Characterisation of healthcare utilisation and cost of haemophilia care in real-life: A 4-year follow-up study in Finland.

INTRODUCTION: Characterisation of outcomes and costs of haemophilia care in common practice settings is essential for evaluation of new treatment options and for developing clinical practices. In Finland, haemophilia care is mostly centralised to University Hospitals, but treatment practices and costs in adult patients have not been systematically evaluated. AIM: This study was designed to characterise healthcare resource utilisation and treatment costs of adult inhibitor-negative haemophilia patients managed in Finnish University Hospitals. METHODS: The study was based on a nationwide cohort, which consists of all adult haemophilia A (HA; n = 120) and B (HB; n = 35) patients treated in University Hospitals from 2012 to 2016. Patient characteristics and data on healthcare utilisation and factor replacement use were collected from medical records. Direct costs of care were evaluated based on wholesale drug prices and healthcare service utilisation with standard unit costs. RESULTS: Most of HA (79%, n = 96) and HB (84%, n = 31) patients received factor replacement therapy. The median annual bleeding rate (ABR) was low, at 0.8 for HA and 0.5 for HB, also among the patients with on-demand therapy. Over 94% (n = 149) of the patients had outpatient visits during the follow-up period. The mean total annual costs of treatment ranged from €2520 to €176,330. The highest individual cost was factor replacement therapy. CONCLUSION: The outcomes of centralising the management of care to University Hospital Treatment Centres show low ABR and lower treatment costs compared with earlier reports from other high-income European populations. Management strategies, including choosing the right therapy between prophylaxis and on-demand, has been successful in Finland.

No association between blood count levels and whole-blood cobalt and chromium levels in 1,900 patients with metal-on-metal hip arthroplasty.

Background and purpose - The accelerated wear of poorly functioning metal-on-metal (MoM) hip implants may cause elevated whole-blood cobalt (Co) and chromium (Cr) levels. Hematological and endocrinological changes have been described as the most sensitive adverse effects due to Co exposure. We studied whether there is an association between whole-blood Co/Cr levels and leukocyte, hemoglobin, or platelet levels. Patients and methods - We analyzed whole-blood Co and Cr values and complete blood counts (including leukocytes, hemoglobin, platelets) from 1,900 patients with MoM hips. The mean age at the time of whole-blood metal ion measurements was 67 years (SD 10). The mean time from primary surgery to whole-blood metal ion measurement was 8.2 years (SD 3.0). The mean interval between postoperative blood counts and metal ion measurements was 0.2 months (SD 2.7). Results - The median Co value was 1.9 µg/L (0.2-225), Cr 1.6 µg/L (0.2-125), mean leukocyte count 6.7 × 109/L (SD 1.9), hemoglobin value 143 g/L (SD 13), and platelet count 277 × 109/L (SD 70). We did not observe clinically significant correlations between whole-blood Co/Cr and leukocyte, hemoglobin, or platelet counts. Interpretation - Elevated whole-blood Co and Cr values are unlikely to explain abnormal blood counts in patients with MoM hips and the reason for possible abnormal blood counts should be sought elsewhere.

Autoimmune heparin-induced thrombocytopenia of delayed onset: a clinical challenge.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) usually appears at 5 to 10 days after initiation of heparin. Autoimmune HIT can arise after discontinuation of heparin treatment (delayed-onset HIT) or without any preceding heparin exposure (spontaneous HIT syndrome). CASE REPORT: This case presents a course of autoimmune HIT with delayed onset. The patient was hospitalized due to influenza pneumonia and received low-molecular-weight heparin thromboprophylaxis for 9 days. Seven days after discharge, she was readmitted because of a cerebral sinus vein thrombosis and severe thrombocytopenia. Intracranial bleeding and brain infarction caused her death. DISCUSSION: Autoimmune HIT was confirmed by functional heparin-induced platelet (PLT) activation test. Intracranial bleeding prevented continuous and effective anticoagulation. PLT transfusions were given, although they are generally advised against in HIT patients due to potential risk of thromboembolic events. CONCLUSION: This case presents that testing PLT-activating antibodies both in the presence and in the absence of current heparin treatment helps to diagnose patients with autoimmune HIT. There is conflicting evidence to refuse PLT transfusion when HIT is complicated with life-threatening bleeding.

A controlled survey of less typical long-term consequences after an extensive waterborne epidemic.

