The acute effect of inhaled nitric oxide on the exercise capacity of patients with advanced interstitial lung disease: a randomized controlled trial.

BACKGROUND: Inhaled nitric oxide (iNO) selectively acts on the pulmonary vasculature of ventilated lung tissue by reducing pulmonary vascular resistance and intrapulmonary shunt. This effect may reduce ventilation/perfusion mismatch and decrease pulmonary hypertension in patients with interstitial lung disease. METHODS: In a prospective, single-blinded, randomized, placebo-controlled trial, participants with advanced interstitial lung disease, underwent two separate six-minute walk tests (6MWT): one with iNO and the other with a placebo. The primary outcome measured the difference in meters between the distances covered in the two tests. Secondary outcomes included oxygen saturation levels, distance-saturation product, and Borg dyspnea score. A predefined subgroup analysis was conducted for patients with pulmonary hypertension. RESULTS: Overall, 44 patients were included in the final analysis. The 6MWT distance was similar for iNO treatment and placebo, median 362 m (IQR 265-409) vs 371 m (IQR 250-407), respectively (p = 0.29). Subgroup analysis for patients with pulmonary hypertension showed no difference in 6MWT distance with iNO and placebo, median 339 (256-402) vs 332 (238-403) for the iNO and placebo tests respectively (P=0.50). No correlation was observed between mean pulmonary artery pressure values and the change in 6MWT distance with iNO versus placebo (spearman correlation Coefficient 0.24, P=0.33). CONCLUSION: In patients with advanced interstitial lung disease, both with and without concurrent pulmonary hypertension, the administration of inhaled nitric oxide failed to elicit beneficial effects on the six-minute walk distance and oxygen saturation. The use of inhaled NO was found to be safe and did not lead to any serious side effects. TRIAL REGISTRATION: (NCT03873298, MOH_2018-04-24_002331).

Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP. METHODS: In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 µg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo2) at week 24. RESULTS: In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo2 at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group. CONCLUSIONS: In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).

A single center Israeli experience in pregnancy post lung transplantation: Feasibility of successful two or more full-term pregnancies in individual lung transplant recipients.

INTRODUCTION: Female lung transplant recipients (LTRs) of reproductive age are increasingly considering pregnancy due to advances in post-transplant management and improved survival. We report our experience with pregnancy in LTRs, with an emphasis on two or more successful full-term pregnancies in individual transplant recipients. METHODS: We conducted a retrospective analysis of pregnancies in LTRs at our transplant center and collected maternal and fetal outcomes. RESULTS: In our patient cohort, eight female LTRs conceived a total of 17 pregnancies, resulting in 13 newborns, 12 at full term, and 11 with a birth weight > 2.5 kg. Three of the LTRs had two or more successful full-term pregnancies. LTRs required a significant tacrolimus dose increase to maintain target trough levels during pregnancy. Six recipients are currently clinically stable and active, three with lung function comparable to pre-pregnancy values, and three with evidence of chronic lung allograft dysfunction (CLAD), but stable lung function. Two of the eight LTRs died subsequent to childbirth secondary to chronic respiratory failure due to CLAD, at a mean of 11 years post-transplantation and a mean of 4.5 years after childbirth. CONCLUSION: Pregnancy following lung transplantation is feasible and can be achieved with acceptable maternal and newborn outcomes. Importantly, LTRs can successfully have two or more full-term pregnancies.

Lung Transplantation for Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation: A Single-center Experience.

