Serum proteomics hint at an early T-cell response and modulation of SARS-CoV-2-related pathogenic pathways in COVID-19-ARDS treated with Ruxolitinib.

Background: Acute respiratory distress syndrome (ARDS) in corona virus disease 19 (COVID-19) is triggered by hyperinflammation, thus providing a rationale for immunosuppressive treatments. The Janus kinase inhibitor Ruxolitinib (Ruxo) has shown efficacy in severe and critical COVID-19. In this study, we hypothesized that Ruxo's mode of action in this condition is reflected by changes in the peripheral blood proteome. Methods: This study included 11 COVID-19 patients, who were treated at our center's Intensive Care Unit (ICU). All patients received standard-of-care treatment and n = 8 patients with ARDS received Ruxo in addition. Blood samples were collected before (day 0) and on days 1, 6, and 10 of Ruxo treatment or, respectively, ICU admission. Serum proteomes were analyzed by mass spectrometry (MS) and cytometric bead array. Results: Linear modeling of MS data yielded 27 significantly differentially regulated proteins on day 1, 69 on day 6 and 72 on day 10. Only five factors (IGLV10-54, PSMB1, PGLYRP1, APOA5, WARS1) were regulated both concordantly and significantly over time. Overrepresentation analysis revealed biological processes involving T-cells only on day 1, while a humoral immune response and complement activation were detected at day 6 and day 10. Pathway enrichment analysis identified the NRF2-pathway early under Ruxo treatment and Network map of SARS-CoV-2 signaling and Statin inhibition of cholesterol production at later time points. Conclusion: Our results indicate that the mechanism of action of Ruxo in COVID-19-ARDS can be related to both known effects of this drug as a modulator of T-cells and the SARS-CoV-2-infection.

[Recurrent Pulmonary Hemorrhages with Hemoptysis as a Result of Vocal Cord Dysfunction (VCD) - An Attempt to Explain]. / Rezidivierende pulmonale Hämorrhagien mit Hämoptoe als Folge einer Vocal Cord Dysfunction (VCD) ­ ein Erklärungsversuch.

We present the case of an otherwise healthy 19-year-old student who has been affected by vocal cord dysfuntion (VCD) since she is fourteen. 3 years after that diagnosis she has also been coughing blood at an increasing rate (1-3 times per week). We postulate that the haemoptoe is the result of breathing against a closed airway which can lead to excessively high negative intrathoracic pressures. Which, in turn, rapture alveolar capillaries. After bilateral injection of Botulinum toxin injection into the muscles vocalis, VCD as well as haemoptoe episodes ceased for three months.

Perfusion Patterns of Peripheral Pulmonary Granulomatous Lesions Using Contrast-Enhanced Ultrasound (CEUS) and Their Correlation with Immunohistochemically Detected Vascularization Patterns.

PURPOSE: To describe the perfusion patterns of peripheral pulmonary granulomatous lesions (PPGLs) by contrast-enhanced ultrasound (CEUS) and their correlation with vascularization patterns (VPs) represented by immunohistochemical (CD34) endothelial staining. PATIENTS AND METHODS: From January 2007 until September 2020, 10 consecutive patients with histologically confirmed PPGLs were investigated by CEUS. The time to enhancement, classified as early pulmonary-arterial (PA) pattern of enhancement versus delayed bronchial-arterial (BA) pattern of enhancement, the extent of enhancement, classified as marked or reduced, the homogeneity of enhancement, classified as homogeneous or inhomogeneous, and the decrease of enhancement, classified as rapid washout (<120 seconds) or a late washout (≥120 seconds), were analyzed retrospectively. Furthermore, the tissue samples from the study patients and as a control group, 10 samples of normal lung tissue obtained by autopsy, and 10 samples of lung tissue with acute pneumonia obtained by autopsy were immunohistochemically stained with CD34 antibody. The presence of avascular areas (AAs) and the VPs were evaluated in all tissue samples. RESULTS: On CEUS, all PPGLs showed a reduced inhomogeneous BA pattern of enhancement and a rapid washout (<120 seconds). On CD34 staining, all PPGLs showed central AAs in granulomas and a chaotic VP similar to angiogenesis in lung tumors. The lung tissue in control groups revealed on CD34 staining a regular alveolar VP. CONCLUSION: The PPGLs on CEUS show an identical perfusion pattern similar to those of malignant lesions. Furthermore, for the first time, neoangiogenesis was demonstrated as a histopathological correlate to BA pattern of enhancement on CEUS.

