a 10-km2 area within the affected community. During the 1,350 trap nights, a total of 234 deer mice were captured, with an average of > 17 deer mice per 100 trap nights of sampling effort. Antibodies against SNV were detected in 111 of 228 (48.7%) deer mice tested, and animals with SNV antibodies were detected at 88% of the localities sampled. Deer mouse abundance (8 deer mice per 100 trap nights) and prevalence of SNV antibodies (12 of 36; 33%) were significantly lower in a neighboring community, where parallel but less intense sampling (i.e., 450 trap nights of sampling effort) was conducted.
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INTRODUCTION
CASE REPORT
DISCUSSION
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The first household cluster included the index cases in the initial Four Corners outbreak during the spring of 1993.2 The cluster involved a 21-year-old woman and a 19-year-old man living in the same household in rural New Mexico. Both died of acute respiratory failure within 5 days of each other. Within 2 weeks, the women’s brother also experienced acute respiratory symptoms, as did his wife 5 days later. The peridomestic studies in the Four Corners region in 1993 found that 32 (30%) of 107 deer mice were seropositive for hantavirus.14 After the first case of HPS in Manitoba, Canada, in 2001, deer mouse seroprevalance studies in Manitoba and Saskatchewan—the two neighboring provinces east of Alberta—identified 11.5% (28 of 244) seroprevalence in Manitoba and 15% (32 of 213) seroprevalence in Saskatchewan.15 The prevalence of SNV antibodies in deer mice associated with our study was considerably higher (48.7%) than these earlier studies and likely contributed to the increased risk for exposure to SNV-infected animals.
Epidemiologically, SNV infections are not generally found in family clusters, and young children are less commonly infected and present with milder disease. In this report, we describe a cluster of four cases confirmed in May 2005 in the western Canadian province of Alberta. Three of these cases involved three generations of a single family. A fourth case, a relative from the same community, was later identified. All met the CDC clinical case definition for HPS, and in two cases, intubation and mechanical ventilation were required.
Clustering of SNV cases is uncommon, in contrast with frequent case clusters of ANDV infection.16 Furthermore, unlike SNV, it has been established that ANDV may be spread through person-to-person transmission.16,17 A large cluster of cases in Argentina in 1996 was notable for epidemiologic links between cases in the setting of low rodent population densities.18 Intervals between many of the cases were consistent with the typical incubation period of 2–3 weeks. Subsequent molecular evidence provided further evidence to support the view of person-to-person tranmission.19
Furthermore, Martinez and others16 reported four case clusters from 2002, with epidmiologic data consistent with interhuman transmission on three occasions. The molecular studies served to strengthen the link between geographically disparate cases. Lazaro and others17 studied 51 cases in southern Argentina between November 1993 and June 2005. Nine clusters, involving 20 cases (39.2%), were identified. Person-to-person transmission was considered probable in eight of the nine clusters.
In contrast, the data surrounding this Canadian SNV case cluster points toward environmental exposures rather than person-to-person transmission. This latter mode of transmission has not been documented in outbreaks of SNV infection and is unlikely to have been a contributing factor in this cluster given the documented exposures and timing of clinical progression. The epidemiologic data provides strong evidence of multiple and distinct environmental exposures. In all four cases involved in this cluster, there had been heavy mouse infestation in and around the respective homes with individual exposures to deer mice and their excrement within the identified incubation period. In each case, there were significant exposures, and the varying localities were all shown to have high numbers of infected rodents.
The epidemiologic data are also supported by the molecular analysis identifying three SNV variants among the four cases. Genetic sequencing revealed a single nucleotide mutation in Case 3 and two mutation differences in Case 4 compared with Cases 1 and 2. It is acknowledged that the sequenced region is small and therefore of limited use for comparison and certainly inconclusive in isolation. However, these findings do add further support to the view that the infections resulted from separate mouse and excreta exposures. As such, person-to-person transmission was not a likely factor.
Increased virulence is also unlikely to be a factor contributing to the cluster observed, because there are several findings that do not support this. First, it is noted that the mortality rate of 25% among this cohort is typical. Verity and others20 previously described a mortality rate of 26% among 19 cases identified in northern Alberta between September 1994 and June 1998, and the overall US mortality rate as of February 2006 was reported at 36%.9 In addition, all cases were PCR-positive, with SNV variants showing > 99% homology with commonly reported SNV strains causing unclustered cases. As such, the epidemiologic data and results of viral genotyping in this study do not support the contention that the clustering was a function of the virulence of the virus.