BACKGROUND: Late-onset pulmonary complications can occur following hematological stem cell transplantation (HSCT). In allogeneic HSCT these complications are often associated with chronic graft-versus-host disease (GVHD). Lung transplantation (LTx) often remains the only viable therapeutic option in these patients. OBJECTIVES: To describe our experience with LTx due to GVHD after HSCT and to compare the long-term survival of this group of patients to the overall survival of our cohort of LTx recipients for other indications. METHODS: We retrospectively retrieved all data on patients who had undergone LTx for end-stage lung disease as a sequela of allogeneic HSCT, between 1997 and 2021, at Rabin Medical Center in Israel. RESULTS: A total of 15 of 850 patients (1.7%) from our cohort of LTx recipients fulfilled the criteria of LTx as a sequela of late pulmonary complication after allogeneic HSCT. The median age at the time of HSCT was 33 years (median 15-53, range 3-60). The median time between HSCT and first signs of chronic pulmonary GVHD was 24 months (interquartile range [IQR] 12-80). The median time from HSCT to LTx was 96 months (IQR 63-120). Multivariate analysis showed that patients transplanted due to GVHD had similar survival compared to patients who were transplanted for other indications. CONCLUSIONS: LTx for GVHD after allogeneic HSCT constitutes an important treatment strategy. The overall survival appears to be comparable to patients after LTx for other indications.

[INTUBATION RELATED TRACHEAL RUPTURE: EXPECTING THE UNEXPECTED].

INTRODUCTION: This case involved a 67-year-old female who was admitted for general anesthesia for a mitral clip procedure. Following anesthesia induction, the patient underwent an uneventful orotracheal intubation. Shortly afterwards she developed an ongoing respiratory failure, accompanied by neck and chest subcutaneous emphysema. Upon workup, she was found to have a 6 cm long tracheal laceration on the posterior side. Emergency repair surgery was performed using an extracorporeal membrane oxygenator (ECMO). The patient passed away 11 days later from sepsis. The aim of this case report is to increase awareness of this rare intubation complication, and explore the best approach to prevent, diagnose and treat tracheal injuries during endotracheal intubation.

Humoral response among patients with interstitial lung disease vaccinated with the BNT162b2 SARS-Cov-2 vaccine: a prospective cohort study.

BACKGROUND: Patients with interstitial lung disease (ILD) are at high risk of severe COVID-19 infection. Additionally, their anti-inflammatory and antifibrotic treatment may cause immunosuppression. Nevertheless, their ability to mount an adequate immune response to messenger RNA SARS-CoV-2 vaccines was not evaluated. Therefore, we aimed to evaluate the humoral response after the BNT162b2 vaccine among idiopathic pulmonary fibrosis (IPF) patients treated with antifibrotic therapy and among non-IPF ILD patients treated with anti-inflammatory therapy. METHODS: We conducted an observational prospective cohort study to evaluate the level of anti-spike (S-IgG) antibodies after two doses of the BNT162b2 vaccine in patients with ILD. The cohort included 40 patients with idiopathic pulmonary fibrosis (IPF) treated with anti-fibrotic therapy and 29 patients with non-IPF ILD treated with anti-inflammatory therapy. For S-IgG titer measurement, one serology test was drawn from all patients 4-6 months after the second vaccine dose. In addition a control group matched for age and sex was created from a healthy control cohort of 107 patients. The study was conducted in Rabin Medical Center (Israel) between June and August 2021. RESULTS: All patients in the anti-fibrotic arm were seropositive (40/40), corresponding to the matched control group (P = 1.0). The anti-fibrotic arm had a significantly lower median antibody titer in comparison to the matched control group (361.10 [IQR, 207-811] AU/ml vs. 820.75 [IQR, 459-1313] AU/ml; P < 0.001). Only 48.3% (14/29) of patients in the anti-inflammatory arm were seropositive in comparison to 100% (29/29) in the healthy control group (P < 0.001). The anti-inflammatory arm had a significantly lower median antibody titer in comparison to the healthy control group (39.6 [IQR, 4.25-165] AU/ml vs. 970.1 [IQR, 505-1926] AU/ml; P < 0.001). CONCLUSION: IPF patients treated with antifibrotic therapy mount an adequate immune response after 2 doses of the BNT162b2 vaccine, and maintain a 100% seropositivity rate 4-6 months after vaccination. However, their antibody titer was reduced in comparison to a healthy control group. Among patients with non-IPF ILD treated with anti-inflammatory therapy, 48% were seronegative 4-6 months after the second vaccine dose. Moreover, treatment with rituximab caused significant immunosuppression, even in comparison to other anti-inflammatory treatments.

