Risk factors associated with hantavirosis fatality : a regional analysis from a case-control study in Brazil

introduction: In Brazil, hantavirus cardiopulmonary syndrome (HCPS) has a high lethality rate that varies by region. This study aimed to identify the risk factors associated with fatal hantavirosis. Methods: This study was a case-control study that included all laboratory confi rmed cases of hantavirosis. The cases were stratifi ed by the different Brazilian regions using data from the Notifi able Diseases Information System. “Cases” were patients who progressed to death, whereas “controls” were patients who were cured. The odds ratio (OR) and the adjusted OR were calculated. Results: Overall, 158 cases and 281 controls were included in this study. In the Midwest region, the cases were 60% less likely to present with fl ank pain, and the time between the beginning of symptoms and death was shorter than the time between the beginning of symptoms and a cure. In the Southeast region, the cases were 60% less likely to present with thrombocytopenia or reside in rural areas compared to those who progressed to a cure. Additionally, the cases sought medical assistance, notifi cation and investigation more quickly than the controls. In the Southern region, the cases that died were 70% less likely to be male compared to the controls. Conclusions: HCPS manifests with nonspecifi c symptoms, and there are few published studies related to the condition, so determining a patient’s therapeutic strategy is diffi cult. This study presents fi ndings from different Brazilian regions and highlights the need for further investigations to improve comprehension about regional risk factors associated with hantavirosis and to reduce morbimortality.

