ARTICLE IN PRESS Travel Medicine and Infectious Disease (2007) 5, 30–34

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Andes Hantavirus as possible cause of disease in travellers to South America$ Constanza Castillloa,, Claudia Nicklasa, Jovita Mardonesb, Gonzalo Ossaa,b a

Department of Internal Medicine, Faculty of Medicine, Universidad de la Frontera, Manuel Montt 112, Temuco, Chile Universidad de la Frontera—Teaching Hospital: Hernan Henrı´quez Aravena, Manuel Montt 115, Temuco, Chile

b

Received 9 December 2005; received in revised form 21 February 2006; accepted 27 February 2006 Available online 15 May 2006

KEYWORDS Hantavirus; Reservoir; Risks; Clinic; Prevention; Tourism

Summary Background: Hantaviruses in Europe and Asia cause haemorrhagic fever with renal syndrome and epidemic nephritis (mortality rate o1–15%). New strains of Hantaviruses cause Hantavirus pulmonary syndrome (HPS) from Canada to South America. Andes virus mortality rate is about 30% in Chile. Method: Clinical charts of 54 patients were reviewed. Results: Inhalation of aerosolized urine, faeces or saliva of rodents is the principal cause of infection. The incubation period is between 8 and 43 days. The main prodromal symptoms are: myalgias, fever, fatigue, gastrointestinal disorders, dyspnoea, petechiae and coughing. After the 4th day pulmonary oedema, hypotension and renal failure appear. Haemorrhagic disorders may occur. The first laboratory tests presenting alterations are: haemoconcentration, leukocytosis, low platelet count o150 m/L, and presence of immunoblasts. The treatment is supportive: mechanical ventilation, vasopressor drugs, haemofiltration or haemodialysis, and extracorporeal membrane oxygenation. There is no specific treatment for HPS. Preventive measures must be empathised. Conclusion: The principal risk factors for tourists are: accommodation in abandoned or closed up facilities; failure to use indicated pathways when walking in forests; camping outside recommended areas; drinking water from natural sources and fishing in risk areas. The risk of infection for foreign tourists in Chile is low. & 2006 Elsevier Ltd. All rights reserved.

$ Data from the manuscript was presented at the First International Conference of the Journal of Travel Medicine and Infectious Disease. 10–11 November 2005, Royal College of Surgeons of England, London, UK (poster P4). Corresponding author. Tel.: +56 45 325755; fax: +56 45 325756. E-mail addresses: [email protected] (C. Castillo), [email protected] (C. Nicklas), [email protected] (J. Mardones), [email protected] (G. Ossa).

1477-8939/$ - see front matter & 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tmaid.2006.02.002

ARTICLE IN PRESS Andes Hantavirus as possible cause of disease in travellers to South America

Introduction Hantaviruses (family Bunyaviridae) are transmitted directly from rodents to humans, without other intermediate vectors. The main cause of infection is the inhalation of aerosolized urine and faeces; an occasional cause is rodent bite (saliva).1–7 Hantaviruses which cause haemorrhagic fever with renal syndrome (HFRS) or epidemic nephritis (EN) with a mortality rate of o1–15% have been recognized for decades in Europe and Asia. Seoul virus transmitted by Rattus sp. has a worldwide distribution and HRFS is also transmitted by rodents of the subfamily Murinae, and EN by rodents of the subfamily Arvicolinae.1–3 New strains of Hantaviruses are recognized, with distribution from Canada to the South American Continent, transmitted by rodents of the subfamily Sigmodontinae.1–3 Hantaviruses in the Americas cause a disease which affects the lungs and heart, and has a higher mortality rate (450% to o25%).1–5,8–12 In Chile the mortality rate of Andes virus HPS is now reduced to about 30%.13 In the 20th century massive changes in the speed and use of international transport have accelerated the rate of spread and enlarged the global extent of infections, not only between humans but also from animals to humans.14 The purpose of this report is describe and discuss the reservoir of the Andes virus, infection risk factors, clinical features, treatment, and especially preventive measures for visitors travelling to Chile.