Predisposing factors of daytime sleepiness in obese OSA patients.

Excessive daytime sleepiness is a common symptom in obese patients with obstructive sleep apnea. We investigated predisposing factors of excessive daytime sleepiness by comparing obese non-sleepy with sleepy patients with obstructive sleep apnea. Excessive daytime sleepiness was determined by the Epworth Sleepiness Scale in 43 patients (34 men and 9 women) with obstructive sleep apnea (apnea-hypopnea index ≥ 15 events per hr) and obesity (body mass index ≥ 30 kg m-2 ). Two subgroups were formed with (Epworth Sleepiness Scale ≥ 11) and without (Epworth Sleepiness Scale < 11) excessive daytime sleepiness. The concept of excessive daytime sleepiness was compared with other established daytime performance tests (Stanford Sleepiness Scale, Multiple Sleep Latency Test, Pupillographic Sleepiness Test, Marburger Vigilance test). Associations were calculated between excessive daytime sleepiness and demographic, metabolic and polysomnographic data. We included 19 sleepy patients (mean Epworth Sleepiness Scale score 15.2) and 24 non-sleepy patients (mean Epworth Sleepiness Scale score 5.8). Epworth Sleepiness Scale was negatively correlated with age and morning cortisol. Epworth Sleepiness Scale was positively correlated with body mass index, Stanford Sleepiness Scale, Beck's Depression Inventory and Marburger Vigilance test. Sleepy obese patients were significantly younger (mean 49.1 years), showed lower morning cortisol level (mean 9.41 µg L-1 ) and a trend to higher body mass index (mean 37.5 kg m- ²) compared with non-sleepy obese patients (mean: 59.3 years, 5.7 µg L-1 , 34.6 kg m- ², respectively). Many different excessive daytime sleepiness phenotypes are probably enclosed in obese patients with obstructive sleep apnea. Epworth Sleepiness Scale scores were best reflected by the objective Marburger Vigilance test results. The objective test can be particularly useful in cohorts where subjective reports are unreliable and operational readiness is paramount. Sleepy and non-sleepy obese patients with obstructive sleep apnea were similar in all polysomnographic parameters. Sleepy patients were younger, heavier and showed lower morning cortisol levels than non-sleepy patients.

The Value of Lung Ultrasound to Detect the Early Pleural and Pulmonary Pathologies in Nonhospitalized COVID-19-Suspected Cases in a Population With a Low Prevalence of COVID-19 Infection: A Prospective Study in 297 Subjects.

OBJECTIVES: This prospective study aimed to evaluate the value of B-mode lung ultrasound (LUS) for the early diagnosis of coronavirus disease 2019 (COVID-19) infection in nonhospitalized COVID-19 suspected cases in a population with a low prevalence of disease. METHODS: From April 2020 to June 2020, in an ambulatory testing center for COVID-19-suspected cases, 297 subjects were examined by LUS before a nasopharyngeal swab was taken for a reverse transcription polymerase chain reaction (RT-PCR) test. The following LUS findings were defined as pathological ultrasound findings and were analyzed: the presence of 1) pleural effusion, 2) B-lines, 3) fragmented visceral pleura, 4) consolidation, and 5) air bronchogram in the consolidation. The LUS findings were compared with the RT-PCR test results. RESULTS: The result of the RT-PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive in 11 and negative in 286 subjects, and the prevalence of COVID-19 infection in the study participants was 3.7%. On LUS, a pathological finding could be detected in 56/297 (18.9%) study participants. The LUS revealed a sensitivity of 27.3%, a specificity of 81.5%, a positive predictive value of 5.4%, a negative predictive value of 96.7%, and a diagnostic accuracy of 79.9% for the identification of COVID-19 infection. CONCLUSIONS: For the identification of COVID-19 infection, LUS is highly sensitive to the patient spectrum and to the prevalence of the disease. Due to the low diagnostic performance in nonhospitalized COVID-19 cases in low-prevalence areas, LUS cannot be considered to be an adequate method for making a diagnosis in this group.

[Salerno, the first medical school in Europe - Birthplace of university medicine]. / Salerno, die erste Medizinschule Europas ­ Die Geburtsstätte der Hochschulmedizin.

