Clinical Characteristics of EGPA Patients in Comparison to GPA Subgroup with Increased Blood Eosinophilia from POLVAS Registry.

Objective: To characterize the eosinophilic granulomatosis with polyangiitis (EGPA) population from the POLVAS registry depending on ANCA status and diagnosis onset, including their comparison with the granulomatosis with polyangiitis (GPA) subset with elevated blood eosinophilia (min. 400/µl) (GPA HE) to develop a differentiating strategy. Methods: A retrospective analysis of the POLVAS registry. Results: The EGPA group comprised 111 patients. The ANCA-positive subset (n = 45 [40.54%]) did not differ from the ANCA-negative one in clinics. Nevertheless, cardiovascular manifestations were more common in ANCA-negative patients than in those with anti-myeloperoxidase (MPO) antibodies (46.97% vs. 26.92%, p = 0.045). Patients diagnosed before 2012 (n = 70 [63.06%]) were younger (median 41 vs. 49 years, p < 0.01), had higher blood eosinophilia at diagnosis (median 4,946 vs. 3,200/µl, p < 0.01), and more often ear/nose/throat (ENT) and cardiovascular involvement. GPA HE comprised 42 (13.00%) out of 323 GPA cases with reported blood eosinophil count. Both GPA subsets had a lower prevalence of respiratory, cardiovascular, and neurologic manifestations but more often renal and ocular involvement than EGPA. EGPA also had cutaneous and gastrointestinal signs more often than GPA with normal blood eosinophilia (GPA NE) but not GPA HE. The model differentiating EGPA from GPA HE, using ANCA status and clinical manifestations, had an AUC of 0.92, sensitivity of 96%, and specificity of 95%. Conclusion: Cardiovascular symptoms were more prevalent in the ANCA-negative subset than in the MPO-ANCA-positive one. Since EGPA and GPE HE share similarities in clinics, diagnostic misleading may result in an inappropriate therapeutic approach. Further studies are needed to optimize their differentiation and tailored therapy, including biologics.

Activity of granulomatosis with polyangiitis and its correlation with mTOR phosphoproteomics in neutrophils.

Introduction: Granulomatosis with polyangiitis (GPA) is a small vessel vasculitis with a complex pathomechanism. Organ damage in GPA is also mediated by extracellular trap formation (NETosis). We analyzed the functional status of phosphoproteins modulating NETosis in neutrophils by the mammalian target of rapamycin (mTOR) pathway in GPA along with NETosis biomarkers. Methods: Phosphoproteins levels measured in isolated neutrophils from 42 patients with GPA (exacerbation n=21; remission n=21) and 21 healthy controls were compared to serum biomarkers of the disease. Results: Neutrophils in active disease manifested lowered levels of phosphorylated mTOR(Ser2448), PTEN(Ser380) and ULK1(Ser555), whereas phosphorylated GSK-3α/ß(Ser21/Ser9) was elevated. Exacerbation of GPA was characterized by elevated neutrophil dsDNA in serum, circulating mitochondrial DNA, and DNA-MPO complexes. A significant negative correlation between mTOR or PTEN phosphoproteins and biomarkers of GPA activity was also present, reflecting the clinical activity score of GPA. Positive correlations between phosphorylated GSK-3 α/ß and circulating mtDNA, DNA-MPO complexes, neutrophil-released dsDNA, or circulating proteins were also significant. Increased serum levels of IGFBP-2, TFF-3, CD147, and CHI3L1 accompanied GPA exacerbation, whereas DPP-IV levels were the lowest in active GPA. Using a principal component analysis basigin, PTEN and mTOR had the highest loadings on the discrimination function, allowing classification between active, remission, and control subjects with 98% performance. Conclusions: We present evidence that inhibited mTOR signaling accompanies NETosis in patients with GPA. The functional status of phosphoproteins suggests simultaneous activation of NETosis and autophagy. These results give rise to the study of autophagy as a mechanism underlying granuloma formation in GPA.

Functional magnetic resonance imaging for the assessment of autonomic dysfunction in patients with antineutrophil cytoplasmic antibody-associated vasculitides.