BACKGROUND: Extensive backflow of treated wastewater caused household water contamination in a Finnish town in 2007. The drinking water of 9 500 residents became heavily polluted with faecal microbes, resulting in a large gastroenteritis epidemic. Cases of reactive arthritis, milder joint symptoms and prolonged gastrointestinal symptoms were observed after the outbreak. A follow-up survey was performed to study less familiar long-term health consequences within a year from the outbreak. METHODS: The contaminated group comprised a sample of residents of the area with polluted water supply (N = 323) and the control group a sample of residents in a nearby municipality (N = 186). The presence of 20 general symptoms or complaints was inquired by a mail survey. Quarterly prevalence of each symptom or complaint was measured. Twelve of these proceeded to further analysis. RESULTS: The response rate was 53% (323/615) in the contaminated group and 54% (186/343) in the control group. Rash, eye irritation, heartburn and weight loss were more prevalent in the contaminated group during the first year quarter. In the last year quarter, only eye irritation was significantly more common in the contaminated group. CONCLUSION: The excess prevalence of four complaints at the first year quarter can be explained by acute gastroenteritis or intensive water chlorination. The excess prevalence of eye irritation at the fourth year quarter cannot be explained by chlorination anymore but might be a sign of co-existing reactive joint disease. In general, long-term consequences of the outbreak can be considered minor in terms of the surveyed symptoms or complaints.

Interferons Induce STAT1-Dependent Expression of Tissue Plasminogen Activator, a Pathogenicity Factor in Puumala Hantavirus Disease.

Hantaviruses are zoonotic viruses that show various degrees of vasculopathy in humans. In this study, we analyzed the regulation of 2 fibrinolytic parameters, tissue plasminogen activator (tPA) and its physiological inhibitor, plasminogen activator inhibitor 1 (PAI-1), in Puumala hantavirus (PUUV)-infected patients and in human microvascular endothelial cells. We detected strong upregulation of tPA in the acute phase of illness and in PUUV-infected macaques and found the tPA level to positively correlate with disease severity. The median levels of PAI-1 during the acute stage did not differ from those during the recovery phase. In concordance, hantaviruses induced tPA but not PAI-1 in microvascular endothelial cells, and the induction was demonstrated to be dependent on type I interferon. Importantly, type I and II interferons directly upregulated tPA through signal transducer and activator of transcription 1 (STAT1), which regulated tPA gene expression via a STAT1-responsive enhancer element. These results suggest that tPA may be a general factor in the immunological response to viruses.

Spleen enlargement is a common finding in acute Puumala hantavirus infection and it does not associate with thrombocytopenia.

The pathogenesis of thrombocytopenia in Puumala hantavirus (PUUV) infection is probably multifactorial. We aimed to evaluate the possible spleen enlargement during acute PUUV infection, and to determine its association with thrombocytopenia and disease severity. Magnetic resonance imaging (MRI) of the spleen was performed in 20 patients with acute PUUV infection. MRI was repeated 5-8 months later. The change in spleen length was compared with markers describing the severity of the disease. In all patients, the spleen length was increased in the acute phase compared with the control phase (median 129 mm vs 111 mm, p < 0.001). The change correlated with maximum C-reactive protein value (r = 0.513, p = 0.021) and inversely with maximum leukocyte count (r = -0.471, p = 0.036), but not with maximum serum creatinine level or minimum platelet count. Enlarged spleen, evaluated by MRI, was shown to be a common finding during acute PUUV infection. However, it does not associate with thrombocytopenia and acute kidney injury.

Risk of lymphoid malignancies increased after Puumala virus infection in Finland, 2009-2019: A retrospective register-based cohort study.

OBJECTIVES: The Puumala virus (PUUV) is a hantavirus that causes hemorrhagic fever with renal syndrome. Studies showing an increased risk of lymphoid malignancies after hantavirus infection, together with the observation that PUUV infects B cells, motivated us to study the risk of lymphoid malignancies after PUUV infection. METHODS: We linked data from the Finnish Cancer Registry and National Infectious Diseases Register for 2009-2019. We used a time-dependent Cox regression model to evaluate the hazard of the lymphoid malignancies grouped according to the HAEMACARE classification. RESULTS: We identified 68 cases of lymphoid malignancies after PUUV infection among 16,075 PUUV-infected individuals during 61,114,826 person-years of observation. A total of 10 cases occurred within 3-<12 months and 38 within 1-<5 years after PUUV infection, and the risk of lymphoid malignancies increased with hazard ratios (HRs) of 2.0 (95% confidence interval [CI], 1.1-3.7) and 1.6 (95% CI, 1.2-2.3), respectively. The group of mature B cell neoplasms showed an increased risk 3-<12 months and 1-<5 years after PUUV infection, HR 2.2 (95% CI, 1.2-4.3) and HR 1.8 (95% CI, 1.3-2.5), respectively. CONCLUSION: PUUV infection is associated with lymphoid malignancies in the Finnish population, supporting the earlier studies. Further research is required to understand the pathophysiological mechanisms behind this association.