Salerno in southern Italy is regarded as the birthplace of modern European university medicine. A practical and scientifically oriented medical discipline developed from monastic and monastery medicine. The Salernitan school, which considered itself as "Civitas Hippocratica", was based initially on the traditions of Hippocrates, the Alexandrian doctors and Galen. In the 11th century a new era began with Constantinus Africanus, who translated the scripts of Greco-Arabic medicine into Latin. By the 12th century, nearly the entire literature by Aristotle, Hippocrates, Galen, Avicenna and Rhazes was available in Latin. Salerno became an important medical training centre - for women and men - with a fixed course curriculum and provided a public health system. Medical training was firmly established under Emperor Friedrich II who placed it under state supervision.

Perfusion Patterns of Peripheral Pulmonary Lesions in COVID-19 Patients Using Contrast-Enhanced Ultrasound (CEUS): A Case Series.

PURPOSE: To describe perfusion patterns of peripheral pulmonary lesions (PPLs) in COVID-19 patients using contrast-enhanced ultrasound (CEUS). PATIENTS AND METHODS: From April 2020 until July 2020, 11 consecutive patients with RT-PCR-confirmed COVID-19 and PPLs sized over 5 mm were investigated by B-mode ultrasound (B-US) and CEUS. The homogeneity of enhancement (homogeneous and inhomogeneous) was examined retrospectively using CEUS. An inhomogeneous enhancement was defined as a perfused lesion with coexisting non-perfused areas (NPA). RESULTS: On B-US, all 11 patients showed an interstitial syndrome (B-lines) with PPLs between 0.5 and 6 cm. On CEUS, all cases showed peripheral NPA during the complete CEUS examination. One patient underwent a partial lung resection with subsequent histopathological examination. The histological examination showed vasculitis, microthrombus in the alveolar capillary, and small obliterated vessels. CONCLUSION: In our case series, PPLs in patients with RT-PCR-confirmed COVID-19 infection presented a CEUS pattern with NPA during the complete CEUS examination. Our findings suggest a peripheral pulmonary perfusion disturbance in patients with COVID-19 infection. In 1 case, the histopathological correlation with the perfusion disturbance in the PPL was proven.

Anti-interleukin-5 therapy (mepolizumab) in life-threatening asthma attack: A case-based discussion.

We report about a case of a compassionate off-label use of the anti-interleukin-5-agent mepolizumab in a ventilated patient with life-threatening asthma attack in eosinophilic asthma. The patient suffered from severe eosinophilic asthma and was transmitted to our hospital with an asthma attack and a life-threatening respiratory state under ventilation. Since high dose steroids had not yielded a sufficient respiratory improvement mepolizumab was administered subcutaneously. After administration of mepolizumab respiratory state and ventilation parameter improved significantly. Two days after administration the patient was weaned could be extubated 8 days later and recovered completely from the asthma attack. The presented clinical case is suggestive of future clinical trials or registry studies to evaluate potential clinical benefits of anti-interleukin-5 treatment in patients with severe exacerbations of eosinophilic asthma.

Benefits of High-Intensity Exercise Training to Patients with Chronic Obstructive Pulmonary Disease: A Controlled Study.

BACKGROUND: Various exercise training programs are used for patients with chronic obstructive pulmonary disease (COPD) of different severity. OBJECTIVES: To investigate the impact of individualized high-intensity training on exercise capacity with COPD. METHODS: A total of 49 patients agreed to participate. Of these, 31 were assigned to the training group and 18 served as controls. The training group exercised twice a week for 90 min with consecutively increasing loads. At the time of enrollment (T0), as well as after 3 (T1) and 6 (T2) months, a 6-min walk test (6-MWT) was performed and data on health-related quality of life, femoral muscle thickness, and various serum markers were obtained. RESULTS: The training group improved in their 6-MWT results (T0 = 407 ± 152 m vs. T1 = 459 ± 127 m, p = 0.002, vs. T2 = 483.2 ± 130.1 m, p = 0.004), in their cross-sectional area of the musculus rectus femoris (T0 = 6.2 ± 1.2 cm2 vs. T1 = 6.9 ± 1.2 cm2, p = 0.003, vs. 7.5 ± 1.6 cm2, p = 0.002), and in their St. George's Respiratory Questionnaire (SGRQ) score (T0 = 43.3 ± 18.0 vs. T1 = 36.0 ± 18.4, p = 0.001, vs. T2 = 34.7 ± 18. 0, p = 0.004). Serum levels of myostatin, irisin, resistin, and α-Klotho did not change significantly within the training period. Of note, the exercise group showed an inverse relationship between serum levels of resistin and those of α-Klotho after 6 months (r = -0.608, p = 0.021). CONCLUSIONS: COPD patients undergoing an individualized, structured, high-intensity training program improved their exercise capacity, gained muscle mass, and improved their quality of life.

