Browsing by Author "Mertz, Gregory"
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Item A 19 Year Analysis of Small Mammals Associated with Human Hantavirus Cases in Chile(2019) Torrez-Pérez, Fernando; Palma, Eduardo; Boric-Bargetto, Dusan; Vial, Cecilia; Ferrés, Marcela; Vial, Pablo; Martínez-Valdebenito, Constanza; Pavletic, Carlos; Parra, Alonso; Marquet, Pablo; Mertz, GregorySmall mammals present in areas where hantavirus cardiopulmonary syndrome (HCPS) cases had occurred in central and southern Chile were captured and analyzed to evaluate theabundance of rodents and seroprevalence rates of antibodies to Andes orthohantavirus (ANDV). Sampling areas ranged from the Coquimbo to Aysén regions (30–45° S approx.) regions. Ninetytwo sites in peridomestic and countryside areas were evaluated in 19 years of sampling. An antibody against ANDV was detected by strip immunoassay in 58 of 1847 specimens captured using Sherman traps. Of the eleven species of rodents sampled, Abrothrix olivacea, Oligoryzomys longicaudatus and Abrothrix hirta were the most frequently trapped. O. longicaudatus had the highest seropositivity rate, and by logistic regression analysis, O. longicaudatus of at least 60 g had 80% or higher probability to be seropositive. Sex, age and wounds were significantly related to seropositivity only for O. longicaudatus. Across administrative regions, the highest seropositivity was found in the El Maule region (34.8–36.2° S), and the highest number of HCPS cases was registered in the Aysén region. Our results highlight the importance of long term and geographically extended studies, particularly for highly fluctuating pathogens and their reservoirs, to understand the implications of the dynamics and transmission of zoonotic diseases in human populations.Publication A non-randomized multicentre trial of human immune plasma for treatment of hantavirus cardiopulmonary syndrome caused by Andes virus(International Medical Press, 2015) Vial, Pablo; Valdivieso, Francisca; Calvo, Mario; Rioseco, María; Riquelme, Raúl; Araneda, Andrés; Tomicic, Vinko; Graf, Jerónimo; Paredes, Laura; Fiorenzano, Matías; Bidart, Teresa; Cuiza, Analía; Marco, Claudia; Hjelle, Brian; Ye, Chunyan; Hanfelt-Goade, Daniel; Vial, Cecilia; Rivera, Juan; Mertz, Gregory; Hantavirus Study Group in Chile; Delgado, IrisBACKGROUND: In Chile, Andes virus (ANDV) is the sole aetiological agent of hantavirus cardiopulmonary syndrome (HCPS) with mean annual incidence of 55 cases, 32% case fatality rate (CFR) and no specific treatment. Neutralizing antibody (NAb) titres at hospital admission correlate inversely with HCPS severity. We designed an open trial to explore safety and efficacy and evaluate pharmacokinetics of immune plasma as a treatment strategy for this disease. METHODS: We performed plasmapheresis on donors at least 6 months after HCPS and measured NAb titres through a focus-reduction neutralization test. Subjects admitted to 10 study sites with suspected/confirmed HCPS were eligible for treatment with immune plasma by intravenous infusion at an ANDV NAb dose of 5,000 U/kg. HCPS was confirmed through immunoglobulin M serology or reverse transcriptase-PCR. The main outcome was mortality within 30 days. RESULTS: From 2008-2012, we enrolled and treated 32 cases and confirmed HCPS in 29. CFR of hantavirus plasma-treated cases was 4/29 (14%); CFR of non-treated cases in the same period in Chile was 63/199 (32%; P=0.049, OR=0.35, CI=0.12, 0.99); CFR of non-treated cases at the same study sites between 2005-2012 was 18/66 (27%; (P=0.15, OR=0.43, CI=0.14, 1.34) and CFR in a previous methylprednisolone treatment study was 20/60 (33%; P=0.052, OR=0.32, CI=0.10, 1.00). We detected no serious adverse events associated to plasma infusion. Plasma NAb titres reached in recipients were variable and viral load remained stable. CONCLUSIONS: Human ANDV immune plasma infusion appears safe for HCPS. We observed a decrease in CFR in treated cases with borderline significance that will