Estimated plasma volume status in COVID-19 patients and its relation to comorbidities and clinical outcomes.

Blood plasma is a large reservoir of circulating mediators of inflammation and its expansion has been associated with unfavorable outcomes in patients with inflammatory and cardiovascular diseases. The aim of this study was to determine clinical and prognostic value of estimated plasma volume status (ePVS) in hospitalized patients with COVID-19. We retrospectively investigated 5871 consecutive COVID-19 patient hospitalized in our tertiary-level institution in period 3/2020-6/2021. ePVS was determined using the Strauss-derived Duarte formula and was correlated with clinical characteristics and unwanted outcomes. Median ePVS was 4.77 dl/g with interquartile range 4.11-5.74. Higher ePVS was significantly associated with older age, female sex, higher comorbidity burden, worse functional status, less severe COVID-19 clinical presentation with lower severity and longer duration of symptoms, but more pronounced inflammatory profile with higher C-reactive protein, interleukin-6 and D-dimer levels (P < 0.05 for all analyses). In the multivariate regression analysis U shaped relationship of ePVS with mortality was revealed, present independently of age, sex, COVID-19 severity and comorbidity burden. In addition, higher ePVS was independently associated with higher tendency for mechanical ventilation, intensive care unit treatment, venous thromboembolism, major bleeding and bacteriemia and lower ePVS was independently associated with tendency for arterial thrombotic events. Higher ePVS, indicative of plasma volume expansion and inflammatory cytokine accumulation, may predispose respiratory deterioration and venous thromboembolism, despite less severe initial clinical presentation. Lower ePVS, indicative of hemoconcentration, may predispose arterial thrombotic events. Both may be associated with higher mortality in hospitalized COVID-19 patients.

Ultrasonic Evaluation of Diaphragm in Patients with Systemic Sclerosis.

The diaphragm is the most important muscle in respiration. Nevertheless, its function is rarely evaluated. Patients with systemic sclerosis (SSc) could be at risk of diaphragmatic dysfunction because of multiple factors. These patients often develop interstitial lung disease (SSc-ILD) and earlier studies have indicated that patients with different ILDs have decreased diaphragmatic mobility on ultrasound (US). This study aimed to evaluate diaphragmatic function in SSc patients using US with regard to the ILD, evaluated with the Warrick score on high-resolution computed tomography (HRCT), and to investigate associations between ultrasonic parameters and dyspnea, lung function, and other important clinical parameters. In this cross-sectional study, we analyzed diaphragm mobility, thickness, lung function, HRCT findings, Modified Medical Research Council (mMRC) dyspnea scale, modified Rodnan skin score (mRSS), autoantibodies, and esophageal diameters on HRCT in patients with SSc. Fifty patients were enrolled in the study. Patients with SSc-ILD had lower diaphragmatic mobility in deep breathing than patients without ILD. The results demonstrated negative correlations between diaphragmatic mobility and mMRC, mRSS, anti-Scl-70 antibodies, esophageal diameters on HRCT, and a positive correlation with lung function. Patients with SSc who experience dyspnea should be evaluated for diaphragmatic dysfunction for accurate symptom phenotyping and personalized pulmonary rehabilitation treatment.

Alpha-gal syndrome-Food or drug allergy: A case report.

Alpha-gal syndrome is an immunoglobulin E-mediated hypersensitivity characterized by delayed allergic reactions to ingested products containing alpha-gal carbohydrate. We present a patient with recurrent urticaria and suspected repaglinide hypersensitivity, who was eventually diagnosed with alpha-gal syndrome, wanting to emphasize possible drug allergy misdiagnosis and required caution with the medication choice.

Proton pump inhibitors use prior to COVID-19 hospitalization is associated with higher Clostridioides difficile infection rate.

BACKGROUND: There are uncertainties regarding associations of prior proton pump inhibitor (PPI) use with susceptibility for COVID-19 and risks associated with SARS-CoV-2 infection. We aimed to evaluate the associations of prior PPI use with outcomes in hospitalized patients with COVID-19. RESEARCH DESIGN AND METHODS: We have retrospectively evaluated a total of 5959 consecutively hospitalized patients with COVID-19 from a tertiary-level institution in the period 3/2020-6/2021. Associations of prior PPI use with outcomes of in-hospital mortality, mechanical ventilation, intensive care unit stay, venous thromboembolism, arterial thrombosis, major bleeding, bacteremia, and Clostridioides difficile infection (C. diff.) were evaluated in entire and case-matched cohorts. RESULTS: Among 5959 evaluated patients, there were 1967 (33%) PPI users. In an entire cohort, prior PPI use was associated with higher in-hospital mortality and higher occurrence of C. diff. Association of prior PPI use with mortality diminished, whereas association with C. diff. persisted after multivariable adjustments. In a matched cohort, prior PPI use was associated only with higher risk of C. diff. but not other outcomes in line with multivariable analysis. CONCLUSIONS: Although prior PPI use might not have a significant impact on clinical course and mortality of SARS-CoV-2 infection, it may predispose patients to the development of complications like higher occurrence of C. diff. and thus substantially impact the course of treatment.