Hantavirosis is an emerging zoonosis that is caused by several rodent-borne hantaviruses of the Bunyaviridae family 1 .On the American continent, these viruses are primarily associated with wild rodents of the Cricetidae family, more specifi cally the Sigmodontinae and Neotominae subfamilies 2,3 .The incubation periods vary from 3 to 60 days, and in nature, the virus is transmitted among rodents when they fi ght over food or when organisms, including humans, come in contact with contaminated excreta 4 .
In Brazil, hantavirosis was fi rst described in 1993 in the municipality of Juquitiba, São Paulo 5 .Since the fi rst cases were observed and technical training for epidemiological investigation was initiated, the disease has been found in new areas, and new genera and variants of hantavirus, as well as additionally species of wild rodents that are involved in the transmission of the virus, have been systematically identifi ed.Hantavirus has been reported in the insectivorous Soricidae and Talpidae families and in bats of the Vespertilionidae and Nycteridae families; however, hantaviruses have still not been associated with human disease [6][7][8][9] .
The most prevalent viral variants of hantavirus are Juquitiba, which occurs in wild rodents living in the Atlantic Forest region; Araraquara, which occurs in wild rodents from the cerrado and caatinga biomes (typical Brazilian vegetation) 10 ; Castelo dos Sonhos, which is present in rodents living in the cerrado and Amazon Rainforest; and Anajatuba, which has been found in wild rodents living in the Amazon Rainforest and fl ooded regions 11 .
In Brazil, hantavirosis manifests as hantavirus cardiopulmonary syndrome (HCPS), and the primary symptoms include fever, myalgia, flank and abdominal pain, severe cephalgia, nausea, vomiting and diarrhea; unfortunately, these unspecifi c symptoms can be confused with many other diseases 11,12 .The most severe symptoms, which begin on approximately the seventh day after the prodromic stage (early disease), primarily consist of a dry cough, tachycardia, tachydyspnea, hypoxemia, noncardiogenic pulmonary edema, hypotension and circulatory collapse 13 .
According to the Epidemiological Surveillance Guide, during the fi rst week of illness, laboratory confi rmed cases of hantavirus present with fever (>38°C), myalgia, cephalgia and respiratory failure of unknown etiology.Additionally, some cases present with an acute disease of unknown etiology that consists of respiratory failure and progresses to death.These individuals often present with fever, myalgia and cephalgia and have been exposed to wild rodents or favorable environmental resULTs MeTHODs Due to the high lethality rates and the incipient knowledge about the natural history of hantavirosis in Brazil, this study aimed to identify risk factors that are associated with hantavirus fatality in the different regions of the country.For this purpose, a case-control study was performed using secondary data from SINAN that were collected between 2007 and 2010.
This study is a case-control study.The data are secondary and were obtained from SINAN; inconsistencies and duplicate records were deleted prior to the analysis.The variables that were used were present in the individual notifi cation form from the national information surveillance epidemiological system in Brazil between 2007 and 2010, and the entry of these results was standardized.Demographic, epidemiological, clinical, laboratory, hospitalization and treatment variables were used in the analysis.Variables concerning expositions were not used, as our aim was to determine prognostic factors associated with death.This study included every serologically confi rmed case of hantavirosis that was registered on SINAN.The authors defi ned "cases" as patients who died from hantavirosis and "controls" as patients who were cured.The numbers of case and control patients did not match, but the analysis was stratifi ed.The odds ratio (OR) was used as the univariate measure of association, and the adjusted OR (AOR) was used as the multivariate measure of association.Statistical signifi cance was set to 5% (p≤0.05), and 95% confi dence intervals were used.For the statistical analysis, the Mann-Whitney U and t tests were used for the continuous variables.Only the variables that demonstrated a signifi cant statistical association with hantavirus fatality are presented.The analysis were performed using the software EpiInfo version 3.5.4.
Because of the different variants of hantavirus that circulate in the different regions of Brazil, the analysis was stratifi ed by region 15 .The Midwest region consists of the Mato Grosso do Sul, Mato Grosso, Goiás and Distrito Federal States.The Southeast region consists of Minas Gerais, Espírito Santo, Rio de Janeiro and São Paulo; and the Southern region contains the Paraná, Santa Catarina and Rio Grande do Sul States.The North and Northeast regions were not included in this analysis because of the low occurrence of hantavirosis cases (8 cases and 15 controls in total).
The study was conducted with secondary data and is presented in a collective manner.Nominal information or any other information that could identify each individual was not accessed; therefore, this study did not require the consideration of the ethics committee on research.
A total of 166 cases and 296 controls were identifi ed in the database.In the Midwest, 72 cases and 104 controls were considered (1:1.4),whereas 48 cases and 84 controls (1:1.7)were included from the Southeast, and 38 cases and 93 controls (1:2.4) were included from the South.The cases and controls were similar in terms of gender, education, ethnicity and age (table 1).
In the Midwest, compared to the controls, the cases were more likely to present with HCPS rather than the prodromic form; to have been hospitalized; and to have presented with signs and symptoms of dyspnea, acute respiratory failure, heart failure, arterial hypertension and pulmonary infi ltrates.The cases also had higher odds of receiving vasoactive drugs and mechanical ventilation.However, the patients who died were 60% less likely to have presented with fl ank pain compared to those who were cured.In the multivariate analysis, fl ank pain, diffuse pulmonary infi ltrates and the use of vasoactive drugs were associated with death.Furthermore, the time between the beginning of symptoms and death was signifi cantly shorter than the time between the beginning of symptoms and a cure (table 2).