require further studies for confirmation.Item A Single-Nucleotide Polymorphism of αVβ3 Integrin Is Associated with the Andes Virus Infection Susceptibility(2019) Martínez-Valdebenito, Constanza; Angulo, Jenniffer; Corre, Nicole Le; Marco, Claudia; Vial, Cecilia; Miquel, Juan Francisco; Cerda, Jaime; Mertz, Gregory; Vial, Pablo; Lopez-Lastra, Marcelo; Ferrés, MarcelaThe Andes Orthohantavirus (ANDV), which causes the hantavirus cardiopulmonary syndrome, enters cells via integrins, and a change from leucine to proline at residue 33 in the PSI domain (L33P), impairs ANDV recognition. We assessed the association between this human polymorphism and ANDV infection. We defined susceptible and protective genotypes as “TT” (coding leucine) and “CC” (coding proline), respectively. TT was present at a rate of 89.2% (66/74) among the first cohort of ANDV cases and at 60% (63/105) among exposed close-household contacts, who remained uninfected (p < 0.05). The protective genotype (CC) was absent in all 85 ANDV cases, in both cohorts, and was present at 11.4% of the exposed close-household contacts who remained uninfected. Logistic regression modeling for risk of infection had an OR of 6.2–12.6 (p < 0.05) in the presence of TT and well-known ANDV risk activities. Moreover, an OR of 7.3 was obtained when the TT condition was analyzed for two groups exposed to the same environmental risk. Host genetic background was found to have an important role in ANDV infection susceptibility, in the studied population.Item Deletions in Genes Participating in Innate Immune Response Modify the Clinical Course of Andes Orthohantavirus Infection(2019) Ribeiro, Grazielle; León, Luis; Pérez, Ruth; Cuiza, Analía; Vial, Pablo; Ferres, Marcela; Mertz, Gregory; Vial, CeciliaAndes orthohantavirus (ANDV) is an important human pathogen causing hantavirus cardiopulmonary syndrome (HCPS) with a fatality rate of 30% in Chile. Around 60% of all cases have a severe clinical course, while the others have a mild clinical course. The main goal of this study was to understand if the genetic variation of patients is associated with the clinical course they develop after ANDV infection. For this, the frequency of copy number variants (CNVs, i.e., deletions and duplications) was studied in 195 patients, 88 with mild and 107 with severe HCPS. CNVs were called from intensity data of the Affymetrix Genome-Wide SNP Array 6.0. The analysis of the data was performed with PennCNV, ParseCNV and R softwares; Results: a deletion of 19, 416 bp in the q31.3 region of chromosome 1 is found more frequently in severe patients (p < 0.05). This region contains Complement Factor H Related (CFHR1) and CFHR3 genes, regulators of the complement cascade. A second deletion of 1.81 kb located in the p13 region of chr20 was significantly more frequent in mild patients (p < 0.05). This region contains the SIRPB1 gene, which participates in the innate immune response, more specifically in neutrophil trans-epithelial migration. Both deletions are associated with the clinical course of HCPS, the first being a risk factor and the second being protective. The participation of genes contained in both deletions in ANDV infection pathophysiology deserves further investigation.Item Factores de riesgo socio-demográficos del síndrome cardiopulmonar por hantavirus(2019) Vial, Cecilia; Valdivieso, Francisca; Cuiza, Analía; Delgado, Iris; Ribeiro, Grazielle; Llop, Elena; Ferrés, Marcela; Repetto, Gabriela; Riquelme, Raúl; Rioseco, María Luisa; Calvo, Mario; Mertz, Gregory; Vial, PabloBackground: Hantavirus cardiopulmonary syndrome (HCPS) is caused by new world hantaviruses, among which Andes hantavirus (ANDV) is endemic to Chile and Southern Argentina. The disease caused by ANDV produces plasma leakage leading to enhanced vascular permeability and has a high case fatality rate (35%), mainly due to respiratory failure, pulmonary edema and myocardial dysfunction, hypoperfusion and shock. Host sociodemographic and genetic factors might influence