Pathogenesis of Extraarticular Manifestations in Rheumatoid Arthritis-A Comprehensive Review.

Rheumatoid arthritis (RA) is among the most prevalent and debilitating autoimmune inflammatory chronic diseases. Although it is primarily characterized by destructive peripheral arthritis, it is a systemic disease, and RA-related extraarticular manifestations (EAMs) can affect almost every organ, exhibit a multitude of clinical presentations, and can even be asymptomatic. Importantly, EAMs largely contribute to the quality of life and mortality of RA patients, particularly substantially increased risk of cardiovascular disease (CVD) which is the leading cause of death in RA patients. In spite of known risk factors related to EAM development, a more in-depth understanding of its pathophysiology is lacking. Improved knowledge of EAMs and their comparison to the pathogenesis of arthritis in RA could lead to a better understanding of RA inflammation overall and its initial phases. Taking into account that RA is a disorder that has many faces and that each person experiences it and responds to treatments differently, gaining a better understanding of the connections between the joint and extra-joint manifestations could help to create new treatments and improve the overall approach to the patient.

Predictors of prolonged hospitalization of COVID-19 patients.

PURPOSE: Despite the importance of hospital bed network during the pandemic, there are scarce data available regarding factors predictive of prolonged length of hospitalization of COVID-19 patients. METHODS: We retrospectively analyzed a total of 5959 consecutive hospitalized COVID-19 patients in period 3/2020-6/2021 from a single tertiary-level institution. Prolonged hospitalization was defined as hospital stay > 21 days to account for mandatory isolation period in immunocompromised patients. RESULTS: Median length of hospital stay was 10 days. A total of 799 (13.4%) patients required prolonged hospitalization. Factors that remained independently associated with prolonged hospitalization in multivariate analysis were severe or critical COVID-19 and worse functional status at the time of hospital admission, referral from other institutions, acute neurological, acute surgical and social indications for admission vs admission indication of COVID-19 pneumonia, obesity, chronic liver disease, hematological malignancy, transplanted organ, occurrence of venous thromboembolism, occurrence of bacterial sepsis and occurrence of Clostridioides difficile infection during hospitalization. Patients requiring prolonged hospitalization experienced higher post-hospital discharge mortality (HR = 2.87, P < 0.001). CONCLUSIONS: Not only severity of COVID-19 clinical presentation but also worse functional status, referral from other hospitals, certain indications for admission, certain chronic comorbidities, and complications that arise during hospital stay independently reflect on the need of prolonged hospitalization. Development of specific measures aimed at improvement of functional status and prevention of complications might reduce the length of hospitalization.

Risks associated with prior oral anticoagulation use in hospitalized COVID-19 patients - A retrospective cohort study on 5392 patients from a tertiary centre.

INTRODUCTION: There are conflicting data on prior oral-anticoagulant (OAC) use and outcomes of hospitalized COVID-19 patients. Due to uncertainties regarding associated risks with the prior OAC use, we have investigated this issue in a large cohort of hospitalized COVID-19 patients from our institution. METHODS: We have retrospectively evaluated a total of 5392 consecutive COVID-19 patients hospitalized in our tertiary center institution in period 3/2020 to 6/2021. Majority of patients received low-molecular-weight-heparin thromboprophylaxis and corticosteroids during hospitalization. Patients' characteristics and clinical outcomes were documented as a part of a hospital registry project and were evaluated according to the prior non-OAC, warfarin and direct oral anticoagulants (DOAC) use. RESULTS: Median age was 72 years, median Charlson comorbidity index (CCI) was 4 points. There were 56.2% male patients. Majority of patients had severe (70.5%) or critical (15.8%) COVID-19 on admission. A total of 84.8% patients did not receive prior OAC, 9% were previously anticoagulated with warfarin and 6.2% were previously anticoagulated with DOACs. In the multivariate regression analyses, prior warfarin use was associated increased in-hospital mortality (OR 1.24, P = 0.048) independently of older age (OR 2.12, P < 0.001), male sex (OR 1.27, P < 0.001), higher CCI (OR 1.26, P < 0.001) and severe or critical COVID-19 on admission (OR 22.66, P < 0.001). Prior DOAC use was associated with higher occurrence of major bleeding (OR 1.72, P = 0.045) independently of higher CCI (OR 1.08, P = 0.017). CONCLUSION: Prior OAC use could be associated with worse clinical outcomes during COVID-19 hospitalization. These phenomena might be OAC type specific and persist after multivariate adjustments.

PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM - A DIAGNOSTIC CHALLENGE.

Primary angiitis of the central nervous system (PACNS) is a rare and severe disease confined to the central nervous system, i.e., the brain and spinal cord. The etiology, pathogenesis and immune mechanism of PACNS have not yet been completely elucidated. The diagnosis is challenging; it is based upon constellation of clinical picture, cerebrospinal fluid analysis, imaging methods or tissue biopsy as the gold standard. In differential diagnosis of PACNS, it is necessary to rule out infectious, malignant or systemic inflammatory diseases, as well as reversible cerebral vasoconstriction syndrome. Immunosuppressants are cornerstone therapy for PACNS, although evidence-based strategies for the management are lacking so far. PACNS is an entity with considerable morbidity and mortality. Awareness of this rare and heterogeneous disease is crucial for establishing early diagnosis and treatment initiation.

Very Early Diagnosis of Systemic Sclerosis in Clinical Practice - Case Report and Review of the Literature.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterised by generalized microangiopathy and fibrosis of skin and internal organs. The 2013 American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) criteria have contributed considerably to classifying patients with SSc in earlier stages, but they still lack sensitivity for a very early stage of the disease. Criteria for a very early diagnosis of SSc (VEDOSS) have been proposed by EULAR Scleroderma Trial and Research group (EUSTAR) which include three red flags: Raynaud's phenomenon, puffy fingers and antinuclear antibody positivity, plus SSc specific antibodies positivity and/or abnormal nailfold capillaroscopy. We report a case of a 54-year-old female patient with 6-week history of puffy fingers, Raynaud phenomenon and positive antinuclear antibodies. Further workup revealed early pathologic capillary pattern by nailfold capillaroscopy and positive anticentromere antibodies. Screening for internal organ involvement detected no heart, lung, or upper gastrointestinal tract involvement. The patient was started on pentoxifylline with further follow-up. The aim of the implementation of VEDOSS criteria is to diagnose SSc at the earliest possible stage, so that subclinical internal organ involvement could be detected and appropriate treatment started at a potentially reversible stage.

Association of polymorphisms in promoter region of TNF-α -238 and -308 with clinical outcomes in patients with immune-mediated inflammatory diseases on anti-TNF therapy.

The hypothesis of the study was that polymorphisms in promoter regions -238 and -308 of TNF-α could be associated with different clinical outcomes in inflammatory bowel diseases (IBD) and immune-mediated rheumatic diseases (IMRD). The aim was to examine the possible association of both polymorphisms with concentration of C-reactive protein (CRP) and fecal calprotectin (fCAL), onset of the remission and development of the ADA in patients on therapy with anti-TNF inhibitors. The prospective study was done in patients with IBD and IMRD on infliximab (IFX) or adalimumab (ADM). Patients were genotyped for TNF-α -238 and -308 polymorphisms. The concentration of CRP, fCAL, IFX or ADM and antibodies to drugs were measured according to manufacturer's instructions and followed-up for 6 or 12 months. Out of all patients (N = 112), number of patients in remission did not differ according to genotypes (for IBD patients P = 0.509 vs 0.223; for IMRD patients P = 0.541 vs 0.132 for TNF-α -238 and -308, respectively). Initial CRP concentration was higher in IBD patients with TNF-α -308 GG than GA/AA genotypes in patients who failed to achieve remission [11.8 (4.4-39.6) vs 3.1 (1.5-6.5), P = 0.033]. In IBD patients with remission, fCAL concentration after at least 6 months of therapy was higher in TNF-α-308 GG than in GA genotype [52 (25-552) vs 20 (20-20) µg/g, P = 0.041]. Our results showed the association of TNF-α -308 GG genotype with a higher concentration of CRP and fecal calprotectin in patients with inflammatory bowel diseases on IFX or ADM therapy. Clinical remission and development of antibodies to anti-TNF drugs were not associated with TNF-α -238 and -308 polymorphisms.

