Highlights•

Clinical relevance of proteinuria in Andes virus is poorly understood

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Proteinuria is a frequent finding in Hantavirus cardiopulmonary syndrome

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Proteinuria was associated with increased in hospital mortality

AbstractObjectives

To determine the relative frequency and prognosis value of proteinuria in hantavirus cardiopulmonary syndrome (HCPS) due to Andes virus.

Methods

This is an observational analytical study with prospectively obtained data from patients admitted to 12 health centers in 9 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

Our database involved 175 patients, 95 of them had measurement of urine protein at the time of hospital admission. They were mainly male (71%) and the median age in years was 35[22-47].Their 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. We identified 73 patients (77%) 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

In patients with HCPS, proteinuria is a frequent finding which is associated with a higher mortality rate.

KeywordsHantavirus cardiopulmonary syndrome (HCPS) is a zoonosis caused by different strains of “New World” orthohantaviruses. Andes orthohantavirus (ANDV) is the primary etiological agent of HCPS in Chile and Argentina, where HCPS reaches mortality rates up to 40%. The main reservoir of ANDV is the long-tailed pygmy rice rat (Oligoryzomys longicaudatus), which transmits ANDV to humans primarily by aerosolization of rodent excrement. Only ANDV has been associated to human-to-human transmission (Maningold T et al., ).After an incubation period that varies from 7 to 39 days, HCPS begins with a febrile prodrome lasting several days followed by rapid onset of a cardiopulmonary phase characterized by respiratory failure and circulatory shock with myocardial dysfunction. A similar clinical picture was described for orthohantavirus disease in North America (Maningold T et al., ; López et al., 2019López R Pérez-Araos R Salazar A et al.Hemodynamic and pulmonary permeability characterization of hantavirus cardiopulmonary syndrome by transpulmonarythermodilution.).In Asia and Europe, “Old World” orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), which has lower lethality that varies from ). In HFRS, proteinuria is reportedly to be virtually a pathognomonic finding and is associated with acute kidney injury severity and prognosis (Mantula PS et al., Mantula et al., 2017Mantula PS Outinen TK Clement JPG et al.Glomerular proteinuria predicts the severity of acute kidney injury in Puumala Hantavirus-induced tubulointerstitial nephritis.; Clement J et al Clement et al., 2019Clement J LeDuc JW McElhinney M et al.Clinical characteristics of rat borne Seould hantavirus disease.). Kidney injury in HCPS is less well defined and is considered as a complication of circulatory dysfunction. Although some series describe the presence of proteinuria (Duchin JS et al., Duchin et al., 1994Duchin JS Koster FT Peters CJ et al.Hantavirus Pulmonary Syndrome: A clinical description of 17 patients with a newly recognized disease.), a link with severity has not been explored. We hypothesize that proteinuria at hospital admission may have a prognostic value in patients with HCPS.

This is an observational analytical study. The cohort was composed of patients from a prospectively obtained database by the Hantavirus Program from the “Instituto de Ciencias e Innovación en Medicina” de la Facultad de Medicina, Clínica Alemana - Universidad del Desarrollo. All primary data considered for this study were collected in 12 health centers from 9 Chilean cities between 2001 and 2018. The diagnosis of HCPS was confirmed in all cases by quantitative ELISA detecting ANDV specific immunoglobulin M and/or by reverse-transcription PCR detecting ANDV RNA in blood sample. The institutional ethics board approved this non-interventional study with anonymized data and waived the informed consent requirement.

Only patients with HCPS and laboratory characterization that included qualitative proteinuria determination at admission were considered. The standard method to qualitative proteinuria detection was urine dipstick (LabStrip U11 Plus, 77 ElektronikaKft, Hungary), with lower detection limits of 30 mg/dl. Patients with HCPS were categorized as proteinuria positive or negative. Primary outcome was inhospital mortality. Categorical variables are shown as number of patients with percentage in parentheses and compared by Fisher's exact test. Continuous variables are expressed as median[IQR] and compared by Mann Whitney U test. Significance was set at p<0.05.

From 175 patients with HCPS enrolled, quantitative proteinuria was available in 95 at admission. They were mainly male (71%) and the median age in years was 35[22-47].Their median duration of the febrile prodrome was 5[4-7] days. Hospital length of stay and hospital mortality rate were 10[7-14] days and 21.1% (table 1), respectively.

Table 1HCPS description and comparison according to proteinuria status.

SP (systolic arterial pressure), DP (diastolic arterial pressure), LDH (lactate dehydrogenase), ALT (alanine aminotransferase), AST (aspartate aminotransferase), Hospital LOS (hospital length of stay). Prodromal time was defined as the number of days with fever before hospital admission.

