Analysis of cytokines in serum and bronchoalveolar lavage fluid in patients with immune-checkpoint inhibitor-associated pneumonitis: a cross-sectional case-control study.

PURPOSE: Immune-checkpoint inhibitors (ICI) present a new treatment for malignancies by boosting the immune system. This has led to a variety of immune-related adverse events, including ICI-associated pneumonitis (ICIaP). Diagnosis thereof is often challenging, and its pathogenesis has not yet been fully understood. The aim of this cross-sectional case-control study was to investigate cytokines in serum and bronchoalveolar lavage fluid (BALF) expressed in patients with ICIaP compared to controls consisting of healthy individuals, patients with lung cancer and patients with interstitial lung diseases (ILD) other than ICIaP. METHODS: From January 2018 until June 2019, 401 adult patients with various lung diseases were prospectively enrolled in a BALF- and serum biobank, called BALOTHEK. Of these, 12 patients were diagnosed with ICIaP (Pembrolizumab, Ipilimumab, or both, and Durvalumab) serving as case group. Subjects with one of three diagnosis groups from BALOTHEK, including lung cancer, ILD other than ICIaP, and healthy individuals, served as matched controls. The following 11 cytokines were simultaneously analyzed in BALF and serum of each study participant: interferon gamma, tumor necrosis factor alpha, interleukin (IL) 1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12p70, IL-13 and IL-17A. This study was approved by the local ethic review committee (BASEC-ID 2017-02,307 and 2018-01,724). RESULTS: Absolute number and percentage of lymphocytes in BALF of patients with ICIaP were significantly higher compared to control groups. For the investigated cytokines in BALF, a significant increase of IL-6 level was shown for patients with ICIaP compared to control groups (p = 0.031, adjusted for multiple comparisons). CONCLUSION: Cytokine profile assessed in BALF shows promising potential for facilitating diagnosis and understanding of pathophysiology of ICIaP. IL-6 may not only contribute to better understanding of pathophysiology but also herald therapeutic implications for Tocilizumab.

Evaluation of cytokines in the tumor microenvironment of lung cancer using bronchoalveolar lavage fluid analysis.

INTRODUCTION: Lung cancer is the leading cause of death by cancer. In recent years, immunotherapy with checkpoint inhibitors (ICI) emerged as a promising new therapeutic approach. However, a deeper understanding of the immunologic responses adjacent to the tumor known as tumor microenvironment (TME) is needed. Our study investigated TME of lung cancer by analyzing cytokines in bronchoalveolar lavage fluid (BALF). MATERIALS AND METHODS: Between January 2018 and June 2019, 119 patients were prospectively enrolled in this study. For each cancer patient, levels of 16 cytokines (fractalkine, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukins (IL): IL-1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A, and IL-23) were measured in BALF and serum and compared to healthy individuals and patients with other lung diseases. RESULTS: There were several significant differences of cytokine levels of patients with lung cancer compared to healthy individuals. However, none of them remained in the multivariate analysis compared to other lung diseases in either BALF or serum. Furthermore, there were no significant differences between the groups in cell differentiation of either BALF or serum. Cytokine levels in BALF were generally near the lower detection limit and showed almost no correlation with their respective levels measured in serum of the same individual. CONCLUSIONS: Cytokines in BALF and serum of lung cancer patients may indicate unspecific inflammation. BAL is not recommendable as a tool to investigate TME of lung cancer. Therefore, cytokines measured in BALF are probably not appropriate as predictors in patients treated with ICIs.

[The Mysterious Cough - a Case-Based Proposal of Differential Diagnosis]. / Der rätselhafte Husten ­ ein fallbasierter Vorschlag einer Abklärungsstrategie.

The Mysterious Cough - a Case-Based Proposal of Differential Diagnosis Abstract. Cough is a frequent complaint in the general practice. Avoidance of overdiagnosis and underdiagnosis is essential. In case of acute cough or subacute (<8 week duration), red flags indicate the need for further evaluation, otherwise it is mostly self-limiting. In case of chronic cough (>8 week duration) and normal baseline examination and after cessation of smoking and medication with ACE-I, cough-variant asthma, gastro-esophageal reflux disease and upper airway cough syndrome are the main causes and should be assessed and empirically treated in a systematic manner.

The association between daily exacerbation symptoms and physical activity in patients with chronic obstructive pulmonary disease.