INTRODUCTION: Nervous system involvement is common in antineutrophil cytoplasmic antibody-associated vasculitides (AAV). While the involvement of the peripheral and central nervous system is well described, it is still unclear how and to what extent the autonomic nervous system (ANS) is affected. Functional magnetic resonance imaging (fMRI) can provide information on both structure and potential damage of the brain, as well as on the function of selected brain centers. OBJECTIVES: The aim of this study was to investigate the ANS dysfunction in AAV patients and its correlation with the results of fMRI performed during the Valsalva maneuver. PATIENTS AND METHODS: A total of 31 patients with AAV and 30 healthy controls were enrolled in the study. Each participant completed the Composite Autonomic Symptom Score (COMPASS)-31 questionnaire. MRI was performed using a 3T scanner. The participants were asked to perform the Valsalva maneuver according to the fixed protocol, and their airway pressure was monitored. During the maneuver, fMRI data were collected. The generalized least­ squares time series analysis and the region of interest (ROI) analysis were subsequently performed. RESULTS: The patients with AAV had a higher median COMPASS­ 31 score than the controls (12.86 vs 2.99, respectively; P <0.01). Structural MRI investigation did not reveal any significant differences between the groups. The brain centers involved in ANS function were detected during fMRI; however, the ROI analysis showed no differences between the study patients and controls. CONCLUSIONS: The patients with AAV reported symptoms related to the ANS dysfunction; however, no differences with respect to the functioning of the ANS brain centers were demonstrated between these patients and healthy controls in the fMRI study during the Valsalva maneuver.

Treatment outcomes in Polish COVID-19 patients requiring hospitalisation in the intensive care unit: a single-centre retrospective study.

INTRODUCTION: COVID-19 has disturbed the functioning of Polish healthcare for the past two years. Due to the high proportion of patients requiring admission to the intensive care unit (ICU), these wards are particularly overwhelmed and are considered the bottleneck of the healthcare system. The aim of this study was to describe clinical outcomes of critically ill patients treated in a single tertiary ICU in Poland, assess factors associated with mortality and compare outcomes of patients treated during the 2nd and 3rd waves of the pandemic. MATERIAL AND METHODS: This is a retrospective single-centre study including patients admitted to the ICU between October 2020 and May 2021 (the 3rd wave) with confirmed SARS-CoV-2 infection. Patients were followed up until death or 90 days after ICU admission. The co-primary endpoints of this study included ICU, 30-day and 90-day mortality. RESULTS: We enrolled 108 patients at a mean age of 64.3 (SD = 12) years, the majority of whom were male (63.9%). Mortality in the ICU, after 30 days and 90 days was 44.4% (48/108), 50.0% (54/108), and 57.9% (62/108), respectively. Mortality at 90 days was associated with increasing age (OR = 3.97, 95% CI: 1.87-8.41) and was significantly higher during the 2nd wave (65.6 vs. 46.5%, log-rank P = 0.043) compared to the 3rd wave of the pandemic. CONCLUSIONS: This retrospective single-centre study confirms the high mortality rate among critically ill patients with COVID-19. Moreover, it suggests a significant association between 90-day mortality and increasing age as well as differences in mortality between the 2nd and 3rd waves of the pandemic in Poland.

Respiratory involvement in antineutrophil cytoplasmic antibody-associated vasculitides: a retrospective study based on POLVAS registry.

OBJECTIVES: The study aimed to characterise the Polish population of (ANCA)-associated vasculitides (AAV) with respiratory involvement (RI), in comparison to the subgroup without lung manifestations and the other cohorts. METHODS: Retrospective analysis of the Polish population of AAV with RI was conducted, based on data from the POLVAS registry. Standard descriptive statistics, χ2 test, and Mann-Whitney U test were used to perform comparisons. RESULTS: Among 461 cases qualified to this study, there were 316 cases with RI (68.5%), 206 with granulomatosis with polyangiitis (GPA) (65.2%), 80 with eosinophilic granulomatosis with polyangiitis (EGPA) (25.3%) and 30 with microscopic polyangiitis (MPA) (9.5%). Proportion of RI in GPA, MPA, and EGPA accounted for 67.8%; 40.0%; 97.6%, respectively. The number of relapses was higher in the RI group (median 1.0 vs. 0.0; p=0.01). In the subgroup of combined GPA and MPA with RI, the trends toward higher proportion of deaths (11.7% vs. 5.7%; p=0.07), relapses requiring hospitalisation (52.2% vs. 42.4%, p=0.07) and relapses requiring admission to the intensive care unit (5.6% vs. 1.4%, p=0.09) were observed, median maximal concentration of CRP was higher (46 vs. 25 mg/l; p=0.01) and more aggressive treatment was administered. CONCLUSIONS: Prevalence of RI in the Polish population of AAV is similar to the values reported in the literature, however, the proportion observed in GPA is closer to those presented in Asian than Western European cohorts. RI seems to be associated with a more severe course of disease and its presence prompts more aggressive treatment.