Preoperative evaluation of pulmonary hypertension in lung transplant candidates: echocardiography versus right heart catheterization.

BACKGROUND: Right heart catheterization (RHC) and echocardiography are both routinely used for pulmonary artery systolic pressure (PASP) assessment in lung transplantation (LT) candidates, although this is not mandated by current guidelines. We aimed to explore the performance of echocardiographic PASP as an indicator of pulmonary hypertension in LT candidates, in order to assess the necessity of RHC. METHODS: From a retrospective registry of 393 LT candidates undergoing RHC and echocardiography during 2015-2019, patients were assessed for the presence of pulmonary hypertension (PH), defined as mean pulmonary artery pressure (mPAP) above 20 mmHg, according to two methods-echocardiography and RHC. The primary outcome was the correlation between the PASP estimated by echocardiography to that measured by RHC. Secondary outcomes were the prediction value of the echocardiographic evaluation and its accuracy. RESULTS: The mean value of PASP estimated by echocardiography was 49.5 ± 20.0 mmHg, compared to 42.5 ± 18.0 mmHg measured by RHC. The correlation between the two measurements was moderate (Pearson's correlation: r = 0.609, p < 0.01). Echocardiography PASP measurements were moderately discriminative to diagnose PH, with an area under the curve (AUC) of 0.72 (95% CI 0.66-0.77). Echocardiographic overestimation of PASP of more than 10 mmHg was found in 35.0% of the patients, and underestimation was found in 11.6% of the patients. CONCLUSION: In the pre-surgical evaluation of LT candidates, echocardiographic estimation of PASP had moderate correlation and limited accuracy compared to the PASP measured by RHC. We thus recommend performing routine RHC to all LT candidates, regardless of the echocardiographic estimation of PASP.

Demographic, exposure and clinical characteristics in a multinational registry of engineered stone workers with silicosis.

OBJECTIVES: To investigate differences in workplace exposure, demographic and clinical findings in engineered stone (ES) workers from a multinational consortium using the Engineered Stone Silicosis Investigators (ESSI) Global Silicosis Registry. METHODS: With ethics board approval in Israel, Spain, Australia and the USA, ES workers ages 18+ with a physician diagnosis of work-related silicosis were enrolled. Demographic, occupational, radiologic, pulmonary function and silica-related comorbidity data were compared cross-sectionally among countries using analysis of variance, Fisher's exact tests and logistic regression. RESULTS: Among 169 ES workers with silicosis, most were men, with mean age 51.7 (±11.4) years. Mean work tenure in stone fabrication or masonry was 19.9 (±9.8) years. Different methods of case ascertainment explained some inter-country differences, for example, workers in Queensland, Australia with a state-based surveillance program were likely to be identified earlier and with shorter work tenure. Overall, 32.5% of workers had progressive massive fibrosis, the most severe form of dust-related pneumoconiosis, of whom 18.5% reported ≤10 years of work tenure. Lung function impairment including restriction, reduced diffusion capacity and hypoxaemia was common, as was autoimmunity. CONCLUSIONS: Findings from a multinational registry represent a unique effort to compare demographic, exposure and clinical information from ES workers with silicosis, and suggest a substantial emerging population of workers worldwide with severe and irreversible silica-associated diseases. This younger worker population is at high risk for disease progression, multiple comorbidities and severe disability. The ESSI registry provides an ongoing framework for investigating epidemiological trends and developing prospective studies for prevention and treatment of these workers.

Long-Term Success of Metal Endobronchial Stents in Lung Transplant Recipients.

