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Sepsis has no proven pharmacologic treatment other than appropriate antibiotic agents, fluids, vasopressors as needed, and possibly corticosteroids. It is generally initiated mainly by the simultaneous recognition by various components of the innate immune system of either pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). In the current study, we employed the murine cecal ligation and puncture (CLP) model for sepsis to evaluate the effect of post-CLP infusion of apoptotic cells (Allocetra-OTS) on a CLP severe sepsis model. Cardiovascular evaluation, acute kidney injury (AKI), acute liver injury (ALI), and hematological and metabolic function were evaluated. Cytokine and chemokine profiles were measured by Multiplex ELISA and mitochondrial function, and glycolysis by Seahorse. The Murine Sepsis Score (MSS) was used for disease severity definition. CLP mice had low blood pressure, poor cardiac output, and lung dysfunction, as well as AKI, ALI, and thrombocytopenia, which correlated with the MSS and corresponded to a cytokine/chemokine storm. Apoptotic cell administration markedly improved the cytokine and chemokine storm and restored the impaired mitochondrial and glycolytic function in white blood cells leading to increased survival, from 6 to 60% (P

Background: Diagnosis of bronchiectasis mandates workup for etiology, and microbiological characterization often being sought via Bronchoscopy. However, whether to perform bronchial biopsies, is unknown. We aimed to assess the current practice and yield of different bronchoscopic procedures in this setting. Methods: Data from an adult cohort undergoing bronchoscopy for bronchiectasis was reviewed, including demographics, etiology, imaging and results of different bronchoscopic procedures performed. Results: 127 subjects were analyzed (mean age 61, 56% female). Inspection of the airways was abnormal in 31%; however, management changed in only one with a foreign body. BAL culture was positive in 44%. Frequent pathogens were Hemophilus Influenza (20%), pseudomonas aeruginosa (8%) and Staphylococcus aureus (7%). NTM and tuberculosis were found in 6% and 1.5% respectively. BAL cytology was performed in 125 procedures, EBB in 51 (40%) and TBLB in 38 (30%). EBB did not contribute to diagnosis in any of our subjects, while TBB showed positive findings in only a single case. Pathology and tissue culture had no benefit over BAL with respect to microbiological diagnosis. Conclusions: In adult subjects with Non-CF bronchiectasis requiring bronchoscopy, BAL cytology and bronchial biopsies are frequently performed but are of minimal additional benefit and should probably be avoided.

Chronic obstructive pulmonary disease(COPD) is a common and debilitating condition, often accompanied by other co-morbidities. The Hadassah Medical Center'smulti-disciplinary approach in treating COPD patients in a one-stop shopfor COPD patients is the first of its kind in Israel. It includes pulmonary physicians, a nurse coordinator, dietitian, psychotherapist, physiotherapist, and a smoking cessation program.To characterize efficacy of such a program in COPD patients.Demographic and clinical data from patients referred to the Hadassah COPD center, including co-morbidities, baseline symptoms (using the CAT questioner), spirometry results, 6-minute walking distance (6MWD) test and current treatment were collected and compared to the same data after 6-12 months of treatment.Some 154 patients were evaluated; mean age 64 years; 67% male; 53% current smokers. Only 74% received chronic treatment for COPD. Average body mass index was 28, CAT score 21.3, and mean FEV1 was 1.38 liters (53% of predicted).The mean exacerbation rate during the year prior to referral was 1.72 with a 1.07 annual admission rate. Following treatment, a small increase was noted in FEV1 to 1.47 liters, 54.4% of predicted; improvement in CAT scores to 16.5 with improvement seen in 70% of patients, and a 42 meter increase in the 6MWD (from 344 to 386 meters) with some improvement of effort capacity in 77% of patients. The rate of smokers decreased to 21%, and 97% of patients received medical treatment for COPD.Multidisciplinary approach is feasible and efficacious in patients with COPD.

