Bioclinical Test to Predict Nephropathia Epidemica Severity at Hospital Admission

Maxime Hentzien, Stéphanie Mestrallet, Pascale Halin, Laure-Anne Pannet, Delphine Lebrun, Moustapha Dramé, Firouzé Bani-Sadr, Jean-Marc Galempoix, Christophe Strady, Jean-Marc Reynes, Christian Penalba, Amélie Servettaz, Maxime Hentzien, Stéphanie Mestrallet, Pascale Halin, Laure-Anne Pannet, Delphine Lebrun, Moustapha Dramé, Firouzé Bani-Sadr, Jean-Marc Galempoix, Christophe Strady, Jean-Marc Reynes, Christian Penalba, Amélie Servettaz

Abstract

We conducted a multicenter, retrospective cohort study of hospitalized patients with serologically proven nephropathia epidemica (NE) living in Ardennes Department, France, during 2000-2014 to develop a bioclinical test predictive of severe disease. Among 205 patients, 45 (22.0%) had severe NE. We found the following factors predictive of severe NE: nephrotoxic drug exposure (p = 0.005, point value 10); visual disorders (p = 0.02, point value 8); microscopic or macroscopic hematuria (p = 0.04, point value 7); leukocyte count >10 × 109 cells/L (p = 0.01, point value 9); and thrombocytopenia <90 × 109/L (p = 0.003, point value 11). When point values for each factor were summed, we found a score of <10 identified low-risk patients (3.3% had severe disease), and a score >20 identified high-risk patients (45.3% had severe disease). If validated in future studies, this test could be used to stratify patients by severity in research studies and in clinical practice.

Keywords: Europe; France; Puumala virus; acute kidney injury; cohort studies; disease severity; hantavirus; hematuria; hemorrhagic disease; hospital admission; leukocytosis; nephropathia epidemica; nephrotoxic drug exposure; prognosis; risk factors; thrombocytopenia; viruses; visual disorder.

Figures

Figure 1
Figure 1
Determination of study population used to derive a bioclinical score that enables identification of patients more likely to develop severe NE. Patients were those living in Ardennes Department, France, who were hospitalized for serologically proven NE during January 2000–December 2014. NE, nephropathia epidemica.
Figure 2
Figure 2
Peak creatinine plasma levels in patients hospitalized for nephropathia epidemica by nephrotoxic drug exposure, Ardennes Department, France, January 2000–December 2014. Top and bottom borders of boxes indicate interquartile ranges (IQRs), horizontal lines within boxes indicate medians, diamonds indicate means, and circles represent outliers. A whisker is drawn from the upper edge of the box to the largest observed value within the upper fence (located at 1.5 × IQR above the 75th percentile), and another is drawn from the lower edge of the box to the smallest observed value within the lower fence (located at 1.5 × IQR below the 25th percentile). Peak plasma creatinine levels were higher in the patients exposed to nephrotoxic drugs (p = 0.002).
Figure 3
Figure 3
Receiver operating characteristic curve of test to predict development of severe nephropathia epidemica among patients hospitalized for nephropathia epidemica, Ardennes Department, January 2000–December 2014. Severe nephropathia epidemica was defined as the occurrence of >1 of the following criteria: hypovolemic, hemorrhagic, or septic shock; plasma creatinine level >353.6 µmol/L; anuria (urine output <300 mL/d); acute kidney injury or hydroelectrolytic disorders requiring dialysis; hemorrhage requiring blood transfusion; admission to the intensive care unit; or death. Area under the curve is 0.80.