The Onset of Systemic Oxidative Stress Associated with the Accumulation of Lipid Peroxidation Product Acrolein in the Skin of Patients with Small-Vessel Vasculitis.

Small-vessel vasculitis (SVV) is the inflammation of the vessel wall that can result in hemorrhage and/or ischemia. Among the histological findings in SVV are increased infiltrating neutrophils, which, due to their oxidative burst and myeloperoxidase activity, release excessive reactive oxygen species, triggering a chain reaction of lipid peroxidation and yielding reactive aldehydes such as acrolein. The implication of oxidative stress in the pathogenesis of SVV was studied, focusing on acrolein immunohistochemistry in the affected skin vessels and systemic stress response. Samples from SVV patients and healthy subjects were collected and analyzed for total serum peroxides, total antioxidant capacity, inflammatory and immunological parameters, as well as for the presence of acrolein-protein adducts in the skin tissue specimens. The obtained data showed that systemic redox homeostasis and iron metabolism are altered in SVV patients. Possible biomarkers in the evaluation of oxidative status, disease activity and prevalence were indicated. Furthermore, a strong correlation between the accumulation of acrolein-protein adducts in the skin and the progression of the disease was revealed. Thus, the results of this study demonstrate that SVV is not only associated with systemic oxidative stress but also with tissue-specific oxidative stress that promotes acrolein formation and protein modification correlating with the severity of cutaneous vasculitis.

Effects of Yoga in Daily Life program in rheumatoid arthritis: A randomized controlled trial.

OBJECTIVES: To explore the feasibility and effectiveness of a yoga program in improving health-related quality of life (HQOL), physical and psychological functioning in rheumatoid arthritis (RA) patients. DESIGN: Single-centre parallel-arms randomized controlled trial comparing yoga (n = 30) and education control group (n = 27). SETTING: Tertiary care University hospital. INTERVENTION: A 12-week yoga program, based on the Yoga in Daily Life system, included 2x weekly/90-minute sessions. The control group had 1xweekly/60-minute educational lectures on arthritis-related topics. MAIN OUTCOME MEASURES: Assessments were performed at baseline, 12 (post-intervention) and 24 weeks (follow-up). The primary outcome was change in The Short Form-36 (SF-36) HQOL at 12 weeks. Linear regression analysis was adjusted for baseline scores. RESULTS: No significant between-group differences were found for SF-36 (all p > 0.05). At 12 weeks the adjusted mean difference between groups favoured yoga for Functional Assessment of Chronic Illness Therapy-fatigue (5.08 CI 1.29 to 8.86; p = 0.009) and Hospital Anxiety and Depression Scale (HADS)-depression (-1.37 CI -2.38 to -0.36); p = 0.008) and at 24 weeks for HADS-anxiety (-1.79 CI -3.34 to - 0.23; p = 0.025), while the impact on fatigue was sustained (5.43 CI 1.33 to 9.54, p = 0.01). The program had no impact on RA disease activity. Feasibility outcomes included recruitment rate 16 %, retention 80.7 %, and adherence to yoga 87.5 vs 82.7 % for control. No serious adverse events were recorded. CONCLUSIONS: Yoga in Daily Life program was not associated with change in health-related quality of life of RA patients. Significant improvements in fatigue and mood were observed at postintervention and follow-up. This yoga program was found feasible and safe for patients and may complement standard RA treat-to-target strategy.

Ambulatory arterial stiffness index and carotid intima-media thickness in hypertensive rheumatoid patients: a comparative cross-sectional study.

AIM: Rheumatoid arthritis is associated with accelerated atherosclerosis. However, little is known about preclinical atherosclerosis in hypertensive rheumatoid arthritis patients. In this cross-sectional study we assessed the expression of preclinical atherosclerosis in hypertensive rheumatoid arthritis patients in comparison with matched hypertensive non-rheumatoid arthritis patients. METHODS: The study included 52 hypertensive rheumatoid arthritis patients and 42 hypertensive non-rheumatoid arthritis patients. The patients were extensively examined clinically and laboratory tested. The expression of preclinical atherosclerosis was estimated by assessing ambulatory arterial stiffness index and common carotid intima-media thickness. RESULTS: Arterial stiffness index and common carotid intima-media thickness were higher in hypertensive rheumatoid arthritis patients than in hypertensive non-rheumatoid arthritis patients. There was no correlation between arterial stiffness index and common carotid intima-media thickness with markers of inflammation and disease activity in hypertensive rheumatoid arthritis patients. CONCLUSION: The expression of subclinical atherosclerosis is more pronounced in hypertensive rheumatoid arthritis than in hypertensive non- rheumatoid arthritis patients.