SummaryBackgroundSepsis has no proven specific pharmacologic treatment. Reported mortality in sepsis ranges from 30%–45%. This study was designed to determine the safety preliminary efficacy of allogenic apoptotic cells administered for immunomodulation in septic patients.MethodsThe primary aim of this phase IB study was to determine the safety profile of apoptotic cell infusion in subjects presenting to the emergency room with sepsis. Sepsis was determined by clinical infections and Sequential Organ Failure Assessment (SOFA) scores >2. The secondary aims were to measure organ dysfunction, intensive care unit (ICU) and hospital stays, and mortality, that were compared to historical controls. Exploratory endpoints included measuring immune modulator agents to elucidate the mechanism of action using Luminex® analysis.FindingsTen patients were treated with apoptotic cells, administered as a single dose or two sequential doses. All 10 patients had mild-to-moderate sepsis with a SOFA score range of 2–6 upon entering the study. No serious adverse events (SAEs) and no related AEs were reported. All 10 study subjects survived while matched historical controls had a mortality rate of 27%. The study subjects exhibited rapid resolution of organ dysfunction and had significantly shorter ICU lengths of stay compared to matched historical controls (pInterpretationAdministration of apoptotic cells to patients with mild-to-moderate sepsis was safe and had a significant immuno-modulating effect, leading to early resolution of the cytokine storm.Trial registrationClinicalTrials.gov Identifier: NCT03925857FundingThe study was sponsored by Enlivex Therapeutics Ltd.

Background Although massive bleeding following transbronchial lung biopsies (TBLB) is rare, even minor hemorrhage may prolong the procedure and result in inadequate sampling. Tranexamic acid (TXA) is an antifibrinolytic agent, which reduces bleeding in numerous scenarios, however, its prophylactic use in mitigating post-TBLB bleeding has not been investigated. We conducted a prospective, randomized, double-blind, placebo-controlled trial to determine whether topical infusion of TXA prior to TBLB would reduce bleeding, shorten procedure duration and increase the number of biopsies obtained. Methods We blindly randomized patients undergoing TBLB to receive topical TXA or placebo in the lobar bronchus prior to biopsies. Vital signs, procedure length, fluid balance (as a measure of the amount of bleeding), operator's assessment of bleeding, and number of biopsies obtained were measured. Data was analyzed using the two-tailed Student's T-Test, Chi-square or Mann-Whitney tests as appropriate. Results Fifty patients were randomized, 26 to the TXA arm. The bleeding in the TXA group was significantly lower (P = 0.0037), with more specimens being obtained (placebo 7 (6, 9) (median and interquartile range) vs. TXA 9 (8, 10), P = 0.023) and no difference in procedure length (placebo 30 min (29.3, 34.3) vs. TXA 30 (24.8, 36), P = 0.90). There were no clinically significant adverse events in any of the groups up to one month of follow up. Conclusion Endobronchial installation of TXA prior to obtaining TBLB results in less bleeding and allows more biopsies to be obtained with no additional adverse events. The prophylactic use of TXA during TBLB may be considered as standard.

BackgroundCirculating biomarkers for lung damage are lacking. Lung epithelium-specific DNA methylation patterns can potentially report the presence of lung-derived cell-free DNA (cfDNA) in blood, as an indication of lung cell death.MethodsWe sorted human lung alveolar and bronchial epithelial cells from surgical specimens, and obtained their methylomes using whole-genome bisulfite sequencing. We developed a PCR sequencing assay determining the methylation status of 17 loci with lung-specific methylation patterns, and used it to assess lung-derived cfDNA in the plasma of healthy volunteers and patients with lung disease.ResultsLoci that are uniquely unmethylated in alveolar or bronchial epithelial cells are enriched for enhancers controlling lung-specific genes. Methylation markers extracted from these methylomes revealed that normal lung cell turnover probably releases cfDNA into the air spaces, rather than to blood. People with advanced lung cancer show a massive elevation of lung cfDNA concentration in blood. Among individuals undergoing bronchoscopy, lung-derived cfDNA is observed in the plasma of those later diagnosed with lung cancer, and to a lesser extent in those diagnosed with other lung diseases. Lung cfDNA is also elevated in patients with acute exacerbation of COPD compared with patients with stable disease, and is associated with future exacerbation and mortality in these patients.ConclusionsUniversal cfDNA methylation markers of normal lung epithelium allow for mutation-independent, sensitive and specific detection of lung-derived cfDNA, reporting on ongoing lung injury. Such markers can find broad utility in the study of normal and pathologic human lung dynamics.