ABO and Rhesus Blood Groups in Acute Puumala Hantavirus Infection.

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome. We aimed to evaluate whether ABO and rhesus blood groups associate with the susceptibility or the severity of PUUV infection. We analyzed blood groups in 289 adult patients treated in Tampere University hospital due to PUUV infection during the years 1982-2017. Patients' blood group distribution was compared to that of healthy, voluntary blood donors living in the Tampere University Hospital responsibility area (n = 21,833). The severity of PUUV infection, as judged by the severity of acute kidney injury (AKI), thrombocytopenia, inflammation, capillary leakage, and the length of hospital care, was analyzed across the groups. The ABO and rhesus blood group distributions did not differ between the patients and blood donors. Patients with non-O blood groups had lower systolic blood pressure compared to patients with blood group O, but there was no difference in other markers of capillary leakage or in the severity of AKI. Minor deviations in the number of platelets and leukocytes were detected between the O and non-O blood groups. To conclude, patients with blood group O may be less susceptible to hypotension, but otherwise blood groups have no major influences on disease susceptibility or severity during acute PUUV infection.

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.

Coagulopathy in Acute Puumala Hantavirus Infection.

Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome (HFRS), also called nephropathia epidemica (NE), which is mainly endemic in Europe and Russia. The clinical features include a low platelet count, altered coagulation, endothelial activation, and acute kidney injury (AKI). Multiple connections between coagulation pathways and inflammatory mediators, as well as complement and kallikrein-kinin systems, have been reported. The bleeding symptoms are usually mild. PUUV-infected patients also have an increased risk for disseminated intravascular coagulation (DIC) and thrombosis.

Elevated serum antiphospholipid antibodies in adults with celiac disease.

BACKGROUND AND AIMS: An increased incidence of thrombosis is suggested in celiac disease. We explored serum levels of antiphospholipid antibodies in untreated and treated adult celiac disease patients. METHODS: A cohort of 179 biopsy-proven celiac disease patients (89 untreated, 90 on long-term gluten-free diet) and 91 non-celiac controls underwent clinical examination, assessment of celiac serology and enzyme immunoassay testing for anticardiolipin IgG and IgM, prothrombin IgG, and phosphatidylserine-prothrombin IgG and IgM. RESULTS: The level of antiphospholipid antibodies was higher in celiac disease patients compared with controls: anticardiolipin IgG 4.9 (0.7-33.8) vs 2.2 (0.4-9.6) U/ml, antiprothrombin IgG 2.9 (0.3-87.8) vs 2.1 (0.5-187.0) U/ml, antiphosphatidylserine-prothrombin IgG 6.9 (0.0-54.1) vs 2.3 (0.5-15.1) U/ml; p < 0.05 for all. Anticardiolipin IgG, antiprothrombin IgG and antiphosphatidylserine-prothrombin IgG were higher in treated compared with untreated patients. The phenotype of celiac disease at presentation (gastrointestinal symptoms, malabsorption or anemia, and extraintestinal symptoms or screen-detected disease) had no effect on the level of serum antiphospholipid antibodies. CONCLUSION: The serum level of antiphospholipid antibodies is increased in adults with celiac disease. The higher level of antibodies in treated patients suggests that the increase is not gluten-dependent. The prothrombotic role of antiphospholipid antibodies in celiac disease warrants further studies.

Diminished coagulation capacity assessed by calibrated automated thrombography during acute Puumala hantavirus infection.