References

    1. Watson DC, Sargianou M, Papa A, Chra P, Starakis I, Panos G. Epidemiology of Hantavirus infections in humans: a comprehensive, global overview. Crit Rev Microbiol. 2014;40:261–72. 10.3109/1040841X.2013.783555
    1. Vaheri A, Henttonen H, Voutilainen L, Mustonen J, Sironen T, Vapalahti O. Hantavirus infections in Europe and their impact on public health. Rev Med Virol. 2013;23:35–49. 10.1002/rmv.1722
    1. Vapalahti O, Mustonen J, Lundkvist A, Henttonen H, Plyusnin A, Vaheri A. Hantavirus infections in Europe. Lancet Infect Dis. 2003;3:653–61. 10.1016/S1473-3099(03)00774-6
    1. Institut Pasteur. Rapports d’activité [cited 2016 Oct 1].
    1. Strady C, Jaussaud R, Remy G, Penalba C. [Hantavirus infections]. Presse Med. 2005;34:391–9.
    1. Hjertqvist M, Klein SL, Ahlm C, Klingstrom J. Mortality rate patterns for hemorrhagic fever with renal syndrome caused by Puumala virus. Emerg Infect Dis. 2010;16:1584–6. 10.3201/eid1610.100242
    1. Miettinen MH, Mäkelä SM, Ala-Houhala IO, Huhtala HSA, Kööbi T, Vaheri AI, et al. Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis. Kidney Int. 2006;69:2043–8. 10.1038/sj.ki.5000334
    1. Braun N, Haap M, Overkamp D, Kimmel M, Alscher MD, Lehnert H, et al. Characterization and outcome following Puumala virus infection: a retrospective analysis of 75 cases. Nephrol Dial Transplant. 2010;25:2997–3003. 10.1093/ndt/gfq118
    1. Outinen TK, Mäkelä S, Clement J, Paakkala A, Pörsti I, Mustonen J. Community acquired severe acute kidney injury caused by hantavirus-induced hemorrhagic fever with renal syndrome has a favorable outcome. Nephron. 2015;130:182–90. 10.1159/000433563
    1. Makary P, Kanerva M, Ollgren J, Virtanen MJ, Vapalahti O, Lyytikäinen O. Disease burden of Puumala virus infections, 1995-2008. Epidemiol Infect. 2010;138:1484–92. 10.1017/S0950268810000087
    1. Latus J, Schwab M, Tacconelli E, Pieper F-M, Wegener D, Dippon J, et al. Clinical course and long-term outcome of hantavirus-associated nephropathia epidemica, Germany. Emerg Infect Dis. 2015;21:76–83. 10.3201/eid2101.140861
    1. Bunz H, Weyrich P, Peter A, Baumann D, Tschritter O, Guthoff M, et al. Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) and proteinuria predict severity of acute kidney injury in Puumala virus infection. BMC Infect Dis. 2015;15:464. 10.1186/s12879-015-1180-9
    1. Latus J, Schwab M, Tacconelli E, Pieper F-M, Wegener D, Rettenmaier B, et al. Acute kidney injury and tools for risk-stratification in 456 patients with hantavirus-induced nephropathia epidemica. Nephrol Dial Transplant. 2015;30:245–51. 10.1093/ndt/gfu319
    1. Mäkelä S, Hurme M, Ala-Houhala I, Mustonen J, Koivisto AM, Partanen J, et al. Polymorphism of the cytokine genes in hospitalized patients with Puumala hantavirus infection. Nephrol Dial Transplant. 2001;16:1368–73. 10.1093/ndt/16.7.1368
    1. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–12. 10.1186/cc2872
    1. Kidney Disease: Improving Global Outcomes Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1–138.
    1. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al.; Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11:R31. 10.1186/cc5713
    1. Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173:676–82. 10.1093/aje/kwq433
    1. Tervo L, Mäkelä S, Syrjänen J, Huttunen R, Rimpelä A, Huhtala H, et al. Smoking is associated with aggravated kidney injury in Puumala hantavirus-induced haemorrhagic fever with renal syndrome. Nephrol Dial Transplant. 2015;30:1693–8. 10.1093/ndt/gfv273
    1. Klein SL, Marks MA, Li W, Glass GE, Fang L-Q, Ma J-Q, et al. Sex differences in the incidence and case fatality rates from hemorrhagic fever with renal syndrome in China, 2004-2008. Clin Infect Dis. 2011;52:1414–21. 10.1093/cid/cir232
    1. Krautkrämer E, Grouls S, Urban E, Schnitzler P, Zeier M. No gender-related differences in the severity of nephropathia epidemica, Germany. BMC Infect Dis. 2013;13:457. 10.1186/1471-2334-13-457
    1. Du H, Wang P-Z, Li J, Bai L, Li H, Yu H-T, et al. Clinical characteristics and outcomes in critical patients with hemorrhagic fever with renal syndrome. BMC Infect Dis. 2014;14:191. 10.1186/1471-2334-14-191
    1. Wagner R, Leicht-Biener U, Mucsi I, Seitz K. Ibuprofen or diclofenac is associated with more severe acute kidney injury in nephropathia epidemica. Scand J Urol Nephrol. 2012;46:65–9. 10.3109/00365599.2011.625041
    1. Hautala N, Kauma H, Rajaniemi S-M, Sironen T, Vapalahti O, Pääkkö E, et al. Signs of general inflammation and kidney function are associated with the ocular features of acute Puumala hantavirus infection. Scand J Infect Dis. 2012;44:956–62. 10.3109/00365548.2012.700119
