Acute Puumala Virus Infection Research Articles

Abdominal CT findings in Puumala hantavirus-infected patients.

Previous clinical studies have reported abdominal findings on ultrasonography or MRI in Puumala hantavirus-infected patients. To determine if abdominal computed tomography (CT) can lead to a diagnosis of Puumala virus infection in the presence of a suggestive clinical picture. CT findings were studied retrospectively in 30 patients who presented to the emergency department of two (Belgian) hospitals with serologically confirmed Puumala hantavirus infection. The most frequent finding was perirenal fascial thickening (90%), followed by perirenal fat stranding (87%). Retroperitoneal fat stranding was found in 19 patients (64%) in the perivesical spaces along the fascia of the external iliac vessels with or without involvement of the presacral fat. Half of the patients had pelvic ascites, and pleural fluid was found in 7 of them. The right and left mean pole-to-pole kidney's lengths were respectively 125.7mm and 127.8mm in 28 patients. Retroperitoneal fat stranding, perirenal fascial thickening and/or perirenal fat stranding were found in most patients with acute Puumala virus infection who have undergone CT. Although nonspecific, these findings may help to suggest Puumala hantavirus infection in the right clinical settings.

Hormonal Defects Are Common during Puumala Hantavirus Infection and Associate with Disease Severity and Biomarkers of Altered Haemostasis.

Central and peripheral hormone deficiencies have been documented during and after acute hantavirus infection. Thrombocytopenia and coagulation abnormalities are common findings in haemorrhagic fever with renal syndrome (HFRS). The associations between coagulation and hormonal abnormalities in HFRS have not been studied yet. Forty-two patients diagnosed with Puumala virus (PUUV) infection were examined during the acute phase and on a follow-up visit approximately one month later. Hormonal defects were common during acute PUUV infection. Overt (clinical) hypogonadism was identified in 80% of the men and approximately 20% of the patients had overt hypothyroidism. At the one-month follow-up visit, six patients had central hormone deficits. Acute peripheral hormone deficits associated with a more severe acute kidney injury (AKI), longer hospital stay and more severe thrombocytopenia. Half of the patients with bleeding symptoms had also peripheral hormonal deficiencies. Patients with free thyroxine levels below the reference range had higher D-dimer level than patients with normal thyroid function, but no thromboembolic events occurred. Acute phase hormonal abnormalities associate with severe disease and altered haemostasis in PUUV infection.

Heterologous boosting of nonrelated toxoid immunity during acute Puumala hantavirus infection

Persistence of immune memory in humans is a crucial yet poorly understood aspect of immunology. Here we have studied the effect of Puumala hantavirus infection on unrelated, pre-existing immune memory by studying T cell- and antibody responses against toxoid vaccine antigens of diphtheria, tetanus and pertussis in a cohort of 45 patients. We found that tetanus- and pertussis -specific IgG concentrations elevate during acute Puumala virus infection. Increase in vaccine IgG was associated with proliferation of heterologous T cells. Interestingly, increases in tetanus-specific IgG persisted a year after the infection while pertussis-specific IgG declined rapidly; a difference in IgG kinetics resembling the difference seen after vaccination against tetanus and pertussis. These results suggest that persistence of immune memory is facilitated by heterologous boosting of old memory during memory formation against newly encountered antigens. They also show that different toxoid antigens may be treated differently. Our study gives new insight into how immune memory formation may alter pre-existing immune memory, and also shows that heterologous immunity may have an impact on vaccination outcomes.

Early Chest Imaging in Patients with Puumala Hantavirus Infection

Purpose:To describe early chest imaging abnormalities in patients with acute Puumala virus infection.Materials and Methods:This retrospective study (2005–2017) comprised 64 patients who were admitted to the emergency department of a Belgian hospital. These patients were diagnosed with serologically confirmed acute Puumala virus infection and had at least one chest X-ray (CRX). Imaging studies were evaluated by two experienced chest radiologists reaching agreement by consensus, and abnormalities were reported according to the Fleischner Society glossary of terms for thoracic imaging. When a patient underwent multiple CRX, only the findings of the first were recorded. Six patients underwent chest high-resolution computed tomography (HRCT).Results:CRX showed abnormal findings in 33 patients (51.5%). Most common findings were linear atelectasis (29.7%) and small pleural effusion (20.3%). HRCT showed interlobular septal thickening in four patients and crazy-paving pattern with consolidations in one patient with adult respiratory distress syndrome.Conclusions:Early CRX commonly showed linear atelectasis and small pleural effusion in Puumala virus infected patients above 30 years of age. Chest HRCT most frequently showed atelectasis and smooth interlobular septal thickening. While uncommon, early and severe pulmonary involvement can be associated with Puumala virus infection, albeit these findings are not specific.

Flash-Like Albuminuria in Acute Kidney Injury Caused by Puumala Hantavirus Infection.