the course and outcome of the disease. Yet, they have not been thoroughly characterized. Aim: To evaluate sociodemographic factors as risk factors in severity of HCPS. Patients and Methods: Study period: 2004-20013, attending in eight collaborative centers, etiological diagnosis was performed by serology or molecular biology, mild and severe HCPS were compared.139 Chilean patients were analyzed, 64 (46%) with severe disease among which 12 (19 %) died. Results: European ethnicity had 5,1 times higher risk than Amerindian ethnic group to develop a severe HCPS, greater seriousness that was also associated with an urban residence. Conclusion: It was observed that ethnicity and type of residence were significant risk factors for HCPS severity. Hypotheses explaining these findings are discussed.Publication Hantavirus in humans: a review of clinical aspects and management(2023) Vial, Pablo; Ferrér, Marcela; Vial, Cecilia; Klingström, Jonas; Ahlm, Clas; López, René; Le Corre, Nicole; Mertz, GregoryHantavirus-induced diseases are emerging zoonoses with endemic appearances and frequent outbreaks in different parts of the world. In humans, hantaviral pathology is characterized by the disruption of the endothelial cell barrier followed by increased capillary permeability, thrombocytopenia due to platelet activation/depletion and an overactive immune response. Genetic vulnerability due to certain human leukocyte antigen haplotypes is associated with disease severity. Typically, two different hantavirus-caused clinical syndromes have been reported: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The primarily affected vascular beds differ in these two entities: renal medullary capillaries in HFRS caused by Old World hantaviruses and pulmonary capillaries in HCPS caused by New World hantaviruses. Disease severity in HFRS ranges from mild, e.g. Puumala virus-associated nephropathia epidemica, to moderate, e.g. Hantaan or Dobrava virus infections. HCPS leads to a severe acute respiratory distress syndrome with high mortality rates. Due to novel insights into organ tropism, hantavirus-associated pathophysiology and overlapping clinical features, HFRS and HCPS are believed to be interconnected syndromes frequently involving the kidneys. As there are no specific antiviral treatments or vaccines approved in Europe or the USA, only preventive measures and public awareness may minimize the risk of hantavirus infection. Treatment remains primarily supportive and, depending on disease severity, more invasive measures (e.g., renal replacement therapy, mechanical ventilation and extracorporeal membrane oxygenation) are needed.Item High-dose intravenous methylprednisolone for hantavirus cardiopulmonary syndrome in Chile: a double-blind, randomized controlled clinical trial(Oxford University Press, 2013) Vial, Pablo; Valdivieso, Francisca; Ferres, Marcela; Riquelme, Raul; Rioseco, Maria; Calvo, Mario; Castillo, Constanza; Diaz, Ricardo; Scholz, Luis; Cuiza, Analía; Belmar, Edith; Hernandez, Carla; Martinez, Jessica; Lee, Sang-Joon; Mertz, GregoryBACKGROUND: Andes virus (ANDV)-related hantavirus cardiopulmonary syndrome (HCPS) has a 35% case fatality rate in Chile and no specific treatment. In an immunomodulatory approach, we evaluated the efficacy of intravenous methylprednisolone for HCPS treatment, through a parallel-group, placebo-controlled clinical trial. METHODS: Patients aged >2 years, with confirmed or suspected HCPS in cardiopulmonary stage, admitted to any of 13 study sites in Chile, were randomized by study center in blocks of 4 with a 1:1 allocation and assigned through sequentially numbered envelopes to receive placebo or methylprednisolone 16 mg/kg/day (≤1000 mg) for 3 days. All personnel remained blinded except the local pharmacist. Infection was confirmed by immunoglobulin M antibodies or ANDV RNA in blood. The composite primary endpoint was death, partial pressure of arterial oxygen/fraction of inspired oxygen ratio ≤55, cardiac index ≤2.2, or