We identified 73(77%) patients with proteinuria at hospital admission. Compared with patients without proteinuria, we did not find difference either in clinical nor in laboratory variables, except in serum creatinine (table 1). However, hospital mortality was higher in patients with proteinuria (26% versus 5%, p=0.036). The relative risk of death in HCPS patients with positive proteinuria was 1.3[1.1-1.6], p=0.002.Our main findings are a high frequency of proteinuria in HCPS, which is associated with a higher mortality rate. In “Old World” orthohantavirus disease, renal involvement is a main target of the infection; being interstitial nephritis its main histological finding (Mustonen J et al., Mustonen et al., 1994Mustonen J Helin H Pietila K et al.Renal biopsy findings and clinicopathologic correlations in nephropathia epidemica.) and proteinuria has been associated with severity of kidney injury (Mantula PS et al., Mantula et al., 2017Mantula PS Outinen TK Clement JPG et al.Glomerular proteinuria predicts the severity of acute kidney injury in Puumala Hantavirus-induced tubulointerstitial nephritis.). In HFRS caused by Puumala orthohantavirus, proteinuria at the moment of diagnosis, along with thrombocytopenia and elevated reactive protein C, allowed prediction of risk of severe acute kidney injury in a large cohort of patients (Latus J et al., Latus et al., 2015Latus J Schwab M Tacconelli E et al.Acute kidney injury and tools for risk-stratification in 456 patients with hantavirus-induced nephropathia epidemica.). Proteins from glomerular and tubular origin have been described (Meier M et al., Meier et al., 2018Meier M Kramer J Jabs WJ et al.Proteinuria and the clinical course of Dobrava-Belgrade Hantavirus infection.), due to tubular cell dysfunction and impairment of both size- and charge-selectivity properties of the glomerular filter leading to increased glomerular permeability (Ala-Houhala I et al., Ala-Houhala et al., 2002Ala-Houhala I Koskinen M Ahola T et al.Increasedglomerular permeability in patients with nephropathiaepidemica caused by Puumala hantavirus.).“New World” orthohantaviruses cause a different syndrome, affecting mainly lungs and heart. Renal involvement is less frequent, with tubular necrosis in the more severe cases (Santos JP et al., Santos et al., 2019Santos JP Adad S Vergara ML et al.Clinical and anatomopathological aspects of patients with Hantavirus cardiopulmonary syndrome in Uberaba, Minas Gerais, Brazil.). Increased lung permeability is a mayor finding, due, at least in part, to endothelial dysfunction (Maningold T et al., ; López et al., 2019López R Pérez-Araos R Salazar A et al.Hemodynamic and pulmonary permeability characterization of hantavirus cardiopulmonary syndrome by transpulmonarythermodilution.). A similar alteration in glomerular endothelial cells may explain a presumable role of positive proteinuria as permeability marker and, therefore, support a hypothesis of proteinuria as prognostic factor in HCPS, although consistent glomerular involvement has not been systematically sought in biopsies from HCPS.

To our best knowledge, this is the first study in patients with HCPS due to ANDV that provides data about frequency and prognosis value of proteinuria. Unlike HFRS, proteinuria appears to lack sensitivity in HCPS, but we propose that this simple test, at admission, may provide a tool to detect more severely ill patients with increased risk of death.

Declaration of Competing Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding sources

This work was supported by Fondo Nacional de Investigación en Salud (FONIS; Grant Number SAO7120045); Fondo Nacional de Ciencia y Tecnología (Fondecyt; Grant Number 1161447 and 1201240) and the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (grant number 5U19AI045452).

Acknowledgments

Hantavirus Study Group in Chile: In addition to the authors, members of the Hantavirus Study Group in Chile who contributed to patient enrollment and follow-up, sample collection and analysis, and data management are as follows: José Miguel Montes, Juan Abarca, Rodrigo Pérez, Luis Miguel Noriega, Francisca Valdivieso (Clínica Alemana de Santiago, Santiago, Chile); Iris Delgado, (Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago, Chile); Constanza Martinez, (Pontificia Universidad Católica de Chile, Santiago, Chile); Juan Carlos Chamorro, Jury Hernandez, Marcelo Pino, Ivonne Vega, Irisol Otarola, (Hospital Dr. Victor Rios Ruiz, Los Angeles, Chile); Carlos Ortega, Elizabeth Daube, (Hospital Dr Guillermo Grant Benavente, Concepción, Chile); Constanza Castillo, Jovita Mardones, Ligia Sanhueza, Jaime Inostroza, (Hospital Dr Hernán Henriquez Aravena, Temuco, Chile); Solange Donoso, Maritza Navarrete, Andrés Araneda, Teresa Aguilera, Carola Osorio, Verónica Yobanolo, (Hospital Base de Valdivia, Valdivia, Chile); Luis Scholz, (Hospital de Osorno, Osorno, Chile); Raul Riquelme, Mauricio Riquelme, Miriam Muñoz, (Hospital de Puerto Montt, Puerto Montt, Chile).

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RevInstMedTrop Sao Paulo. 61: e55https://doi.org/10.1590/S1678-9946201961055Article InfoPublication History

Accepted: July 9, 2021

Received in revised form: July 7, 2021

Received: April 22, 2021

Publication stageIn Press Journal Pre-ProofIdentification

DOI: https://doi.org/10.1016/j.ijid.2021.07.026

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© 2021 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

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