Transient proteinuria and acute kidney injury (AKI) are characteristics of Puumala virus (PUUV) infection. Albuminuria peaks around the fifth day and associates with AKI severity. To evaluate albuminuria disappearance rate, we quantified albumin excretion at different time points after the fever onset. The study included 141 consecutive patients hospitalized due to acute PUUV infection in Tampere University Hospital, Finland. Timed overnight albumin excretion (cU-Alb) was measured during the acute phase in 133 patients, once or twice during the convalescent phase within three months in 94 patients, and at six months in 36 patients. During hospitalization, 30% of the patients had moderately increased albuminuria (cU-Alb 20–200 μg/min), while 57% presented with severely increased albuminuria (cU-Alb >200 μg/min). Median cU-Alb was 311 μg/min (range 2.2–6460) ≤7 days after fever onset, 235 μg/min (range 6.8–5479) at 8–13 days and 2.8 μg/min (range 0.5–18.2) at 14–20 days. After that, only one of the measurements showed albuminuria (35.4 μg/min at day 44). At six months, the median cU-Alb was 2.0 μg/min (range 0.6–14.5). Albuminuria makes a flash-like appearance in PUUV infection and returns rapidly to normal levels within 2–3 weeks after fever onset. In the case of AKI, this is a unique phenomenon.

Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus-associated syndromes.

Two related hyperinflammatory syndromes are distinguished following infection of humans with hantaviruses: haemorrhagic fever with renal syndrome (HFRS) seen in Eurasia and hantavirus pulmonary syndrome (HPS) seen in the Americas. Fatality rates are high, up to 10% for HFRS and around 35%–40% for HPS. Puumala virus (PUUV) is the most common HFRS‐causing hantavirus in Europe. Here, we describe recent insights into the generation of innate and adaptive cell‐mediated immune responses following clinical infection with PUUV. First described are studies demonstrating a marked redistribution of peripheral blood mononuclear phagocytes (MNP) to the airways, a process that may underlie local immune activation at the site of primary infection. We then describe observations of an excessive natural killer (NK) cell activation and the persistence of highly elevated numbers of NK cells in peripheral blood following PUUV infection. A similar vigorous CD8 Tcell response is also described, though Tcell responses decline with viraemia. Like MNPs, many NK cells and CD8 T cells also localize to the lung upon acute PUUV infection. Following this, findings demonstrating the ability of hantaviruses, including PUUV, to cause apoptosis resistance in infected target cells, are described. These observations, and associated inflammatory cytokine responses, may provide new insights into HFRS and HPS disease pathogenesis. Based on similarities between inflammatory responses in severe hantavirus infections and other hyperinflammatory disease syndromes, we speculate whether some therapeutic interventions that have been successful in the latter conditions may also be applicable in severe hantavirus infections.

Glomerular Proteinuria Predicts the Severity of Acute Kidney Injury in Puumala Hantavirus-Induced Tubulointerstitial Nephritis

Background:Puumala virus (PUUV)-induced hemorrhagic fever with renal syndrome is common in many European countries. The typical renal histologic lesion is acute tubulointerstitial nephritis. We examined the type and kinetics of urine protein excretion and prognostic significance of proteinuria for the severity of acute kidney injury (AKI) in acute PUUV infection. Methods: The amount of dipstick albuminuria at hospital admission was analyzed in 205 patients with acute PUUV infection. Dipstick albuminuria at admission was graded into 3 categories: 0-1+, 2+, and 3+. In 70 patients, 24-h urinary excretion of protein, overnight urinary excretion of albumin, immunoglobulin (Ig) G, and α1-microglobulin also were measured over 3 consecutive days during the hospital stay. Results: Maximum median daily proteinuria, overnight albuminuria, and IgG excretion were observed over 5 days, while that of creatinine values was observed 9 days after the onset of the disease. The medians of maximum plasma creatinine levels during hospital stay were different in the 3 categories of dipstick albuminuria: 0-1+: 98 µmol/L (58-1,499), 2+: 139 µmol/L (71-829), and 3+: 363 µmol/L (51-1,285; p < 0.001). Dipstick albuminuria ≥2+ at admission could be detected in 89% of the patients who subsequently developed severe AKI. Glomerular proteinuria, but not tubular proteinuria (α1-microglobulin), correlated with the severity of the emerging AKI. Conclusion: In acute PUUV infection, maximum median proteinuria values preceded the most severe phase of AKI by a few days. A highly useful finding for clinical work was that a quick and simple albuminuria dipstick test at hospital admission predicted the severity of the upcoming AKI.