Background Granulocyte colony - stimulating factor (G-CSF) is frequently used in healthy adults prior to stem cell donation in order to mobilize stem cells to peripheral blood. Adverse events of G-CSF occur in about 30% and mainly include bone pain, fatigue, and headache. Pulmonary adverse events are rare. Case presentation Here, we describe a case of a healthy donor who developed diffuse alveolar hemorrhage after G-CSF administration. We suggest the underlying mechanism of this injury. Conclusion Diffuse alveolar hemorrhage can occur following G-CSF administration. Treating physicians should be aware of this infrequent but often life-threatening pulmonary side effect of G-CSF.

Heart disease is a leading non-obstetric cause of maternal morbidity and mortality during pregnancy. Improvement in diagnostic, medical, and interventional management of women with preexisting congenital and acquired heart disease has enabled many of these women to reach childbearing age. These women are predisposed to cardiac and obstetric complications during pregnancy and delivery and challenge obstetricians, cardiologists, anesthesiologists, and intensivists in their treatment. We describe the critical preexisting heart diseases that may be encountered in pregnant women and discuss evaluation and management required to enable these women to have good pregnancy outcomes. These diseases require good understanding of the physiology involved and cooperation between skilled multidisciplinary teams.

Mycoplasma pneumoniae is a leading cause of respiratory disease. In the Intensive Care Unit (ICU) setting M. pneumoniae is not considered a common pathogen. In 2010-13 an epidemic of M. pneumoniae-associated infections was reported and we observed an increase of M. pneumoniae patients admitted to ICU. We analysed the cohort of all M. pneumoniae-positive patients' admissions during 2007 to 2012 at the Hadassah-Hebrew University Medical Centre (a 1100-bed tertiary medical centre). Mycoplasma pneumoniae diagnosis was made routinely using PCR on throat swabs and other respiratory samples. Clinical parameters were retrospectively extracted. We identified 416 M. pneumoniae-infected patients; of which 68 (16.3%) were admitted to ICU. Of these, 48% (173/416) were paediatric patients with ICU admission rate of 4.6% (8/173). In the 19- to 65-year age group ICU admission rate rose to 18% (32/171), and to 38.8% (28/72) for patients older than 65 years. The mean APACHE II score on ICU admission was 20, with a median ICU stay of 7 days, and median hospital stay of 11.5 days. Of the ICU-admitted patients, 54.4% (37/68) were mechanically ventilated upon ICU admission. In 38.2% (26/68), additional pathogens were identified mostly later as secondary pathogens. A concomitant cardiac manifestation occurred in up to 36.8% (25/68) of patients. The in-hospital mortality was 29.4% (20/68) and correlated with APACHE II score. Contrary to previous reports, a substantial proportion (16.3%) of our M. pneumoniae-infected patients required ICU admission, especially in the adult population, with significant morbidity and mortality.

Background Intensive care unit (ICU) physicians should provide relatives of critically ill patients with appropriate and clear information, regarding prognosis, treatment options and expectations. Objectives To assess whether a structured communication tool improves satisfaction with care and engenders realistic expectations among relatives of critically ill patients. Study design A controlled, pre-post intervention design was implemented in the General and Medical ICUs in the Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Methods Forty relatives of patients who received usual communication from the medical staff (control group) were interviewed. We then implemented a structured communication tool and another forty family members were interviewed (intervention group). The ICU physicians who participated in the family meeting were also interviewed. Results Satisfaction in the intervention group was higher regarding ease of obtaining the information (90% vs 70%, p = .025) and the consistency of information provided (92.5% vs 77.5%, p = .057). There was better correlation between physicians' and relatives' expectations in the intervention group regarding hospital survival (Kappa 0.322 vs 0.054, p = .01). Physicians predicted more accurately patients' actual hospital survival. Conclusions A structured communication tool was associated with improved family satisfaction with communication and expectations regarding hospital survival. Further research is required to evaluate this promising intervention.