Prognostic value of preoperative electrocardiography in predicting myocardial injury after vascular surgery.

BACKGROUND: The current European guidelines recommend that a preoperative electrocardiogram (ECG) should be performed routinely in patients scheduled for high-risk surgery. However, the evidence regarding ECG as a predictor of perioperative cardiac complications is weak. AIM: To evaluate the association of preoperative ECG with short- and long-term outcomes in patients undergoing high-risk vascular procedures. METHODS: This was a substudy of the international Vascular events In noncardiac Surgery patIents cohort evaluatioN (VISION) Study and included consecutive patients undergoing vascular procedures in a single tertiary center. In each patient, a preoperative 12-lead ECG was evaluated by two experienced clinicians following the Polish Cardiac Society recommendations. We performed routine perioperative troponin monitoring at five time points (one preoperative and four postoperative measurements) to evaluate whether preoperative ECG abnormalities are associated with myocardial injury after noncardiac surgery (MINS) and 1-year major adverse cardiovascular events (MACE) including cardiac death, myocardial infarction, and stroke. RESULTS: The study group comprised 348 patients, 80.5% of whom were male and the median age (interquartile range [IQR]) was 65 (59-72) years. The incidence of MINS and 1-year MACE was 18.7% and 14.4%, respectively. Multivariable analysis showed that none of the predefined ECG abnormalities (ST depression, left axis deviation, atrial fibrillation, and bundle branch block) was associated with the incidence of MINS or 1-year MACE. CONCLUSION: This study confirmed that preoperative ECG abnormalities are frequent in patients undergoing high-risk vascular surgery. However, we did not find evidence supporting the relation between preoperative ECG abnormalities and postoperative adverse cardiac outcomes in high-risk patients.

ANCA-associated vasculitis patients treated in Polish intensive care units - retrospective characteristics based on the POLVAS registry.

INTRODUCTION: ANCA-associated vasculitides (AAV) is a group of rare disorders where inflammation and damage of the small blood vessels lead to dysfunction of the supplied organs. In severe flares of the disease patients may require intensive care unit (ICU) admission and treatment. The study aims to characterize Polish patients with AAV who were admitted to the ICU and compare them to the others. MATERIAL AND METHODS: An observational, retrospective study based on the POLVAS - registry of Polish adult patients with AAV was carried out. Patients admitted to the ICU (ICU group) were identified and compared with the patients who did not require ICU admission (non-ICU group). Characteristics and comparison between groups were made using standard statistic descriptive methods. RESULTS: 30 patients admitted to the ICU were identified among 573 cases included in the registry. All patients in the ICU group with available data were ANCA positive. The clinical manifestations related to the ICU admission were respiratory, renal and central nervous system involvement. The treatment regimen for remission induction was similar in both groups. Almost half of the patients in the ICU-group (48.3%) required dialysis, whereas in the non-ICU group it was 21.8% (P = 0.01). Infections were also more frequent in the ICU group (72.4% vs. 36.9% P < 0.001). The mortality rate among patients who needed ICU treatment was significantly higher when compared to the rest of the patients (53.6% vs. 7.8%; P < 0.001). CONCLUSIONS: In the Polish AAV cohort one in twenty patients required ICU admission. This group was characterized by multiple organ involvement and high mortality.

Treatment and its side effects in ANCA-associated vasculitides - Study based on POLVAS registry data.