BACKGROUND: Bronchial stenosis is a common complication following lung transplantation. We evaluated long-term associations of the use of self-expandable metal stents (SEMSs) with lung function tests, patient safety, and survival. METHODS: A retrospective chart review of 582 lung transplantations performed at our institution between January 2002 and January 2018. Fifty-four patients with SEMSs (intervention group) were matched one-to-one to patients without SEMSs (control group) using propensity score matching for age, sex, the year, and type of transplantation (unilateral/bilateral), and underlying disease. Data regarding long-term lung function and survival were compared between the groups. RESULTS: During a median follow-up of 54.8 months, the difference in survival between the study groups was not statistically significant (p = 0.2). Following 5, 7.5 and 10 years, values of mean forced expiratory volume in 1 second (FEV1) were comparable between patients with and without SEMSs as follows: 59.5 versus 62.6% (p = 0.2), 55.9 versus 55.0% (p = 0.4), and 63.5 versus 61.9% (p = 0.3), respectively. In the intervention group, a significant increase in the mean FEV1 was observed in 60 days after stent insertion (from 41.9 ± 12.8 to 49.5 ± 16.7% days, p < 0.001). Long-term complications following stent insertion included severe bleeding (1.8%), stent fractures (7.4%), stent stenosis (7.4%), stent collapse (3.7%), endobronchial pressure ulcer (1.9%), and stent migration (1.9%). CONCLUSION: SEMS insertion is associated with a positive sustained effect on lung function, without increasing long-term mortality. Thus, airway stenosis after lung transplantation can be safely and successfully treated using endobronchial metal stenting, with tight bronchoscopic follow-up and maintenance.

Dexmedetomidine versus propofol sedation in flexible bronchoscopy: a randomized controlled trial.

BACKGROUND: Dexmedetomidine (DEX), is a highly selective alpha2 adrenoceptor (α2-AR) agonist, successfully used in various procedures including flexible bronchoscopy. Randomized controlled trials (RCTs) evaluating DEX sedation during bronchoscopy report equivocal results regarding respiratory and hemodynamic outcomes. METHODS: We conducted an RCT to evaluate the efficacy and safety of dexmedetomidine compared to propofol for sedation during bronchoscopy. The primary outcome was the number of desaturation events, secondary outcomes were transcutaneous Pco2 level, hemodynamic adverse events and physician and patient satisfaction. RESULTS: Overall, 63 patients were included, 30 and 33 in the DEX and propofol groups, respectively. The number of desaturation events was similar between groups, median (IQR) 1 (0-1) and 1 (0-2) in the DEX and control groups, respectively (P = 0.29). Median desaturation time was 1 (0-2) and 1 (0-3) minutes in the DEX and control groups, respectively (P = 0.48). Adverse events included hypotension, 33% vs 21.1% in intervention and control groups, respectively (P = 0.04), bradycardia, cough, and delayed recovery from sedation. Total adverse events were 22 and 7 in DEX and propofol groups, respectively (P = 0.009). CONCLUSION: Dexmedetomidine sedation during bronchoscopy did not show differences in oxygen saturation and transcutaneous CO2 level in comparison to propofol. Moreover, DEX sedation required a significantly higher number of rescue boluses, due to inadequate sedation and was associated with a higher rate of adverse events. Trial registration NCT04211298, registration date: 26.12.2019.

Use of capnography for prediction of obstruction severity in non-intubated COPD and asthma patients.

BACKGROUND: Capnography waveform contains essential information regarding physiological characteristics of the airway and thus indicative of the level of airway obstruction. Our aim was to develop a capnography-based, point-of-care tool that can estimate the level of obstruction in patients with asthma and COPD. METHODS: Two prospective observational studies conducted between September 2016 and May 2018 at Rabin Medical Center, Israel, included healthy, asthma and COPD patient groups. Each patient underwent spirometry test and continuous capnography, as part of, either methacholine challenge test for asthma diagnosis or bronchodilator reversibility test for asthma and COPD routine evaluation. Continuous capnography signal, divided into single breaths waveforms, were analyzed to identify waveform features, to create a predictive model for FEV1 using an artificial neural network. The gold standard for comparison was FEV1 measured with spirometry. MEASUREMENTS AND MAIN RESULTS: Overall 160 patients analyzed. Model prediction included 32/88 waveform features and three demographic features (age, gender and height). The model showed excellent correlation with FEV1 (R = 0.84), R2 achieved was 0.7 with mean square error of 0.13. CONCLUSION: In this study we have developed a model to evaluate FEV1 in asthma and COPD patients. Using this model, as a point-of-care tool, we can evaluate the airway obstruction level without reliance on patient cooperation. Moreover, continuous FEV1 monitoring can identify disease fluctuations, response to treatment and guide therapy. TRIAL REGISTRATION: clinical trials.gov, NCT02805114. Registered 17 June 2016, https://clinicaltrials.gov/ct2/show/NCT02805114.