DIscUssIOn
In the Southeast, the cases were more likely to have presented with hypovolemic shock, hypotension and acute respiratory failure.Furthermore, compared to the controls, there were increased levels of leukocytes with a shift to the left and the increased use of vasoactive drugs and mechanical ventilation.Nevertheless, the cases of hantavirosis that progressed to death were 70% less likely to live in rural areas or present with headaches and thrombocytopenia compared to the patients who progressed to a cure.A logistic regression analysis showed that thrombocytopenia and the use of mechanical ventilation were associated with the cases.Furthermore, the fi rst medical assistance, notifi cation, investigation and the course of the disease occurred more quickly in the cases than in the controls (table 3).
In the South, death was signifi cantly associated with clinical manifestations related to HCPS, hypovolemic shock, respiratory and cardiac failure, dyspnea, hypotension, pleural effusion, hematocrit greater than 45%, pulmonary infi ltrates and the use of vasoactive drugs and mechanical ventilation.As in the other regions, the time between the beginning of symptoms and death was signifi cantly shorter than the time between the beginning of symptoms and a cure, and the time between the beginning of symptoms and disease notifi cation was signifi cantly shorter for the cases.Patients who progressed to death were 60% less likely to be male than patients who were cured.In the adjusted analysis, shock, the use of vasoactive drugs and being male remained statistically signifi cant (table 4).
Despite the low incidence in Brazil, hantavirosis manifests as a severe illness.The limited amount of scientifi c literature on the topic hampers the decision-making process concerning patient care in some situations, as there are limited profi les of disease occurrence and there is limited evidence related to the disease.The risk factors for contracting hantavirus are known 11 .
This study provides important new information on the risk factors associated with death from hantavirus, demonstrating the differences in the Brazilian regions.While we know there are other risk factors associated with death from hantavirosis, we only analyzed parameters that were present in the SINAN database.For example, this study found that the odds of dying from hantavirosis in the Southern region were the lowest among men, whereas in the Southeast region, the odds of dying from hantavirosis were the lowest among people living in rural areas, which is the typical profi le of affected individuals 11 .These  When analyzing the course of the disease between the beginning of symptoms and either cure or death, those who progressed to death generally did so in a third of the time as those who progressed to a cure.These results may be due to the movement of the different hantavirus variants that have been registered and isolated from human cases in Brazilian regions 15 .However, more detailed studies are needed to determine the mechanisms of infection and immune response, the pathogenicity and diagnostic potential of the variants and the appropriate supportive treatment for the disease.
The symptoms and laboratory fi ndings related to death were clearly related to the severity and evolution of the cases.The notifi cation form from the SINAN was not designed to monitor the patient's evolution, and there was only one registration for each patient.Because we gathered our data from this information system, the registration of symptoms can be a predictor or a consequence of other conditions, but at the time of the investigation, the included patients were registered and presented as having hantavirosis.However, a study conducted with the same data but with a focus on the prognostic factors for hantavirosis fatality found that respiratory distress syndrome (RDS) and the need for mechanical respiratory assistance were also associated with death.When these variables were excluded from the model, dyspnea and hemoconcentration were associated with an increased risk of death [18][19][20] .We did not use the same exclusion in our study; however, we identifi ed factors that could aid in the prognosis of death, such as thrombocytopenia.
This study aimed to present epidemiological evidence that may support other studies concerning the progression of hantavirosis, especially regional studies that consider the variant forms of the virus, the means of exposure to the disease, the evolution of the disease and access to medical assistance.This study will contribute to health education actions and provide scientifi c evidence for medical personnel.

TABLE 2 -
Variables associated with hantavirosis fatality in the Midwest region of Brazil, 2007-2010.

TABLE 4 -
Variables associated with hantavirosis fatality in the Southern region of Brazil, 2007-2010.

TABLE 3 -
13riables associated with hantavirosis fatality in the Southern region of Brazil, 2007-2010.Risk factors associated with hantavirosis fatality, Brazil differences are most likely related to regional differences in who receives more and appropriate attention at the time of patient care.For example, patients with hantavirosis require treatment that is designed for hantavirosis rather than for other diseases with similar symptoms, such as dengue.A recent study performed in the State of Ceará found anti-hantavirus antibody titers in patients suspected of having dengue16, which demonstrates the need to strengthen the differential diagnosis to provide a clinical-epidemiological approach at the time of suspicion.Because of the nonspecifi c signs and symptoms associated with hantavirosis, which are easily confused with other diseases, appropriate supportive treatment (there is no specifi c treatment) is necessary to control the lethality rate of hantavirosis13.
Willemann MCA and Oliveira SV -