Therapy with plasma purified alpha1-antitrypsin (Prolastin®) induces time-dependent changes in plasma levels of MMP-9 and MPO.

The common Z mutation (Glu342Lys) of α1-antitrypsin (A1AT) results in the polymerization and intracellular retention of A1AT protein. The concomitant deficiency of functional A1AT predisposes PiZZ subjects to early onset emphysema. Clinical studies have implied that, among the biomarkers associated with emphysema, matrix metalloproteinase 9 (MMP-9) is of particular importance. Increased plasma MMP-9 levels are proposed to predict the decline of lung function as well as greater COPD exacerbations in A1AT deficiency-associated emphysema. The aim of the present study was to investigate the effect of A1AT therapy (Prolastin) on plasma MMP-9 and myeloperoxidase (MPO) levels. In total 34 PiZZ emphysema patients were recruited: 12 patients without and 22 with weekly intravenous (60 mg/kg body weight) A1AT therapy. The quantitative analysis of A1AT, MMP-9 and MPO was performed in serum and in supernatants of blood neutrophils isolated from patients before and after therapy. Patients with Prolastin therapy showed significantly lower serum MMP-9 and MPO levels than those without therapy. However, parallel analysis revealed that a rapid infusion of Prolastin is accompanied by a transient elevation of plasma MMP-9 and MPO levels. Experiments with freshly isolated blood neutrophils confirmed that therapy with Prolastin causes transient MMP-9 and MPO release. Prolastin induced the rapid release of MMP-9 and MPO when added directly to neutrophil cultures and this reaction was associated with the presence of IgA in A1AT preparation. Our data support the conclusion that changes in plasma levels of MMP-9 and MPO mirror the effect of Prolastin on blood neutrophils.

Imbalance in distribution of functional autologous regulatory T cells in rheumatoid arthritis.

OBJECTIVES: Regulatory T cells (Tregs) exert their anti-inflammatory activity predominantly by cell contact-dependent mechanisms. A study was undertaken to investigate the regulatory capacity of autologous peripheral blood Tregs in contact with synovial tissue cell cultures, and to evaluate their presence in peripheral blood, synovial tissue and synovial fluid of patients with rheumatoid arthritis (RA). METHODS: 44 patients with RA and 5 with osteoarthritis were included in the study. The frequency of interferon (IFN)gamma-secreting cells was quantified in synovial tissue cell cultures, CD3-depleted synovial tissue cell cultures, synovial tissue cultures co-cultured with autologous CD4+ and with CD4+CD25+ peripheral blood T cells by ELISPOT. Total CD3+, Th1 polarised and Tregs were quantified by real-time PCR for CD3epsilon, T-bet and FoxP3 mRNA, and by immunohistochemistry for FoxP3 protein. RESULTS: RA synovial tissue cell cultures exhibited spontaneous expression of IFNgamma which was abrogated by depletion of CD3+ T cells and specifically reduced by co-culture with autologous peripheral blood Treg. The presence of Treg in RA synovitis was indicated by FoxP3 mRNA expression and confirmed by immunohistochemistry. The amount of FoxP3 transcripts, however, was lower in the synovial membrane than in peripheral blood or synovial fluid. The T-bet/FoxP3 ratio correlated with both a higher grade of synovial tissue lymphocyte infiltration and higher disease activity. CONCLUSION: This study has shown, for the first time in human RA, the efficacy of autologous Tregs in reducing the inflammatory activity of synovial tissue cell cultures ex vivo, while in the synovium FoxP3+ Tregs of patients with RA are reduced compared with peripheral blood and synovial fluid. This local imbalance of Th1 and Treg may be responsible for repeated rheumatic flares and thus will be of interest as a target for future treatments.