: Coagulation abnormalities are associated with Puumala-virus-induced hemorrhagic fever with renal syndrome (PUUV-HFRS). We evaluated the coagulation capacity of plasma during acute PUUV-HFRS by measuring thrombin generation using calibrated automated thrombography (CAT). The study cohort comprised 27 prospectively collected, consecutive, hospital-treated patients with acute PUUV infection. Blood samples were drawn in the acute phase and at the control visit approximately 5 weeks later. To evaluate thrombin generation, the lag time of initiation, endogenous thrombin potential (ETP), and peak and time to peak thrombin concentration were assessed by CAT in platelet poor plasma without corn trypsin inhibitor. Plasma levels of D-dimer, fibrinogen and prothrombin fragments (F1 + 2) were also evaluated. When the acute phase was compared with the control phase, ETP was decreased (median 1154 nmol/l/min, range 67-1785 vs. median 1385 nmol/l/min, range 670-1970; P < 0.001), while the lag time was prolonged (median 3.8 min, range 2.1-7.7 vs. median 2.9 min, range 2.0-4.1; P < 0.001). Low ETP correlated with low peak thrombin concentration (r = 0.833, P < 0.001). Prolonged time to peak associated with the lag time (r = 0.78, P < 0.001). ETP was associated with thrombocytopenia (r = 0.472, P = 0.015) and weakly with fibrinogen level (r = 0.386, P = 0.047). The measured CAT parameters did not associate with D-dimer and F1 + 2 levels. Decreased ETP together with low peak and prolonged lag time indicate decreased plasma potential for thrombin generation in vitro. Together with low platelet count and enhanced fibrinolysis, this further refers to altered blood coagulation and increased propensity toward bleeding in acute PUUV-HFRS.

Kidney disease in Puumala hantavirus infection.

Acute kidney injury (AKI) remains a predominant clinical expression of nephropathia epidemica (NE). Its pathogenesis is not yet fully understood. Here, we describe the tissue injury comprehensively and present new data aimed to characterize the injury and explain its pathophysiology. When compared to tubulointerstitial nephritis of a wide variety of other aetiologies, a high degree of proteinuria is a distinguished trait of NE, a finding that is also helpful in the clinical suspicion of the disease. Recently, novel biomarkers for the prediction of severe AKI, including neutrophil gelatinase-associated lipocalin (NGAL), have been identified and ultrastructural tissue changes have been more accurately described. A role for soluble urokinase-type plasminogen activator (suPAR) in the pathogenesis of NE has been suggested, and data on gene polymorphisms, in relation to the severity of AKI have been presented. Smoking is a risk factor for NE and smoking is also associated with aggravated AKI in NE. Although no specific treatment is in sight, recent case reports concerning therapy directed against vascular permeability and vasodilation are of interest. In fact, future work trying to explain the pathophysiology of AKI might need concentrated efforts towards the mechanisms of increased vascular permeability and vasodilatation, which irrespective of organ manifestation, are two major determinants of NE.

Haematuria is a marker for the severity of acute kidney injury but does not associate with thrombocytopenia in acute Puumala hantavirus infection.

BACKGROUND: Puumala hantavirus (PUUV) causes haemorrhagic fever with renal syndrome characterized by thrombocytopenia, capillary leakage and acute kidney injury (AKI) with proteinuria and haematuria. Although the typical histologic lesion is acute tubulointerstitial nephritis, the amount of glomerular proteinuria predicts the severity of upcoming AKI. Here, we studied the associations of haematuria and proteinuria with the severity of emerging AKI, thrombocytopenia and markers of coagulation and fibrinolysis in PUUV infection. METHODS: We examined 205 consecutive patients treated for serologically confirmed acute PUUV infection at Tampere University Hospital during 1997-2014. The patients were divided into three groups according to the combined positive result in urine haemoglobin and albumin dipstick tests: 0-2 + (n = 58), 3-4 + (n = 100) and 5-6 + (n = 47). RESULTS: The medians of maximum creatinine concentrations in the three groups were: 0-2 + 100 µmol/L (range 52-1499), 3-4 + 204 µmol/L (range 65-1071) and 5-6 + 361 µmol/l (range 51-1285) (p < .001). The number of blood platelets (p = .069), and the levels of fibrinogen, prothrombin fragments F1 + 2 and d-dimer (p = .602, p = .113, p = .289, respectively) were not significantly different between the groups. When the amount of haematuria in the dipstick test was examined separately, no association with thrombocytopenia was detected (p = .307 between groups 0, 1+ and 2-3+). CONCLUSIONS: Combined positive result of haematuria and proteinuria in the dipstick test at hospital admission predicted the severity of upcoming AKI in acute PUUV infection. As haematuria was not associated with the severity of thrombocytopenia, it did not indicate increased bleeding tendency, but was rather a marker of acute kidney injury.