Pembrolizumab is a monoclonal antibody against the programmed cell death 1 (PD-1) receptor, and is widely used for the treatment of various malignancies, most commonly malignant melanoma. Here we report the first documented and pathology proven case of Organizing Pneumonia complicating treatment with Pembrolizumab. This was a man who presented with a dense lung consolidation four months following treatment with Pembrolizumab. A thorough microbiological workup was negative and his findings did not improve with broad spectrum anti-microbial treatment. Transbronchial biopsy revealed organizing pneumonia, and treatment with cortico-steroids resulted in complete resolution of clinical and radiological disease. This report highlights the importance of recognizing immune related adverse events, specifically pulmonary inflammation, in patients receiving treatment with novel immune-modulating agents.

Background: The association between sarcoidosis and malignancy is poorly defined. Sarcoidosis can precede, be diagnosed concurrently with, or follow malignancy. Objectives: We describe the clinical and radiological features of patients with sarcoidosis following malignancy to determine whether this association is causal or coincidental. Methods: We performed a search for all patients with confirmed sarcoidosis following malignancy in our institution during 2001-2015. Clinical and radiological features, bronchoscopic findings, bronchoalveolar lavage cell counts, and pulmonary function tests (PFTs) were reviewed to evaluate patterns of disease involvement. Details of the histological type of cancer, staging, treatment, and follow-up were reviewed. Results: Twenty-nine patients were identified. The most prevalent malignancies were breast cancer and lymphoma (24% each). Based on the incidence of these malignancies, we estimated the incidence of sarcoidosis was 175 times higher after lymphoma and 38 times higher after breast cancer as compared to the general population. Most patients had early stage cancer (stage I, II) (75%), and only 2 patients (7%) had recurrence of their malignancy after diagnosis of sarcoidosis. Sarcoidosis was diagnosed within 5 years of malignancy in over half the patients, 76% were asymptomatic and 69% had normal PFTs. Mediastinal lymphadenopathy was present in 81% of cases, hilar lymphadenopathy in 67%, and pulmonary parenchymal involvement in 41%. Fifty percent of patients had received Adriamycin, 38% cyclophosphamide, and 33% vincristine. Conclusions: Sarcoidosis following malignancy is indistinguishable from “idiopathic” sarcoidosis, although it is frequently asymptomatic. The high frequency of sarcoidosis after specific cancers but not others, suggests a causative association between malignancy and development of sarcoidosis.

Background. Intellivent-adaptive support ventilation (ASV) is a closed-loop, fully automatic method of mechanical ventilation. This advanced mode of ventilation adjusts ventilation and oxygenation parameters according to patient weight, lung function (as assessed by the ventilator) and continuous input of end-tidal carbon dioxide and oxygen saturation. Our study compares the efficacy of this new mode with ASV and synchronised intermittent mandatory ventilation (SIMV) modes.Methods. We conducted a within-group comparison of three modes of ventilation, ASV, Intellivent-ASV and SIMV, using a Hamilton S1 ventilator (Hamilton Medical, Switzerland). Subjects were ventilated for 2 hours on each mode, and at the end of each 2-hour period, parameters of ventilation and haemodynamics were measured.Results. Twenty subjects participated in this study. Their mean age was 67.3 years (range 22 - 82 years). The most common diagnosis at presentation was pneumonia (55%), followed by chronic obstructive pulmonary disease (16%) and acute respiratory distress syndrome (11%). Mean (standard deviation) levels of positive end-expiratory pressure (PEEP) were significantly higher in the Intellivent-ASV group (7.6 (5) v. 5.1 (2) and 5.2 (2) cm H2O in the ASV and SIMV groups, respectively (p