Overall, the ecological factors that contribute to exposure and risk of disease development remain unclear. It is of interest that, despite the large number of potential exposures of humans to rodent excreta annually, HPS is a rare disease that usually presents with single, isolated cases. The uncommon occurrence of clustering may be caused by the infrequency of common exposure and the duration of infectiousness of deer mice with excretion of viable virus. Infectious dose and further unidentified variables may also play a role. When clustering is observed, however, it is certainly caused by a number of interconnected variables, and the observed phenomenon is undoubtedly influenced by rodent abundance and the prevalence of rodent infection. As documented by the field studies performed in response to this reported cluster, the seroprevalence was 48.7% among 228 deer mice captured within the community. The excessive deer mouse population also noted may be explained in part by an early snowfall in the fall of 2004 in that region of Alberta, with relatively consistent snow cover lasting through to the spring of 2005. This snow cover may have afforded protection to the deer mice from predators, allowing the population to flourish. Undoubtedly, the cluster involved complex interactions of multiple variables, although previous SNV outbreaks and clusters have occurred in the setting of specific climate conditions, showing the significant influence the environment has on infectious diseases and human health.21,22
Although these cases of SNV infection in Alberta in May 2005 showed many classic features, there are two unique findings. To our knowledge, this is the first family cluster reported in Canada and includes one of the youngest cases of HPS to be reported in North America. An abundant deer mouse population with a high SNV infection rate seems to have contributed to the development of this cluster. As described above, the youngest reported case of SNV infection involved a 4-year-old boy in New Mexico in June 1993, although the case did not meet the CDC surveillance case definition for HPS. Within this cluster presently described, the 7-year-old boy met criteria for HPS, although presented with disease milder than the associated adult cases as is commonly observed in the pediatric population. Was it not for the severity of the associated adult cases, the boy’s diagnosis may have been missed. As such, under appropriate ecological and geographic conditions with exposure risk, clinicians should consider HPS within the differential diagnosis of young children presenting with community-acquired pneumonia.
Received December 8, 2006. Accepted for publication July 22, 2007.
Acknowledgments: We acknowledge the contributions and the collaborative efforts of the community leaders, the community’s health director, and the community’s health staff in response to this outbreak. We also acknowledge the work and involvement of the community’s Environmental Health Officer, Simon Sihota. In addition, the authors thank T. G. Ksiazek, Centers for Disease Control and Prevention, for providing us with mouse hyperimmune serum for the IgM ELISA and positive control sera for the IgG ELISAs and thank Mike Drebot for critically reviewing the text and providing valuable assistance in the preparation of this manuscript.
* Address correspondence to Duncan Webster, St. John Regional Hospital, P.O. Box 2100, St. John, New Brunswick, Canada E2L 4L2. E-mail: dvwebste{at}dal.ca 
Authors’ addresses: Duncan Webster, Division of Infectious Diseases, Dalhousie University, QE II Health Sciences Centre, Dickson Building, 1278 Tower Road, Halifax, Nova Scotia, Canada B3H 2Y9, Telephone: 902-473-5553, Fax: 902-473-7394. Bonita Lee, Provincial Laboratory for Public Health, 2B2.01 Walter C. MacKenzie Health Sciences Centre, 8440 112 Street, Edmonton, Alberta, Canada T6G 2J2, Telephone: 780-407-3414, Fax: 780-407-8961. Ari Joffe, Department of Pediatrics, University of Alberta, 8440 112 Street, Edmonton, Alberta, Canada T6G 2R7, Telephone: 780-407-1673, Fax: 780-407-3214. Wendy Sligl, Division of Infectious Diseases, Department of Internal Medicine, University of Alberta, 8440 112 Street, Edmonton, Alberta, Canada T6G 2B7, Telephone: 780-407-8077, Fax: 780-407-7137. Daryl Dick, Allen Grolla, Heinz Feldmann, David Safronetz, and Robbin Lindsay, Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, Manitoba, Canada R3E 3R2, Telephone: 204-789-2000, Fax: 204-789-2082. Wadieh Yacoub, First Nations and Inuit Health Branch, Alberta Region, 730-9700 Jasper Avenue, Edmonton, Alberta, Canada T5J 4C3, Telephone: 780-495-3391, Fax: 780-495-8070. Karen Grimsrud, Alberta Health and Wellness, 10025 Jasper Avenue, PO Box 1360, Edmonton, Alberta, Canada T5J 2N3, Telephone: 780-427-5263, Fax: 780-427-7683.
Reprint requests: Duncan Webster, Division of Infectious Diseases, St. John Regional Hospital, P.O. Box 2100, St. John, New Brunswick, Canada E2L 4L2, Telephone: 506-648-6807, Fax: 506-648-7379, E-mail: dvwebste{at}dal.ca.
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ABSTRACT
INTRODUCTION
CASE REPORT
DISCUSSION
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