ventricular tachycardia or fibrillation within 28 days. Safety endpoints included the number of serious adverse events (SAEs) and quantification of viral RNA in blood. Analysis was by intention to treat. RESULTS: Infection was confirmed in 60 of 66 (91%) enrollees. Fifteen of 30 placebo-treated patients and 11 of 30 methylprednisolone-treated patients progressed to the primary endpoint (P = .43). We observed no significant difference in mortality between treatment groups (P = .41). There was a trend toward more severe disease in placebo recipients at entry. More subjects in the placebo group experienced SAEs (P = .02). There were no SAEs clearly related to methylprednisolone administration, and methylprednisolone did not increase viral load. CONCLUSIONS: Although methylprednisolone appears to be safe, it did not provide significant clinical benefit to patients. Our results do not support the use of methylprednisolone for HCPS. CLINICAL TRIALS REGISTRATION: NCT00128180.Item Knowledge, attitudes, and practices regarding hantavirus disease and acceptance of a vaccine trial in rural communities of southern Chile(Taylor & Francis Online, 2016) Valdivieso, Francisca; Gonzalez, Claudia; Najera, Manuel; Olea, Andrea; Cuiza, Analía; Aguilera, Ximena; Mertz, GregoryAndes hantavirus cardiopulmonary syndrome, transmitted by Oligoryzomys longicaudatus, has no approved treatment, a case fatality rate of 35%, and documented person-to-person transmission. An Andes vaccine, highly needed for prevention, is in development. We aimed to evaluate knowledge, attitudes and practices (KAP) regarding hantavirus disease and willingness to participate in a future Andes vaccine trials through a cross sectional face-to-face oral survey of a randomly selected adult sample from 2 rural communes in southern Chile. Human subjects approval was obtained from our institutional IRBs, and participants signed informed consent. We enrolled 319 subjects from Corral and 321 from Curarrehue; 98% had heard about hantavirus disease and its reservoir but only half knew about transmission, symptoms and prevention. Participants fear the disease but are only partially aware of their own risk. One third of participants reported presence of rodents inside their homes. Despite moderate confidence in their health system, most subjects perceived vaccines as beneficial, and 93% would accept an approved hantavirus vaccine. Half would agree to participate in a vaccine trial and 29% would allow their children to participate. Motivations to participate were mainly altruistic, while risk perception was the main reason for declining. Knowledge about hantavirus disease and prevention practices require reinforcement, and a vaccine trial seems feasible in these populations.Item Mother-to-Child Transmission of Andes Virus through Breast Milk, Chile(2020-08) Ferrés, Marcela; Martínez-Valdebenito, Constanza; Angulo, Jenniffer; Henríquez, Carolina; Vera-Otaróla, Jorge; Vergara, María José; Pérez, Javier; Fernández, Jorge; Sotomayor, Viviana; Valdés, María Francisca; González-Candia, Diego; Tischler, Nicole D.; Vial, Cecilia; Vial, Pablo; Mertz, Gregory; Le Corre, NicoleAndes virus (ANDV) is the only hantavirus transmitted between humans through close contact. We detected the genome and proteins of ANDV in breast milk cells from an infected mother in Chile who transmitted the virus to her child, suggesting gastrointestinal infection through breast milk as a route of ANDV person-to-person transmission.Item Person-to-Person Household and Nosocomial Transmission of Andes Hantavirus, Southern Chile, 2011(Centers for Desease Control and Prevention, 2014) Martinez-Valdebenito, Constanza; Calvo, Mario; Vial, Cecilia; Mansilla, Rita; Marco, Claudia; Palma, Eduardo; Vial, Pablo; Valdivieso, Francisca; Mertz, Gregory; Ferrés, MarcelaAndes hantavirus (ANDV) causes hantavirus cardiopulmonary syndrome in Chile and is the only hantavirus for which person-to-person transmission has been proven. We describe an outbreak of 5 human