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forestry. The population of the Coastal Area is supported by farming, forestry, fishing and tourism. The IX Region is one of the poorest regions of the country. It is one of the regions with the highest incidence of HPS cases. In our group of Andes virus HPS patients 68.5% were males and 31.5% females. The mean age was of 32.4 yr (largest standard deviation ¼ 13.1; range: 9–64 yr). Only 16.7% of those affected were of the indigenous (mapuche) population. Of the patients, 74% became infected in rural areas near their homes or place of work. Of those infected in the area 20% were Chilean tourists. In 6% the precise site of contagion was unknown. Only one North American zoology student suffered HPS in the IX Region. This patient had a high-risk exposure, working in the forest of the ‘‘Nahuelbuta’’ National Park, and was bitten by an Oligoryzomys longicaudatus. After 14 days, symptoms began and he was referred to Temuco, where he was treated successfully.

Major risk factors for inhabitants Entering into an abandoned or closed up storage buildings or facilities near their homes or place of work (39.5%); forestry activities (23.3%); agricultural activities (18.8%) and fishing (2.2%) (in many cases the inhabitants were exposed to the risk of infection through more than one activity, especially forestry and agriculture). On six occasions (11%) family clusters occurred, affecting especially the sexual partner (5/6).

Method

Major risk factors for tourists

Of the 64 HPS cases which occurred in the IX Region of Chile between 1997 and 2004, the clinical charts and epidemiological questionnaires of 54 confirmed Andes virus HPS cases sent to Temuco, capital and referral centre of the IX Region, were reviewed. These records were reviewed retrospectively with the consent of the patient or a family member. HPS is serologically confirmed using the enzyme-linked immune assay following the technique described by Rossi C and co-workers and accepted by the World Health Organization Collaborating Centre for virus reference and research.15 A database was prepared, avoiding identification of the patient by using only the initials of the first and last names, and a number. Data recorded: gender, age, ethnic group, city, rural towns and country of residence. We also reviewed the risk factors, date of the first symptoms, clinical features, laboratory tests, treatment, outcome and preventive measures. Statistical analysis was performed with the STATA 8.0.

Camping outside recommended areas or without suitable tents; accommodation in closed up facilities and failure to use indicated pathways when walking in forests. Fishing was a minor risk factor (p40:05).

Results The IX Region of Chile is located in the South of the country, between parallels 371 and 401 South and meridians 701 and 741 West. About 40% of the inhabitants live in rural areas. The region has three geographical sectors. The Lower Andes is a rural area with small towns; the population there lives primarily from farming, woodcutting and tourist services. The Central Valley is a predominantly urban area in which the main sources of income are industry, farming and

Clinical features The first symptoms began on average 6 days (range 1–13 days) after exposure (25.9% on the 4th day and 33.3% on the 7th day): myalgia, fever and fatigue (100%), headache (60%), nausea and vomiting (50%), facial rash (74%), abdominal pain (40%), lumbar pain (38%) and conjuntival injection (30%). Further symptoms appeared subsequently: dyspnoea (80%), coughing (50%), petechiae especially in the axilar regions and eyelids (60%), and central nervous system manifestations (30%). During the cardiopulmonary stage the major clinical features were tachycardia, dyspnoea, coughing, fever, hypotension or shock, renal failure and pulmonary oedema. Chest X-rays showed bilateral, interstitial shadows with Kerley-B Lines in 42%, bilateral alveolar flooding in 39% and unilateral interstitial pulmonary oedema in 10%. Pleural effusion was seen in 15% of the cases and seven patients developed atelectasis. Haemorrhagic disorders occurred in 50% of the cases. The sources of bleeding were: haemoptysis, multiple puncture sites, epistaxis, macroscopic haematuria, haematemesis, lung haemorrhage and haemothorax. Patients might suffer bleeding from more than one source. For laboratory results see Table 1.

ARTICLE IN PRESS 32

C. Castillo et al.

Table 1

Nosocomial prevention

Laboratory results in 54 HPS cases.

Laboratory parameter

%

Low platelet count Leukocytosis Haemoconcentration Immunoblasts Elevated aspartate aminotransferase (ASAT) Hyponatremia Prolonged partial thromboplastine time Elevated alanine aminotransferase (ALAT) Elevated blood urea nitrogen Elevated serum amylase Elevated serum creatinine Prolonged prothrombine time Elevated alkaline phosfatase Hyperkalemia Hypernatremia Elevated bilirubin

92 87 84 61 98 91 87 85 76 67 48 42 28 5 2 1

Blood smear parameters: low platelet count, leukocytosis, haemoconcentration and the presence of immunoblasts are the characteristic tetrad seen in HPS. None of the laboratory tests presenting alterations had statistical significance in the clinical evolution or outcome.