Background: Evidence from longitudinal studies on the impact of exacerbation symptoms on physical activity in chronic obstructive pulmonary disease (COPD) is lacking. The aim of this first exploratory study was to assess the association between exacerbation symptoms and physical activity, and to quantify the relative influence of specific symptoms. Methods: We recruited COPD patients at high risk for exacerbations from 2 pulmonary rehabilitation clinics and 1 acute care clinic in Switzerland. For 3 months after discharge, patients completed a daily symptom diary on a smartphone application, the EXAcerbations of Chronic pulmonary disease Tool (EXACT), and wore a pedometer to measure daily steps. We used mixed-effects models to determine the association of daily steps with exacerbation symptoms. Results: A total of 21 patients (Global Initiative for Chronic Obstructive Lung Disease grades 2-4) were enrolled for a mean of 94.4 days (standard deviation 4.2). The baseline median number of daily steps was 3,264.6 (interquartile range [IQR]: 1,851.3-4,784.1) and EXACT score was 37.0 (IQR: 30.9-41.4). A 12-point increase in EXACT score (indicating the start of an exacerbation) was statistically significantly associated with a decrease in daily steps of 653.3 (95% CI 969.7-336.9). Chest symptoms (tightness, discomfort and congestion) were more strongly associated with change in steps than breathlessness, and cough and sputum (z-value -4.5 vs -2.9 and -3.0). Conclusion: This is the first study to show that, in a small cohort of COPD patients, increases in exacerbation symptoms were associated with a statistically and clinically significant reduction in daily physical activity. These results underscore the importance for symptom control and exacerbation prevention in COPD patients.

Acute exacerbated COPD: room for improvement in key elements of care.

INTRODUCTION: Hospitalizations because of acute exacerbated COPD (AECOPD) are a major burden to patients and the health care system. Interventions during acute and post-acute hospital care exist not only to improve short-term outcomes but also to prevent future exacerbations and disease progression. We aimed at measuring the implementation rates of acute and post-acute hospital care interventions for AECOPD. METHODS: We performed 24 months (January 1, 2012, to December 31, 2013) retrospective medical chart review of consecutive cases hospitalized to one of three public hospitals in the canton of Zurich due to AECOPD. Implementation rates of five acute care and seven post-acute care interventions were assessed. RESULTS: Data from 263 hospitalizations (61% male, mean age 68.5 years, 47% active smokers) were analyzed. The median length of stay was 9 days (interquartile range [IQR] 6-12 days). In all, 32% of hospitalizations were caused by individuals with previous hospitalizations because of AECOPD. Implementation rates of four acute care interventions were >75% (lowest was appropriate antibiotic therapy with 56%). Compared to this, implementation rates of five post-acute care interventions were <25% (lowest was patient education and self-management advice with 2%). CONCLUSION: The results of this audit revealed room for improvement mainly in post-acute care interventions for AECOPD.

Lung Volume Reduction Surgery on Extracorporeal Life Support.

Lung volume reduction surgery improves exercise tolerance, lung function, and quality of life for selected patients with emphysema. Lung volume reduction surgery is well established for patients in a highly elective setting. It is, however, contraindicated in cases of acute cardiorespiratory failure. We present the case of a patient with severe emphysema who had acute respiratory failure and decompensated cor pulmonale requiring life-saving venovenoarterial extracorporeal life support after admission to the emergency unit. He underwent lung volume reduction surgery with intent to wean from extracorporeal life support. He had complete functional recovery after 4 months.

Evidence for an association between tako-tsubo cardiomyopathy and bronchial asthma: retrospective analysis in a primary care hospital.

OBJECTIVE: We investigated the prevalence of bronchial asthma in patients with Tako-Tsubo Syndrome (TTS). DESIGN: This retrospective case-series study was conducted in a primary care hospital in Zurich, Switzerland. Data of all patients with newly diagnosed TTS (2002 - 2012) were assessed electronically by the use of ICD-10. Asthma prevalence was compared to published epidemiologic data. SETTING: Bronchial asthma is characterized by airway inflammation and, during attack, release of endogenous catecholamines. Sympathomimetic drugs are the mainstay of treatment for asthma patients. Likewise, catecholamine mediated diffuse microvascular myocardial dysfunction seems to be of critical importance for the development of TTS. RESULTS: 20 cases of TTS were identified. 90% were female, showed a median age of 70±13y [25y - 90y], an apical and/or midventricular ballooning pattern with preserved basal function and a median initial LVEF of 34±9% [25% - 55%]. 65% of patients underwent coronary angiography to rule out significant coronary artery disease. Hypertension was present in 45% of patients, 35% were smokers, none was suffering from diabetes. Prevalence of asthma in patients with TTS was significantly higher compared to the normal population (25% vs. 7%, p=0.012). In 30% of the TTS patients an iatrogenic cause for development of TTS was identified. CONCLUSION: Prevalence of asthma was significantly higher in patients with TTS compared to epidemiologic data from an age-matched population. Phenotypes of patients developing obstructive ventilatory disease and TTS might share common pathogenic mechanisms beyond the use of bronchodilatators. In addition, we identified other iatrogenic etiologies in patients with TTS.