PURPOSE: The aim of this study is to present the treatment modalities and associated side effects in a Polish nation-wide ANCA-associated vasculitides (AAV) patients' cohort. MATERIALS AND METHODS: Retrospective analysis of patients diagnosed with AAV between 1990 and 2016, included in the POLVAS registry was performed. Standard descriptive statistic methods were used with an emphasis on the treatment modalities. RESULTS: There were 625 patients diagnosed with AAV included in this study: 417 cases of granulomatosis with polyangiitis (GPA; 66.7%), 106 cases of microscopic polyangiitis (MPA; 17.0%) and 102 cases of eosinophilic granulomatosis with polyangiitis (EGPA; 16.3%). The mean age at the date of diagnosis was 50.4 (±15.7) years and the median observational period amounted to 4.0 (2.0-8.0) years. Glucocorticosteroids (GCs) were the medicaments most frequently used for remission induction (593/622; 95.3%), followed by cyclophosphamide (487/622; 78.3%), rituximab (44/622; 7.1%), and methotrexate (39/622; 6.3%). GCs were also most frequently administered for maintenance therapy (499/592; 84.3%), followed by azathioprine (224/592; 37.8%), methotrexate (136/592; 23.0%) and mycophenolate mofetil (99/592; 16.7%). The median cumulative doses of cyclophosphamide and rituximab equalled 7.99 g (4.18-14.0) and 2000 mg (1500-2800), respectively. The most commonly observed adverse events included: infections - 214/551 cases (38.8%), which were associated with the time of observation (OR = 1.05; 95% CI 1.01-1.10), the use of GCs intravenous pulses (OR = 2.76; 95% CI 1.68-4.54) and need for haemodialysis (OR = 1.73; 95% CI 1.10-2.71). CONCLUSIONS: Polish patients with AAV were predominantly treated according to appropriate guidelines. The most frequent adverse events were typical for usually administered immunosuppressive treatment.

Clinical profile of patients with systemic autoimmune diseases treated in the intensive care unit who developed diffuse alveolar haemorrhage - an observational retrospective cohort study.

BACKGROUND: Patients with autoimmune diseases constitute a relatively low percentage of the intensive care unit (ICU) population but their prognosis is particularly poor, partially due to involvement of multiple organs as well as complications related to immunosuppressive treatment. Diffuse alveolar haemorrhage (DAH) is one of the most life-threatening presentations of autoimmune diseases, associated with worse outcomes. The aim of this study is to report about clinical factors associated with DAH in the ICU setting and to assess the survival in 5-year follow-up. METHODS: This is an observational, retrospective, cohort study performed in the ICU of the University Hospital in Krakow, Poland. We enrolled 21 patients treated for the first time in the ICU due to autoimmune diseases, who developed DAH. Severity of patients' clinical condition was assessed on the first day using APACHE II, APACHE III, SAPS II and SOFA scores. Mortality was assessed during the ICU stay and in 5-year follow-up. RESULTS: The median age of the study population was 53 (18-78) years and 13 (61.9%) of patients were females. The most common diagnoses were granulomatosis with polyangiitis (38.1%), systemic lupus erythematosus (23.8%) and microscopic polyangiitis (14.3%). Most of the patients required mechanical ventilation (85.7%), renal replacement therapy (57.1%) and blood product transfusions (71.4%). Mortality in the ICU was 52.4%, while in both 1-year and 5-year follow-up it was 76.2%. CONCLUSION: Patients who develop DAH in the course of autoimmune diseases and are treated in the ICU have a poor prognosis and often require advanced therapeutic measures.

Oral manifestations of granulomatosis with polyangiitis - Clinical and radiological assessment.

BACKGROUND/PURPOSE: Granulomatosis with polyangiitis (GPA) is a type of primary systemic vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). GPA mainly affects medium and small vessels and may manifest in different organs, most commonly upper respiratory tract. Oral lesions occur in 6-13% of GPA patients and might be the first symptom observed by the patient. This study presents the evaluation of orofacial manifestations of patients with GPA. MATERIALS AND METHODS: Prospective study was conducted between June 2014 and November 2017 in Department of Allergy and Immunology at University Hospital in Krakow. Patients diagnosed with GPA, after medical assessment, were examined including precise dental inspection, bacterial and fungal flora of oral cavity evaluation and Cone Beam Computed Tomography (CBCT) imaging. RESULTS: Nine patients were enrolled in the study. Characteristic for GPA strawberry gingivitis was observed in one patient. Bone destruction and inflammatory lesions in paranasal sinuses was confirmed by CBCT in 55.6% of patients. Fungal infection was revealed in 66.7% of patients. CONCLUSION: These findings oblige dentists to consult patient with laryngologist or internal medicine physician to establish further diagnostic approach, because early diagnosis of GPA is crucial for implementing appropriate treatment and preventing chronic organ damage.