Efficacy and safety of mepolizumab in a real-world cohort of patients with severe eosinophilic asthma.

BACKGROUND: The interleukin 5 (IL-5) pathway is an important component in the pathophysiology of severe eosinophilic asthma. Mepolizumab is a monoclonal antibody that targets the IL-5 pathway. Clinical trials showed efficacy of Mepolizumab in patients with severe eosinophilic asthma. However, reports on experience with treatment in a real-world cohort are limited. OBJECTIVES: Evaluation of the efficacy and safety of Mepolizumab for treatment of severe eosinophilic asthma in a real-world cohort of patients. METHODS: A clinical prospective observational trial included all patients >18 years treated with Mepolizumab between March 2016 to March 2019 at Rabin Medical Center. The composite primary outcome measures evaluated: increase in FEV1 by≥ 200 ml and/or decrease in exacerbation rate of ≥50% and/or cessation of oral corticosteroids (OCS) treatment or ≥50% decrease in dosage. Also evaluated: blood eosinophil count, adverse events and quality of life. RESULTS: Of 61 patients, 50 (82.0%) achieved the primary outcome. The number of patients who suffered from frequent exacerbations decreased from 52 (85.2%) to 8 (13.1%) (p < 0.001). Twenty-two patients (68%) stopped OCS treatment or received >50% reduced dosage (p < 0.001). Mean FEV1 increased from 1.72 ± 0.78 liters to 1.87 ± 0.85 liters (p = 0.043). Response to therapy was seen within six months. Forty-nine patients (80%) reported an improvement in quality of life (p < 0.001). Only minor adverse events were reported. CONCLUSION: Treatment with mepolizumab was well tolerated and significantly lowered the exacerbation rate and OCS dependence in a real-world cohort of severe eosinophilic asthma patients. Response to therapy was within six months and treatment effect was sustained over time.

Trends in Kaposi's Sarcoma Morbidity: A Retrospective Cohort Study of Heart and Lung Transplant Recipients.

Data on post-transplant Kaposi's sarcoma in heart and lung transplant recipients are sparse. This study examined the incidence of biopsy-proven post-transplant Kaposi's sarcoma in thoracic organ recipients over a period of 20 years. As mammalian target of rapamycin inhibitors were introduced in 2006 as optional maintenance immunosuppressive therapy, the overall results were analysed and stratified into 2 groups: 1996 to 2005 and 2006 to 2016. A total of 867 transplant recipients met the study criteria. Post-transplant Kaposi's sarcoma was diagnosed in 7 (0.81%) patients. Five cases (0.19% of transplant recipients) were recorded in 1996 to 2005 and 2 (0.03% of transplant recipients) in 2006 to 2016 (p = 0.04). Multivariable logistic regression analyses identified the following as risk factors: period of transplantation (odds ratio (OR) 4.844, 95% confidence interval (95% CI) 1.156-20.291), age at transplantation (OR 1.066, 95% CI 0.992-1.145), and North African origin (OR 7.282, 95% CI 12.55-42.254). This study found a decreased incidence of post-transplant Kaposi's sarcoma over the last 20 years, mainly attributed.

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix-fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH4OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of 'HIF1α signaling pathway' (KEGG, p < 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib.

The European MultiPartner IPF registry (EMPIRE): validating long-term prognostic factors in idiopathic pulmonary fibrosis.