[GRANULOMATOSIS WITH POLYANGIITIS (GPA) LIMITED TO UPPER RESPIRATORY TRACT--A CASE REPORT]. / GRANULOMATOZA S POLIANGIITISOM (GPA) I LOKALIZIRANIM ZAHVACANJEM GORNJEGA DISNOG SUSTAVA PRIKAZ BOLESNICE.

Granulomatosis with polyangiitis (Wegener's granulomatosis) is one of the anti-neutrophil cytoplasmic anti-body-associated small vessel vasculitides. Upper and lower respiratory system and kidneys are most commonly affected. The disease is characterized by granulomatous inflammation of the respiratory tract and necrotizing vasculitis of small to medium-sized blood vessels. Most patients show involvement of more than one organ systems at the time of diagnosis, and constitutional symptoms may be present. In around a quarter of patients the disease is initially localised, with involvement of upper respiratory tract or lungs. We report a 21-year-old female patient with chronic rhinitis, saddle nose deformity and subglottic stenosis who presented with inspiratory stridor and impending respiratory failure. Initially, urgent tracheotomy was performed. The patient was diagnosed with granulomatosis with polyangiitis limited to upper respiratory tract. Treatment with glucocorticoids and methotrexate was followed by clinical improvement.

Different Therapeutic Paths (Colchicine vs. Anakinra) in Two Patients With Schnitzler's Syndrome.

Schnitzler's syndrome is a rare autoinflammatory syndrome with unidentified mechanism of disease and etiology with unknown definitive treatment algorithm. The two obligatory criteria for the diagnosis of Schnitzler's syndrome include chronic urticarial rash and monoclonal gammopathy (immunoglobulin M or immunoglobulin G). In this article, we describe two patients with different courses of disease with different average lengths of time between initial symptoms and the final diagnosis (6 months to 8 years). Exclusion of more common conditions is needed to ensure the correct diagnosis. Treatment strategy depends on the patient's constitutional symptoms (fever, malaise, generalized myalgia, and arthralgias) and laboratory tests of inflammation. Treatment includes usage of conventional drugs and cytokine blockade (interleukin-1 and interleukin-6). Further studies are needed to determine the precise mechanism of disease and the appropriate targeted therapy.

Scabies in a Patient with Rheumatoid Arthritis Treated with Adalimumab - A Case Report.

Rheumatoid arthritis is a chronic systemic inflammatory disease characterized by synovitis, erosions, and destruction of affected joints. If untreated, it leads to severe disability and premature mortality. Tumor necrosis factor alpha (TNF-α) inhibitors are biological drugs used in treatment of rheumatoid arthritis. Possible side effects include skin allergic reactions, which, if generalized, are the reason for discontinuation of the drug. We report the case of a 46-year-old female patient with rheumatoid arthritis who presented with pruritus and erythematous papular exanthema after administration of the second dose of adalimumab. At first, we suspected a drug hypersensitivity reaction. As the signs and symptoms persisted for 2 months after discontinuation of adalimumab and despite continuous administration of antihistamines and glucocorticoids, further work-up was performed, and scabies was diagnosed. The patient was treated with topical 10% crotamiton. The symptoms were persistent and additional applications of the preparation were needed. After clinical remission of scabies, treatment of active rheumatoid arthritis with adalimumab was restarted without any complications.

[Henoch-Schönlein purpura with late-onset necrotising glomerulonephritis--a case report]. / Prikaz bolesnice s Henoch-Schönleinovom purpurom i kasnom pojavom nekrotizirajuceg glomerulonefritisa.

Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children, while it is rare in adults. Typical clinical manifestations include palpable purpura without thrombocytopenia and/or coagulopathy, arthritis/arthralgia, abdominal pain, and/or renal involvement. In adulthood the disease tends to be more serious than in children, with renal manifestations developing over a period of several days to one month after initial symptoms. In this article we present a 22-year-old female patient with cutaneous vasculitis and arthralgia, in whom renal disease developed 8 weeks after disease onset with microscopic hematuria and proteinuria in urinalysis. Renal biopsy subsequently performed revealed focal necrotising glomerulonephritis with IgA deposits. The patient was treated with high dose methylprednisolone followed by gradual tapering, which induced complete remission of the disease. In conclusion, patients with HSP should be carefully monitored for systemic involvement, since serious renal disease can develop even as late as two months after disease onset.