Factors Associated with the Clinical Severity of Puumala Hantavirus Infection

Hemorrhagic fever with renal syndrome (HFRS), caused by Puumala hantavirus (PUUV), also called nephropathia epidemica, is a common febrile illness in Finland. PUUV infection begins with a sudden high fever accompanied by headache, vomiting, abdominal and back pain, and visual disturbances. Renal involvement comprises the oliguric phase followed by polyuria and usually spontaneous recovery. Acute kidney injury (AKI) is severe in one-third of hospitalized patients. Nevertheless, the outcome of PUUV infection is usually favorable, and the case fatality rate is <1%.

Cigarette smoking and alcohol consumption have been shown to affect the course of several infections. Smoking leads to structural and functional changes in the airways. In addition, smoking alters the immune system in several ways, affecting the susceptibility to acquire infection, and the clinical course of some infections. Furthermore, alcohol consumption affects the susceptibility to and course of some infections.

This study was carried out to investigate the possible effects of these two life- style factors on the clinical course of PUUV infection. It also aimed to examine abdominal fluid collections during the acute phase of PUUV infection by means of magnetic resonance imaging (MRI), and the role of a biomarker, soluble urokinase- type plasminogen activator receptor (suPAR), as a predictor of the clinical severity of PUUV infection.

A history of smoking among 357 patients was collected via a questionnaire. Cigarette smoking predisposed patients to more severe AKI, and current smokers had higher maximum serum creatinine levels than nonsmokers. A severe AKI, defined as serum creatinine level ≥ 353.6 μmol/L, was more prevalent in smokers than in nonsmokers. Smoking cessation returned the risk of severe AKI to the same level as in never-smokers.

Alcohol consumption was studied by detecting biomarkers showing previous alcohol use in 66 patients. A combination marker, GGT-CDT, can detect heavy alcohol consumption with a sensitivity of 90% and specificity of 98%. The other measured biomarker was urinary ethyl glucuronide (EtG), which detects recent alcohol consumption. Altogether, 41% of the patients showed biochemical signs of recent alcohol consumption at the control visit. Nevertheless, alcohol use did not seem to predispose patients to more severe PUUV infection. The levels of liver enzymes and serum amylase were also evaluated. Liver enzymes were slightly elevated during acute infection but were not associated with more severe infection. No cases of acute pancreatitis were found.

The hallmark of the pathogenesis of hantaviral diseases is increased endothelial permeability with capillary leakage. Pleural fluid is often reported during PUUV infection, but the presence of abdominal fluid collections is far less well studied. The present study was aimed at investigating abdominal fluid below the diaphragm and the amount of pleural fluid by means of MRI in 27 PUUV-infected patients. Fluid collections were assessed in relation to the patients’ symptoms and clinical and laboratory findings. All patients showed additional fluid. Fluid was detected most frequently in the perirenal space, next to the psoas muscle, and in the pouch of Douglas. Pleural fluid was found in 25 of the patients. Patients with more severe fluid collections did not have symptoms more often than patients with lesser amounts of fluid. The amounts of both intraperitoneal and retroperitoneal fluid correlated inversely with serum creatinine levels. The amount of retroperitoneal fluid also showed an inverse correlation with serum cystatin C concentrations. Increased intraperitoneal fluid was also associated with higher C-reactive protein (CRP) concentration.

Several biomarkers have been shown to predict disease severity in infectious diseases. SuPAR is a multifunctional glycoprotein the concentrations of which are elevated in various inflammatory and infectious conditions. SuPAR levels were measured in 97 patients in the acute phase of PUUV infection and in the convalescence phase. SuPAR concentrations were significantly higher in the acute phase compared with the convalescence phase. Higher concentrations were associated with more severe AKI. Plasma suPAR levels correlated with serum creatinine concentrations, and patients who needed dialysis treatment had higher suPAR concentrations than patients who did not need dialysis.

In conclusion, cigarette smoking leads to more severe AKI in hospitalized patients with PUUV infection. On the other hand, alcohol consumption does not seem to affect the course of the infection. Levels of liver enzymes are often elevated but are not associated with disease severity. In abdominal MRI, fluid collections are present in hospitalized PUUV-infected patients. More prominent fluid collections were not associated with more severe AKI. In fact, more prominent fluid may present as a protective sign against severe AKI. When evaluating patients with biomarkers, plasma suPAR concentrations were associated with more severe AKI in PUUV-infected patients.