BACKGROUND: Several registries of idiopathic pulmonary fibrosis (IPF) have been established to better understand its natural history, though their size and duration of follow-up are limited. Here, we describe the large European MultiPartner IPF Registry (EMPIRE) and validate predictors of long-term survival in IPF. METHODS: The multinational prospective EMPIRE registry enrolled IPF patients from 48 sites in 10 Central and Eastern European countries since 2014. Survival from IPF diagnosis until death was estimated, accounting for left-truncation. The Cox proportional hazards regression model was used to estimate adjusted hazard ratios (HR) of death for prognostic factors, using restricted cubic splines to fit continuous factors. RESULTS: The cohort included 1620 patients (mean age at diagnosis 67.6 years, 71% male, 63% smoking history), including 75% enrolled within 6 months of diagnosis. Median survival was 4.5 years, with 45% surviving 5 years post-diagnosis. Compared with GAP stage I, mortality was higher with GAP stages II (HR 2.9; 95% CI: 2.3-3.7) and III (HR 4.0; 95% CI: 2.8-5.7) while, with redefined cut-offs, the corresponding HRs were 2.7 (95% CI: 1.8-4.0) and 5.8 (95% CI: 4.0-8.3) respectively. Mortality was higher with concurrent pulmonary hypertension (HR 2.0; 95% CI: 1.5-2.9) and lung cancer (HR 2.6; 95% CI: 1.3-4.9). CONCLUSIONS: EMPIRE, one of the largest long-term registries of patients with IPF, provides a more accurate confirmation of prognostic factors and co-morbidities on longer term five-year mortality. It also suggests that some fine-tuning of the indices for mortality may provide a more accurate long-term prognostic profile for these patients.

Mucormycosis in lung transplant recipients: A systematic review of the literature and a case series.

BACKGROUND: Mucormycosis is a rare infection in lung transplant recipients (LTR). Our objective was to better define the clinical presentation and optimal management of this frequently lethal infection. METHODS: A systematic review of the literature was performed to identify all published cases of mucormycosis in LTR using PubMed/MEDLINE. These cases were analyzed together with a new case series from our clinic. RESULTS: Literature search yielded 44 articles matching the inclusion criteria, describing 121 cases. Six additional cases were identified from our clinic. Data regarding infection site and outcome were available for a total of 53 patients. The lungs were the most common site of infection (62%), followed by rhinocerebral and disseminated disease. Most cases (78%) developed in the first post-transplant year, with over 40% of them in the first month. Additional risk factors for mucormycosis were identified in over half of the patients. Surgical debridement was uncommon in pulmonary infection (9%). Posaconazole therapy was used in 35% of cases, mostly in combination with amphotericin B. Overall mortality was 32% but varied according to site of infection. CONCLUSION: Mucormycosis in LTRs tends to be an early post-surgical infection, associated with additional risk factors and intensified immunosuppressive states, and most often affects the lungs, where surgical debridement is rarely feasible. Posaconazole as first-line therapy should be further explored.

Routine comprehensive Aspergillus screening of bronchoalveolar lavage samples in lung transplant recipients.

BACKGROUND: Invasive aspergillosis is a significant cause of morbidity and mortality in lung transplant recipients (LTRs). Early diagnosis may improve outcome, yet is challenging. We assessed the diagnostic yield of a routine, comprehensive, prospectively employed Aspergillus screening strategy in LTRs. METHODS: During a 6-month period, all bronchoalveolar lavage (BAL) samples (including post-transplant surveillance) obtained from LTRs at our center were routinely tested for Aspergillus PCR, galactomannan (GM), and fungal culture. Invasive aspergillosis (IA) was defined using EORTC/MSG and ISHLT criteria for proven and probable aspergillosis. RESULTS: Ninety-five consecutive BAL samples were tested. PCR, GM, and fungal culture were positive in 28.4%, 30.6%, and 7.4%, respectively. Five cases of IA (two proven, three probable) were identified. Fungal culture failed to detect 40% of IA cases, which were detected by a positive PCR and/or GM. However, the majority of positive PCR samples represented colonization (59.3%). Sensitivity of PCR, GM, and culture for IA was 80%, 60%, and 60%, respectively, and specificity was 74%, 71%, and 96%. CONCLUSIONS: In LTRs, a routine prospectively employed screening strategy in which all BAL samples were screened for Aspergillus PCR and GM, detected aspergillosis cases that were otherwise missed by a false-negative fungal culture, but resulted in more cases of colonization being detected. Clinical judgment is thus warranted to avoid unnecessary treatment of colonization.