cases of ANDV infection in which symptoms developed in 2 household contacts and 2 health care workers after exposure to the index case-patient. Results of an epidemiologic investigation and sequence analysis of the virus isolates support person-to-person transmission of ANDV for the 4 secondary case-patients, including nosocomial transmission for the 2 health care workers. Health care personnel who have direct contact with ANDV case-patients or their body fluids should take precautions to prevent transmission of the virus. In addition, because the incubation period of ANDV after environmental exposure is longer than that for person-to-person exposure, all persons exposed to a confirmed ANDV case-patient or with possible environmental exposure to the virus should be monitored for 42 days for clinical symptoms.Item Platelet Count in Patients with Mild Disease at Admission is Associated with Progression to Severe Hantavirus Cardiopulmonary Syndrome(2019) López, René; Vial, Cecilia; Graf, Jerónimo; Calvo, Mario; Ferrés, Marcela; Mertz, Gregory; Cuiza, Analía; Agüero, Begonia; Aguilera, Dante; Araya, Diego; Pailamilla, Ignacia; Paratori, Flavia; Torres-Torres, Víctor; Vial, Pablo; HantavirusStudy Group in ChileBACKGROUND: Hantavirus cardiopulmonary syndrome (HCPS) has a mortality up to 35-40% and its treatment is mainly supportive. A variable to predict progression from mild to severe disease is unavailable. This study was performed in patients with documented infection by Andes orthohantavirus, and the aim was to find a simple variable to predict progression to moderate/severe HCPS in patients with mild disease at admission. METHODS: We performed a retrospective analysis of 175 patients between 2001 and 2018. Patients were categorized into mild, moderate, and severe disease according to organ failure and advanced support need at hospital admission (e.g., mechanical ventilation, vasopressors). Progression to moderate/severe disease was defined accordingly. Clinical and laboratory variables associated with progression were explored. RESULTS: Forty patients with mild disease were identified; 14 of them progressed to moderate/severe disease. Only platelet count was different between those who progressed versus those that did not (37 (34-58) vs. 83 (64-177) K/mm3, p < 0.001). A ROC curve analysis showed an AUC = 0.889 (0.78-1.0) p < 0.001, with a platelet count greater than 115K /mm3 ruling out progression to moderate/severe disease. CONCLUSIONS: In patients with mild disease at presentation, platelet count could help to define priority of evacuation to tertiary care centers.Item Proteinuria in Hantavirus Cardiopulmonary Syndrome: A Frequent Finding Linked To Mortality(2021) López, René; Espinoza, Mauricio; Graf, Jerónimo; Mertz, Gregory; Ferrés, Marcela; Calvo, Mario; Vial, Cecilia; Vial, Pablo; Hantavirus Study Group in ChileObjectives: To determine the relative frequency and prognosis value of proteinuria in hantavirus cardiopulmonary syndrome (HCPS) due to Andes virus. Methods: This observational analytical study prospectively obtained data from patients admitted to 12 health centers in nine Chilean cities between 2001 and 2018. Only patients with confirmed Andes virus HCPS and laboratory characterization that included qualitative proteinuria determination at admission were considered. Results: The database involved 175 patients, 95 of them had a measurement of urine protein at the time of hospital admission. They were mainly male (71%) and the median age was 35 [22-47] years. Median duration of the febrile prodromal time was 5 [4-7] days. Hospital length of stay and hospital mortality rate were 10 [7-14] days and 21.1%, respectively. Seventy-three patients (77%) were identified with proteinuria at admission, which was associated with increased mortality rate (26% versus 5%, p=0.036) and the relative risk was 1.3 [1.1-1.6], p=0.002. Conclusions: Proteinuria is a frequent finding in patients with HCPS, which is associated with a higher mortality rate.