A minor role of asparaginase in predisposing to cerebral venous thromboses in adult acute lymphoblastic leukemia patients.

Cerebral venous thrombosis (CVT) covers up to a third of all venous thromboses (VTs) detected in patients with acute lymphoblastic leukemia (ALL). It usually hampers patients' lives and may also endanger efficient leukemia treatment. Although many factors have been suggested to account for an elevated risk of VTs in patients with ALL, there still is a lack of studies focusing on CVTs and especially in the setting of adult ALL patients. We studied in our retrospective population-based cohort the occurrence, characteristics, as well as risk factors for VTs in 186 consecutively diagnosed Finnish adult ALL patients treated with a national pediatric-inspired treatment protocol ALL2000. In the risk factor analyses for VTs we found a distinction of the characteristics of the patients acquiring CVT from those with other kinds of VTs or without thrombosis. In contrast to previous studies we were also able to compare the effects of asparaginase in relation to CVT occurrence. Notably, more than half of the CVTs were diagnosed prior the administration of asparaginase which accentuates the role of other risk factors on the pathophysiology of CVT compared to truncal or central venous line (CVL) VTs in adult ALL patients.

Thrombocytopenia associates with the severity of inflammation and variables reflecting capillary leakage in Puumala Hantavirus infection, an analysis of 546 Finnish patients.

BACKGROUND: Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) in humans. Hantavirus infections are characterized by thrombocytopenia. Our objective was to assess the association of thrombocytopenia with disease severity in HFRS induced by Puumala hantavirus (PUUV). METHODS: Altogether 546 patients treated for acute serologically confirmed PUUV infection during 1982-2013 at Tampere University Hospital, Finland, were examined. Blood platelet count was determined daily and analysed in relation to different variables reflecting disease severity. The patients were divided into two groups according to the minimum platelet count: severe thrombocytopenia (<69 × 10(9)/L, i.e. below median) and no severe thrombocytopenia (≥69 × 10(9)/L). RESULTS: Thrombocytopenia (platelet count <150 × 10(9)/L) was detected in 90% of patients, and in 28% of patients platelet count was <50 × 10(9)/L. Patients with severe thrombocytopenia had longer stay (8 versus 7 days, p = 0.002) and greater weight gain (2.8 versus 2.0 kg, p < 0.001) at the hospital, higher blood leukocyte count (11.2 × 10(9)/L versus 9.6 × 10(9)/L, p < 0.001), plasma C-reactive protein (81 versus 59 mg/L, p < 0.001), maximum hematocrit (0.44 versus 0.42, p < 0.001), urinary protein excretion (1.7 versus 1.1 g/24 h, p = 0.002), and lower plasma albumin concentration (27 versus 32 g/L, p < 0.001) than patients without severe thrombocytopenia (comparisons between medians). Maximum creatinine concentration did not differ between patients with or without severe thrombocytopenia (median 235 versus 214 µmol/L, p = 0.217). CONCLUSIONS: The severity of thrombocytopenia associates with the degree of inflammation and variables reflecting capillary leakage, but not with the severity of acute kidney injury in PUUV infected Finnish patients.

Elevated thrombopoietin and platelet indices confirm active thrombopoiesis but fail to predict clinical severity of puumala hantavirus infection.

We evaluated the mechanisms of thrombocytopenia and procoagulant changes in relation with clinical variables in a cohort of patients with acute hantavirus disease.Blood samples of 33 prospectively recruited, consecutive, hospitalized patients with acute Puumala virus-induced hemorrhagic fever with renal syndrome (HFRS) were collected acutely and at the recovery visit (control). Serum thrombopoietin (TPO) and activity of plasma microparticles (MPs) from various cell sources were measured with enzyme-linked immunosorbent assay-based methods. The results were related to data on platelet indices and functions, coagulation variables, and clinical disease.Serum TPO was nearly 4-fold higher acutely compared with the control (median 207 pg/mL, range 56-1258 pg/mL vs. median 58 pg/mL, range 11-241 pg/mL, P < 0.001) and coincided with high mean platelet volume (MPV) and immature platelet fraction (IPF%). Prothrombin fragments and D-dimer were high acutely compared with the control (F1 + 2 median 704 pmol/L, range 284-1875 pmol/L vs. median 249 pmol/L, range 118-556 pmol/L, P < 0.001; D-dimer median 2.8 mg/L, range 0.6-34.0 mg/L vs. median 0.4 mg/L, range 0.2-1.1 mg/L, P < 0.001), and associated with low platelet count and severe acute kidney injury (AKI). MPs' procoagulant activity was high acutely only among patients with mild AKI (plasma creatinine below the median at the time of the measurement).Upregulated TPO together with high MPV and IPF% confirm active thrombopoiesis, but do not predict severity of HFRS. Simultaneously, elevated prothrombin fragments and D-dimer suggest increased consumption of platelets in patients with severe AKI. Activity of platelet-derived MPs in HFRS should be studied with flow cytometry in a larger cohort of patients.