    1. Theiler G, Langer-Wegscheider B, Zollner-Schwetz I, Valentin T, Hönigl M, Schnedl W, et al. Blurred vision and myopic shift in Puumala virus infections are independent of disease severity. Clin Microbiol Infect. 2012;18:E435–7. 10.1111/j.1469-0691.2012.03997.x
    1. Hautala N, Kauma H, Vapalahti O, Mähönen S-M, Vainio O, Vaheri A, et al. Prospective study on ocular findings in acute Puumala hantavirus infection in hospitalised patients. Br J Ophthalmol. 2011;95:559–62. 10.1136/bjo.2010.185413
    1. Skarphedinsson S, Thiesson HC, Shakar SA, Tepel M. Factors predicting kidney damage in Puumala virus infected patients in Southern Denmark. Eur J Clin Microbiol Infect Dis. 2015;34:2017–21. 10.1007/s10096-015-2446-2
    1. Outinen TK, Mantula P, Laine OK, Pörsti I, Vaheri A, Mäkelä SM, et al. Haematuria is a marker for the severity of acute kidney injury but does not associate with thrombocytopenia in acute Puumala hantavirus infection. Infect Dis (Lond). 2017;49:840–6. 10.1080/23744235.2017.1358461
    1. Latus J, Kitterer D, Dippon J, Müller S, Artunc F, Segerer S, et al. Polyuria in hantavirus infection reflects disease severity and is associated with prolonged hospital stay: a systematic analysis of 335 patients from southern Germany. Nephron, Exp Nephrol. 2014;128:111–5. 10.1159/000368934
    1. Kim YK, Lee SC, Kim C, Heo ST, Choi C, Kim JM. Clinical and laboratory predictors of oliguric renal failure in haemorrhagic fever with renal syndrome caused by Hantaan virus. J Infect. 2007;54:381–6. 10.1016/j.jinf.2006.07.006
    1. Wang M, Wang J, Wang T, Li J, Hui L, Ha X. Thrombocytopenia as a predictor of severe acute kidney injury in patients with Hantaan virus infections. PLoS One. 2013;8:e53236. 10.1371/journal.pone.0053236
    1. Libraty DH, Mäkelä S, Vlk J, Hurme M, Vaheri A, Ennis FA, et al. The degree of leukocytosis and urine GATA-3 mRNA levels are risk factors for severe acute kidney injury in Puumala virus nephropathia epidemica. PLoS One. 2012;7:e35402. 10.1371/journal.pone.0035402
    1. Du H, Li J, Yu H-T, Jiang W, Zhang Y, Wang J-N, et al. Early indicators of severity and construction of a risk model for prognosis based upon laboratory parameters in patients with hemorrhagic fever with renal syndrome. Clin Chem Lab Med. 2014;52:1667–75.
    1. Du H, Li J, Yu H, Lian J, Zhang Y, Zhang Y, et al. HMGB-1 as a novel predictor of disease severity and prognosis in patients with hemorrhagic fever with renal syndrome. Mediators Inflamm. 2015;2015:696248. 10.1155/2015/696248
    1. Outinen TK, Mäkelä SM, Ala-Houhala IO, Huhtala HS, Hurme M, Paakkala AS, et al. The severity of Puumala hantavirus induced nephropathia epidemica can be better evaluated using plasma interleukin-6 than C-reactive protein determinations. BMC Infect Dis. 2010;10:132. 10.1186/1471-2334-10-132
    1. Latus J, Kitterer D, Segerer S, Artunc F, Alscher MD, Braun N. Severe thrombocytopenia in hantavirus-induced nephropathia epidemica. Infection. 2015;43:83–7. 10.1007/s15010-014-0699-9
    1. Rasche FM, Uhel B, Krüger DH, Karges W, Czock D, Hampl W, et al. Thrombocytopenia and acute renal failure in Puumala hantavirus infections. Emerg Infect Dis. 2004;10:1420–5. 10.3201/eid1008.031069
    1. Turčinov D, Puljiz I, Markotić A, Kuzman I, Begovac J. Clinical and laboratory findings in patients with oliguric and non-oliguric hantavirus haemorrhagic fever with renal syndrome: an analysis of 128 patients. Clin Microbiol Infect. 2013;19:674–9. 10.1111/j.1469-0691.2012.03994.x
    1. Mantula PS, Outinen TK, Clement JPG, Huhtala HSA, Pörsti IH, Vaheri A, et al. Glomerular proteinuria predicts the severity of acute kidney injury in Puumala hantavirus-induced tubulointerstitial nephritis. Nephron. 2017;136:193–201. 10.1159/000459634
    1. Mustonen J, Mäkelä S, Outinen T, Laine O, Jylhävä J, Arstila PT, et al. The pathogenesis of nephropathia epidemica: new knowledge and unanswered questions. Antiviral Res. 2013;100:589–604. 10.1016/j.antiviral.2013.10.001
    1. Hautala T, Partanen T, Sironen T, Rajaniemi S-M, Hautala N, Vainio O, et al. Elevated cerebrospinal fluid neopterin concentration is associated with disease severity in acute Puumala hantavirus infection. Clin Dev Immunol. 2013;2013:634632. 10.1155/2013/634632
    1. Mustonen J, Partanen J, Kanerva M, Pietilä K, Vapalahti O, Pasternack A, et al. Genetic susceptibility to severe course of nephropathia epidemica caused by Puumala hantavirus. Kidney Int. 1996;49:217–21. 10.1038/ki.1996.29

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