Smoking Is a Risk Factor for Severe Acute Kidney Injury in Hantavirus-Induced Nephropathia Epidemica

Background/Aims: Hantaviruses are zoonotic pathogens causing emerging diseases worldwide. Patients typically present with fever, acute kidney injury (AKI) and thrombocytopenia. Puumala virus (PUUV) that causes nephropathia epidemica (NE) is common in Germany. Recently, a study from Finland revealed an association between nicotine consumption and the severity of AKI in NE. Differences between individuals in Finland and Germany might modulate the effect; therefore, the aim of our study was to prove that smoking is a risk factor for a severe course of NE in Germany. Methods: A cross-sectional prospective survey of 485 patients with hantavirus infections was performed. Clinical and laboratory data during the acute course of the disease were obtained from medical reports and files, while follow-up (including smoking status) data were collected prospectively. Results: Smoking information was available for 298 out of 485 patients (61%). Male was the predominant gender (67%), median age at the time of diagnosis was 50 (interquartile range, IQR 41-60) years and 34% of patients were current smokers during the phase of acute NE. Patients in the smoking group were significantly younger than in the non-smoking group (p < 0.0001). Peak serum creatinine levels were significantly higher in the smoking group than in the non-smoking patients (median 301 (IQR 186-469 μmol/l) vs. median 240 (IQR 137-469 μmol/l), p < 0.05). In addition, severe AKI (stages 2 and 3 using KDIGO criteria) was more common in current smokers (80%) than in the non-smokers (68%, p < 0.05). Conclusion: Current smoking is a risk factor for severity of AKI in patients with acute PUUV infection in Germany. Therefore, information about smoking habits needs to be an integral part of the documentation in patients with suspected acute PUUV infection, and increased monitoring of kidney function should be done in NE patients who are current smokers.

Plasma pentraxin-3 and coagulation and fibrinolysis variables during acute Puumala hantavirus infection and associated thrombocytopenia.

Thrombocytopenia and altered coagulation characterize all hantavirus infections. To further assess the newly discovered predictive biomarkers of disease severity during acute Puumala virus (PUUV) infection, we studied the associations between them and the variables reflecting coagulation, fibrinolysis and endothelial activation. Nineteen hospital-treated patients with serologically confirmed acute PUUV infection were included. Acutely, plasma levels of pentraxin-3 (PTX3), cell-free DNA (cf-DNA), complement components SC5b-9 and C3 and interleukin-6 (IL-6) were recorded as well as platelet ligands and markers of coagulation and fibrinolysis. High values of plasma PTX3 associated with thrombin formation (prothrombin fragments F1+2; r = 0.46, P = 0.05), consumption of platelet ligand fibrinogen (r = -0.70, P < 0.001) and natural anticoagulants antithrombin (AT) (r = -0.74, P < 0.001), protein C (r = -0.77, P < 0.001) and protein S free antigen (r = -0.81, P < 0.001) and a decreased endothelial marker ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 domain 13) (r = -0.48, P = 0.04). Plasma level of AT associated with C3 (r = 0.76, P < 0.001), IL-6 (r = -0.56, P = 0.01) and cf-DNA (r = -0.47, P = 0.04). High cf-DNA coincided with increased prothrombin fragments F1+2 (r = 0.47, P = 0.04). Low C3 levels reflecting the activation of complement system through the alternative route predicted loss of all natural anticoagulants (for protein C r = 0.53, P = 0.03 and for protein S free antigen r = 0.64, P = 0.004). Variables depicting altered coagulation follow the new predictive biomarkers of disease severity, especially PTX3, in acute PUUV infection. The findings are consistent with the previous observations of these biomarkers also being predictive for low platelet count and underline the cross-talk of inflammation and coagulation systems in acute PUUV infection.

Headache and low platelets in a patient with acute leukemia

Persistence of immune memory in humans is a crucial yet poorly understood aspect of immunology. Here we have studied the effect of Puumala hantavirus infection on unrelated, pre-existing immune memory by studying T cell- and antibody responses against toxoid vaccine antigens of diphtheria, tetanus and pertussis in a cohort of 45 patients. We found that tetanus- and pertussis -specific IgG concentrations elevate during acute Puumala virus infection. Increase in vaccine IgG was associated with proliferation of heterologous T cells. Interestingly, increases in tetanus-specific IgG persisted a year after the infection while pertussis-specific IgG declined rapidly; a difference in IgG kinetics resembling the difference seen after vaccination against tetanus and pertussis. These results suggest that persistence of immune memory is facilitated by heterologous boosting of old memory during memory formation against newly encountered antigens. They also show that different toxoid antigens may be treated differently. Our study gives new insight into how immune memory formation may alter pre-existing immune memory, and also shows that heterologous immunity may have an impact on vaccination outcomes.

Thrombocytopenia and Acute Renal Failure in Puumala Hantavirus Infections

Nephropathia epidemica, caused by Puumala virus (PUUV) infection, is a form of hemorrhagic fever with renal syndrome of variable severity. Early prognostic markers for the severity of renal failure have not been established. We evaluated clinical and laboratory parameters of 15 consecutive patients with acute PUUV infection, which is endemic in the Alb-Danube region, South Germany. Severe renal failure (serum creatinine >620 micromol/L) was observed in seven patients; four required hemodialysis treatment. Low platelet count (<60 x 109/L), but not leukocyte count, C-reactive protein, or other parameters obtained at the initial evaluation, was significantly associated with subsequent severe renal failure (p = 0.004). Maximum serum creatinine was preceded by platelet count nadirs by a median of 4 days. Thrombocytopenia <60 x 109/L appears predictive of a severe course of acute renal failure in nephropathia epidemica, with potential value for risk-adapted clinical disease management.