Frailty is associated with an increased mortality among patients ≥ 80 years old treated in Polish ICUs

BACKGROUND: The increasing population of very old intensive care patients (VIPs) is a major challenge currently faced by clinicians and policymakers. Reliable indicators of VIPs' prognosis and purposefulness of their admission to the intensive care unit (ICU) are urgently needed. METHODS: This is a report from the Polish sample of the VIP1 multicentre cohort study (NCT03134807). Patients ≥ 80 years of age admitted to the ICU were included in the study. Information on the type and reason for admission, demographics, utilisation of ICU procedures, ICU length of stay, organ dysfunction and the decision to apply end-of-life care was collected. The primary objective was to investigate the impact of frailty syndrome on ICU and 30-day survival of VIPs. Frailty was assessed with the Clinical Frailty Scale (≥ 5 points on a scale of 1-9). RESULTS: We enrolled 272 participants with a median age of 84 (81-87) years. Frailty was diagnosed in 170 (62.5%) patients. The ICU and 30-day survival rates were equal to 54.6% and 47.3% respectively. Three variables were found to significantly increase the odds of death in the ICU in a multiple logistic regression model: SOFA score (OR = 1.16; 95%CI 1.16-1.24), acute mode of admission (OR = 5.1; 95%CI 1.67-15.57) and frailty (OR = 2.25; 95%CI 1.26-4.01). CONCLUSION: Measuring frailty in critically ill older adults can facilitate making more informed clinical decisions and help avoid futile interventions.

Patients with small-vessel vasculitides have the highest mortality among systemic autoimmune diseases patients treated in intensive care unit: A retrospective study with 5-year follow-up.

PURPOSE: Systemic autoimmune diseases are a heterogeneous group of disorders associated with dysfunction of multiple organs and unpredictable course. Complicated management and treatment become even more challenging when patients require critical care. This study aims to compare outcomes of small-vessel vasculitides (SVV) and other systemic autoimmune diseases (SAD) patients admitted to the intensive care unit (ICU). MATERIALS AND METHODS: Retrospective, observational study conducted in the ICU of Allergy and Immunology Department at the University Hospital in Krakow, Poland, between years 2001-2014, with 5-years follow-up and no lost to follow-up patients. RESULTS: 74 patients with autoimmune diseases were enrolled in the study - 23 with SVV and 51 with SAD. Patients in the SVV group achieved higher scores in APACHE II and III SAPS II and SOFA at ICU admission. The SVV patients required renal replacement techniques, blood products transfusion and immunosuppressive treatment more often. SVV patients had higher ICU mortality (60.9% vs. 35.3%, p = .04), however after discharge from ICU, in long term follow-up (1 year and 5 years) mortality was similar in both studied groups. CONCLUSIONS: Among systemic autoimmune diseases small vessel vasculitides appear to be associated with the highest ICU mortality, higher requirement for advanced procedures and aggressive immunosuppressive therapy.

Effectiveness of plasmapheresis in ANCA clearance in patients with ANCA-associated vasculitides.

Introduction: Plasmapheresis is a therapeutic method based on removal of high molecular weight particles from blood. It is used in a variety of clinical entities in which pathogenic role of such particles has been proven e.g. ANCA-associated vasculitides (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]). Efficacy of plasmapheresis in ANCA antibodies removal and its impact on disease activity has not been adequately investigated so far. Influence of antibodies levels on disease activity also remains unknown. Objectives: Analysis of plasmapheresis effect on serum ANCA levels in patients with ANCA-associated vasculitides. Patients and methods: Seven patients with diagnoses of ANCA-associated vasculitides were enrolled in the study between November 2015 and April 2016. All of them underwent plasmapheresis procedures. Serum ANCA levels were measured before and after plasmaphereses using fluoroimmunoenzymatic assay (FEIA). Disease activity was assessed using Birmingham Activity Vasculitis Score; BVAS ver. 3 before first plasma exchange procedure. Results: Patients in disease exacerbation (BVAS 5-10) with positive ANCA antibodies were enrolled in the study: 2 patients with GPA and 5 patients with MPA. Number of performed plasmapheresis procedures ranged from 5 to 7 (median=7). Decrease of serum antibodies concentration was observed in all patients (mean decrease of 88.3% (±10.1%)) with statistically significant difference in mean antibodies concentration before and after plasmapheresis procedures (113.0 vs 15.4; p=0.014). Conclusions: Plasmapheresis is an effective method of ANCA antibodies removal in patients in disease exacerbation.