Severe Puumala virus infection in a patient with a lymphoproliferative disease treated with icatibant.

Early identification of patients at risk of a severe course of hantaviral disease and lack of effective medication represent a global challenge in the treatment of this emerging infection. We describe a 67-year-old female patient with a history of chronic lymphoproliferative disease involving the spleen and an extremely severe acute Puumala hantavirus infection. She was treated with the bradykinin receptor antagonist icatibant and recovered. She is the second patient with a spleen abnormality and severe Puumala infection treated with icatibant in our hospital. We suggest that patients with spleen abnormalities may be more susceptible to severe hantavirus disease. The activation of the kinin-kallikrein system and the formation of bradykinin in hantavirus-infected endothelial cells indicate that the role of bradykinin receptor antagonist icatibant in the treatment of hantavirus disease is worth studying.

An outbreak of human metapneumovirus in a rehabilitation center for alcoholics in Tampere, Finland.

Reports of respiratory tract infections in a rehabilitation center for alcoholics triggered the epidemiological investigations in Tampere, Finland. Twenty-nine out of 40 residents (attack rate 73%) and four members of staff fulfilled the case criteria: cough; worsening of dyspnea; or rhinitis with or without fever. Ten cases were hospitalized, one needed treatment in the intensive care unit. All cases recovered. Serum hMPV antibody titer was high (10 240 or more) in 20 (69%) of the 29 tested cases and the difference was significant when compared with the titer measured from the voluntary laboratory personnel (n = 14, p < 0.001). The titers were rising in three out of the five cases from whom coupled samples could be obtained. Rt-PCR for hMPV was positive in three out of the eight tested cases. No other causative agent for the outbreak was detected. The outcome of hMPV infection among institutionalized smoking alcoholics was good with no mortality.

Endothelial Nitric Oxide Synthase G894T Polymorphism Associates with Disease Severity in Puumala Hantavirus Infection.

INTRODUCTION: Hantavirus infections are characterized by both activation and dysfunction of the endothelial cells. The underlying mechanisms of the disease pathogenesis are not fully understood. Here we tested the hypothesis whether the polymorphisms of endothelial nitric oxide synthase, eNOS G894T, and inducible nitric oxide synthase, iNOS G2087A, are associated with the severity of acute Puumala hantavirus (PUUV) infection. PATIENTS AND METHODS: Hospitalized patients (n = 172) with serologically verified PUUV infection were examined. Clinical and laboratory variables reflecting disease severity were determined. The polymorphisms of eNOS G894T (Glu298Asp, rs1799983) and iNOS G2087A (Ser608Leu, rs2297518) were genotyped. RESULTS: The rare eNOS G894T genotype was associated with the severity of acute kidney injury (AKI). The non-carriers of G-allele (TT-homozygotes) had higher maximum level of serum creatinine than the carriers of G-allele (GT-heterozygotes and GG-homozygotes; median 326, range 102-1041 vs. median 175, range 51-1499 µmol/l; p = 0.018, respectively). The length of hospital stay was longer in the non-carriers of G-allele than in G-allele carriers (median 8, range 3-14 vs. median 6, range 2-15 days; p = 0.032). The rare A-allele carriers (i.e. AA-homozygotes and GA-heterozygotes) of iNOS G2087A had lower minimum systolic and diastolic blood pressure than the non-carriers of A-allele (median 110, range 74-170 vs.116, range 86-162 mmHg, p = 0.019, and median 68, range 40-90 vs. 72, range 48-100 mmHg; p = 0.003, respectively). CONCLUSIONS: Patients with the TT-homozygous genotype of eNOS G894T had more severe PUUV-induced AKI than the other genotypes. The eNOS G894T polymorphism may play role in the endothelial dysfunction observed during acute PUUV infection.