Treatment Patients without respiratory failure or hypotension were clinically observed and laboratory tests were performed. If signs of respiratory failure were present: respiratory rate 420 X0 , oxygen saturation (Sat O2o90%); and if arterial pressure was dropping the patient was sent to a centre with an intensive care unit (ICU). During transport, oxygen supply through a mask was required. Hypotension was treated with crystalloid intravenous infusion, taking care not administer an excessive amount which can worsen the pulmonary oedema. Supportive treatment at ICU and specific treatment alternatives are discussed later. Mechanical ventilation (MV) was required in 40% of our cases, vasopressor drugs (VPD) in 50%, and three patients required haemodialysis. In none of them was extracorporeal membrane oxygenation (ECMO) performed. The mortality rate was 37% (20/54).

Prevention Preventive educational campaigns for inhabitants are continuously reinforced by the Ministerio de Salud de Chile (Chilean Ministry of Health) and have recently included awareness for females living in rural areas who share the same risk activities when helping their husbands.

Principal risk factors for tourists Camping outside recommended areas or without suitable tents; accommodation in abandoned or closed up facilities and failure to use indicated pathways when walking in forests.

Patients were treated in an isolated room when one was available. Health care workers in the ICU used masks, goggles, gloves and gown (not always disposable units, which are ideal). None of the health care workers developed either clinical or asymptomatic HPS. None of the health care workers who had direct contact with index cases from the early stages of the disease had positive antibodies against Hantavirus (seroconversion).

Discussion O. longicaudatus, a wild rodent of the subfamily Sigmodontinae, is the reservoir of the Andes virus in southern Argentina and Chile.16–18 Its normal habitat is forests, bushes and river banks. Because it is nocturnal humans are not aware of its presence by day. When its natural source of food becomes scarce, as happens after a year with extensive rains associated with the ‘‘El Nin ˜o’’ phenomenon, the reservoir of the Andes virus invades human habitats in search of food. It uses trees and abandoned birds’ nests to rest and reproduce. This behaviour is well known, and the population, especially children, have been educated not to climb trees or collect abandoned birds’ nests in risk areas of the country. The principal transmission mechanism of Hantavirus to human beings is the inhalation of aerosols from faeces, urine or saliva of infected rodents.1–7,19,20 Person-to-person transmission was documented in southern Argentina,21,22 but not proven in northern Argentina, Chile or other countries.3,4,19,20,23 In El Bolso ´n, Bariloche, southern Argentina, an epidemic cluster occurred in 1996. The cluster predominantly affected family members of index cases and health care workers who were also family members or were socially related to the patients. However, a physician residing in Buenos Aires who did not visit the epidemic areas in southern Argentina developed an HPS after direct contact with an HPS patient proceeding from this epidemic cluster. Furthermore, genetic analysis showed that a single virus caused the outbreak.21,22 In Chile about 11% of the cases occurred in family clusters, affecting principally the sexual partner. Occasionally there are situations in which the means of contagion is still unclear. The Ministerio de Salud de Chile concluded that the most probable explanation is exposure to a common source of infection. Genetic analysis was not performed.13 HPS caused by the Andes virus in Chile has an incubation period of between 8 and 43 days. In eleven patients who stayed for 1–3 days as tourists in a risk area and became infected, the incubation period was calculated between 10 and 35 days (average 18).24 The diagnosis of HPS was confirmed using the enzymelinked immune assay (ELISA).3,19 In Chile immunoglobulin class IgM of the Sin Nombre virus, and class IgG of Laguna Negra virus are provided by the Centre for Disease Control and Prevention. The Universidad Austral de Chile and the Instituto de Salud Pu ´blica de Chile are the qualified test centres for the ELISA tests in Chile. Viral ARN can be detected in patients’ fluids by the reverse transcriptase chain reaction (RT-PCR).3,19