Radiologic Characteristics of Non-tuberculous Mycobacteria Infection in Patients with Bronchiectasis.

INTRODUCTION: Non-tuberculous mycobacteria pulmonary disease (NTM-pd) commonly complicates bronchiectasis. However, clinical and radiological features of NTM-pd and bronchiectasis are very similar. We aimed to develop a radiologic prediction tool for bronchiectasis to identify NTM-pd. METHODS: We reviewed clinical, laboratory and radiological data in patients with bronchiectasis. Radiologic features on CT scans and the individual components of the Bhalla scoring system were compared between people with and without NTM-pd. Logistic regression and receiver-operating curve (ROC) analysis were performed to predict NTM-pd. RESULTS: People with NTM-pd had more pulmonary segments with bronchiectasis (13 ± 5 vs. 11 ± 5, p = 0.03), presence of mucus plugging (47% vs. 19%, p < 0.0001) and tree in bud infiltrates (53% vs. 28%, p = 0.004). The total modified- Bhalla score was worse among people with NTM-pd (median [IQR] 11[9,13] vs. 9[8,12], p = 0.03). Logistic regression identified the number of pulmonary segments involved, presence of bullae, consolidations, and a total score of 10 or more to be independently associated with presence of NTM-pd. ROC analysis with radiographic variables only identified an AUC of 0.706 (95% CI 0.644-0.762). When people with chronic Pseudomonas infection were excluded from the ROC analysis, prediction for NTM was improved: AUC = 0.87 (95% CI 0.796-0.945). DISCUSSION AND CONCLUSIONS: Radiological features together with advanced age and female gender may predict NTM-pd among people with bronchiectasis. Infection with Pseudomonas aeruginosa may resemble NTM radiographically, and this prediction rule may better differentiate people with and without NTM-pd when Pseudomonas infection is not present.

Lung Transplantation in Idiopathic Pulmonary Fibrosis: Risk Factors and Outcome.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has poor prognosis. Anti-fibrotic treatment has been shown to slow disease progression. Lung transplantation (LTx) offers a survival benefit. The 5-year survival after LTx in IPF is between 40 and 50. OBJECTIVES: To evaluate which IPF patients have better prognosis following LTx. METHODS: A retrospective study was conducted with all IPF patients who had undergone LTx in the Rabin Medical Center between 2010 and 2018. We collected data on pre-evaluation of pulmonary function tests, echocardiographic and right heart catherization, and anti-fibrotic treatments. The Kaplan-Meier method was used for survival analysis. RESULTS: Among148 patients who underwent LTx, 58 were double LTx (DLT) and 90 single LTx (SLT). Mean age was 58.07 ± 9.78 years; 104 males and 44 females. DLT patients had significantly lower survival rates than SLT in the short and medium term after LTx. Patients with saturation above 80% after the 6-minute walk test (6MWT) had higher survival rates. Patients over 65 years of age had a lower survival rates. Those with pulmonary hypertension (PHT) above 30 mmHg had a poorer prognosis with lower survival rates. CONCLUSIONS: IPF patients with higher mean PHT, older age (> 65 years), and desaturation following 6MWT had lower survival rates following LTx. DLT may decrease survival rate compared to SLT just for the short and medium period of time after LTx. These results may lead to better selection of IPF patient candidates for LTx. Additional studies are warranted for choosing which patients will have better prognosis after LTx.