Pilomotor seizures and status in non-paraneoplastic limbic encephalitis.

BACKGROUND AND AIMS: To describe an unusual clinical presentation of a patient with voltage-gated potassium channel Ab- positive, non-paraneoplastic limbic encephalitis. METHODS: We performed video-EEG monitoring, structural MRI, (18)F-FDG-PET, (1)H-MRS, neuropsychological testing and antibody serology. RESULTS: A 42-year-old male patient presented in an acute phase of non-paraneoplastic limbic encephalitis confirmed by MRI, with antibodies to voltage-gated potassium channels. His pilomotor status was pharmacoresistant to antiepileptic drugs, but responded to corticosteroid and azathioprine treatment. The MRI findings improved. The pilomotor seizures recurred when the immunosuppressive therapy was discontinued after 18 months. MRI at that time was consistent with hippocampal sclerosis. Complete seizure control was achieved after reintroduction of steroids. CONCLUSION: Pilomotor seizures were the predominant seizure type in this case of non-paraneoplastic limbic encephalitis. Immunosuppressive therapy may provide recovery including seizure control. However, long-term immunosuppression may be necessary to prevent relapse. Hippocampal sclerosis and chronic epilepsy might evolve as sequelae of limbic encephalitis.

Event-related brain potentials in memory: correlates of episodic, semantic and implicit memory.

OBJECTIVE: To study cognitive evoked potentials, recorded from scalp EEG and foramen ovale electrodes, during activation of explicit and implicit memory. The subgroups of explicit memory, episodic and semantic memory, are looked at separately. METHODS: A word-learning task was used, which has been shown to activate hippocampus in H(2)(15)O positron emission tomography studies. Subjects had to study and remember word pairs using different learning strategies: (i) associative word learning (AWL), which activates the episodic memory, (ii) deep single word encoding (DSWE), which activates the semantic memory, and (iii) shallow single word encoding (SSWE), which activates the implicit memory and serves as a baseline. The test included the 'remember/know' paradigm as a behavioural learning control. During the task condition, a 10-20 scalp EEG with additional electrodes in both temporal lobes regions was recorded from 11 healthy volunteers. In one patient with mesiotemporal lobe epilepsy, the EEG was recorded from bilateral foramen ovale electrodes directly from mesial temporal lobe structures. Event-related potentials (ERPs) were calculated off-line and visual and statistical analyses were made. RESULTS: Associative learning strategy produced the best memory performance and the best noetic awareness experience, whereas shallow single word encoding produced the worst performance and the smallest noetic awareness. Deep single word encoding performance was in between. ERPs differed according to the test condition, during both encoding and retrieval, from both the scalp EEG and the foramen ovale electrode recordings. Encoding showed significant differences between the shallow single word encoding (SSWE), which is mainly a function of graphical characteristics, and the other two strategies, deep single word (DSWE) and associative learning (AWL), in which there is a semantic processing of the meaning. ERPs generated by these two categories, which are both functions of explicit memory, differed as well, indicating the presence or the absence of associative binding. Retrieval showed a significant test effect between the word pairs learned by association (AWL) and the ones learned by encoding the words in isolation of each other (DSWE and SSWE). The comparison of the ERPs generated by autonoetic awareness ('remember') and noetic awareness ('know') exhibited a significant test effect as well. CONCLUSIONS: The results of behavioural data, in particular that of the 'remember/know' procedure, are evidence that the task paradigm was efficient in activating different kinds of memory. Associative word learning generated a high degree of autonoetic awareness, which is a result of the episodic memory, whereas both kinds of single word learning generated less. AWL, DSWE and SSWE resulted in different electrophysiological correlates, both for encoding as well as retrieval, indicating that different brain structures were activated in different temporal sequence.