ARTICLE IN PRESS Andes Hantavirus as possible cause of disease in travellers to South America Viral proteins in tissues can be observed through immunohistochemistry.3,9,19 Viruses can be cultured in Vero E6 cells. The first human isolate of Hantavirus (Andes virus) was done at the Instituto de Salud Pu ´blica de Chile from serum of an asymptomatic 10-yr-old Chilean patient.25 The clinical features of HPS caused by the Andes virus, and other strains in Central and South America are different from the first cases documented in the North American and Canadian cases. The course of HPS is frequently similar to that of haemorrhagic fever syndrome, with petechiae, renal failure and free bleeding.2–5,7–11 HPS is commonly confused with community-acquired pneumonias, intra-abdominal processes, pyelonephritis, acute respiratory distress syndrome and sepsis. Broad spectrum antibiotic therapy has to be administered until the diagnosis is confirmed.2,3,26 The presence of the tetrad of haemoconcentration, leukocytosis, low platelet count and 410% of immunoblasts in the blood smear of a patient exposed to rodents is strongly predictive of HPS.2,3,10,12,19 Hantaviruses trigger a humoral defensive response, developing neutralizing antibodies. Patients who have a mild course of Hantavirus cardiopulmonary syndrome are more likely to exhibit a high titre of neutralizing antibodies against Sin Nombre virus, the aetiologic agent of HPS in North America, at the time of hospital admission.27 On the other hand Hantaviruses trigger deleterious immunological cell mechanisms. The proportion of T cells expressing the CD8 phenotype are increased in HPS, producing high levels of inflammatory mediators which are responsible for respiratory failure and refractory shock.3,19,28

Treatment The treatment of HPS is supportive. There is no specific treatment with good safety and proven efficacy. Intravenous Ribavirin is efficient in HFRS, but not in HPS cases.29,30 Supportive treatment consists in monitoring respiratory and haemodynamic parameters. In patients without hypotension care must be taken not to administer excessive intravenous fluids. A vascular leak syndrome results in translocation of plasma into the extra vascular compartment (especially into the lungs) and may lead to or exacerbate pulmonary oedema. If respiratory failure begins, oxygen supply is needed, and the patient must be sent to an ICU as soon as possible.2,3,7,8,10,12,31,32 The supportive treatment of HPS at ICU is: administer high oxygen fraction (FiO2) through a mask or MV using tidal volume of 7 ml/kg, initial FiO2 of 1.0, and positive end expiratory pressure (PEEP) of 8–15 H2O cm. Permissive hypercapnia is not recommended, because of metabolic acidosis. Haemodynamic support: measure central venous pressure, pulmonary artery occlusion pressure (PAOP), systemic vascular resistance index (SVRI) and cardiac index (CI). PAOP must not exceed 8–10 mmHg. In order to monitor these parameters the use of a Swan Ganz catheter or PiCCO monitoring technique is needed. If renal failure occurs, haemodialysis is required.6,8,31,32 Cases with CI o2.5 L/min/m2 need extracorporeal circulatory membrane oxygenation.3,32

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In many centres in Chile, high doses of systemic corticosteroids over a short period of time was used empirically.8,33 Our results show that there is no statistical evidence that intravenous corticosteroids have an effect on the clinical evolution (Fisher’s exact test ¼ 0.007) or outcome (Fisher’s exact test ¼ 1.000) (1-sided Fisher’s exact test ¼ 0.546) (p40:05). Alternatives such as the administration of methylprednisolone, neutralizing antibodies and drugs that stop the systemic inflammatory response syndrome are under study. Because no specific treatment is now available for HPS, and considering the high mortality rate, prevention is the most important issue. The recommendations for tourists who travel to endemic areas (from the southern edge of the Chilean desert to the last region before the Antarctic) are: avoid accommodation in abandoned or closed up facilities; keep to signed paths when walking through forests; avoid fishing in risk areas. In Chile only 4% became infected after fishing, principally in the X Region in areas associated with silviculture. No foreign tourists became infected after fishing.13 Southern Chile is famed internationally for its fly fishing. When camping, it is recommended to choose a clear, sunny place, away from bushes or forests, to use a tent with a sewn-in ground-sheet and to put garbage in hermetic containers. Do not drink water from natural sources. Occasionally tourists may become infected when collecting berries in the fields or woods and eating the fruit without first washing it.13 Only 1% of tourists coming from foreign countries became infected in Chile. One North American patient, two tourists from Spain and one from France have become infected in southern Chile. One tourist proceeding from Germany became infected in either southern Chile or Argentina.

Acknowledgements William Barne (British teacher and translator at Idiomas Vilcun Ltda, Temuco) for linguistic revision and correction of the manuscript.

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