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In the assessment of central airway obstruction and disease, no imaging technique is an adequate substitute for bronchoscopy. The indications for rigid bronchoscopy include multiple malignant and benign disorders, with most interventions performed for treatment of complications of lung cancer. The rigid bronchoscope is a useful tool for managing most types of airway stenoses, and it facilitates other endobronchial therapies, including stent placement, argon plasma coagulation, balloon dilatation, electrocautery probes, and laser therapy. Certain patients with benign lesions or post-intubation or post-tracheostomy stenosis may benefit from rigid bronchoscopic techniques instead of surgery. Although use of the rigid bronchoscope requires general anesthesia, it provides a stable airway and often results in fast removal of foreign bodies. [ABSTRACT FROM AUTHOR]

Rationale: Follow-up of patients with emphysema treated with endobronchial valves is limited to 3-12 months after treatment in prior reports. To date, no comparative data exist between treatment and control subjects with a longer follow-up. Objectives: To assess the durability of the Spiration Valve System (SVS) in patients with severe heterogeneous emphysema over a 24-month period. Methods: EMPROVE, a multicenter randomized controlled trial, presents a rigorous comparison between treatment and control groups for up to 24 months. Lung function, respiratory symptoms, and quality-of-life (QOL) measures were assessed. Results: A significant improvement in forced expiratory volume in 1 second was maintained at 24 months in the SVS treatment group versus the control group. Similarly, significant improvements were maintained in several QOL measures, including the St. George's Respiratory Questionnaire and the COPD Assessment Test. Patients in the SVS treatment group experienced significantly less dyspnea than those in the control group, as indicated by the modified Medical Research Council dyspnea scale score. Adverse events at 24 months did not significantly differ between the SVS treatment and control groups. Acute chronic obstructive pulmonary disease exacerbation rates in the SVS treatment and control groups were 13.7% (14 of 102) and 15.6% (7 of 45), respectively. Pneumothorax rates in the SVS treatment and control groups were 1.0% (1 of 102) and 0.0% (0 of 45), respectively. Conclusions: SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and QOL, as well as a statistically significant reduction in dyspnea, for at least 24 months while maintaining an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Background: Therapeutic options for managing laryngotracheal stenosis (LTS) are limited. Endoscopy is a minimally invasive approach to treating LTS, but carries a high risk of stenosis recurrence. Mitomycin C (MMC) is often used as an adjunct therapy to delay the time to symptomatic recurrence of LTS. This review synthesizes the current literature on the topic of MMC as an adjunct treatment strategy for LTS., Methods: A focused literature search was carried out from PubMed on June 12, 2022 using the terms "mitomycin c AND stenosis" in all fields with no date limitations. Evidence-based recommendations relevant to the clinical application of MMC as an adjunct therapy for LTS were formulated. Three questions were addressed: 1) efficacy of MMC, 2) single versus multiple application(s) of MMC, and 3) safety of MMC. The evidence rating and recommendation strength were guided by the GRADE system., Results: Twenty-nine studies were reviewed. The efficacy of MMC as an adjunct therapy for LTS varied across studies. Randomized controlled trials have not shown an outcome difference with MMC use, although methodologic flaws including underpowering were noted. A meta-analysis of observational studies with a comparator arm found the unadjusted probability of remaining symptom-free for > 1 year is greater with versus without MMC application (73% vs. 35%). Single versus multiple application(s) of MMC resulted in similar restenosis rates at long-term follow-up. Complications related to MMC use are rarely reported using conventional doses (0.4 mg/mL). Overall, the quality of evidence was low and the recommendation for intervention was weak., Conclusion: The role for MMC as an adjunct therapy in LTS is uncertain. While safe in its application, the efficacy of MMC in reducing stenosis recurrence remains a matter of debate. Large, prospective studies are needed to inform future recommendations., Competing Interests: Disclosure: W.S. grant money for trial from GALA for Rheoplasty study and royalties from UpToDate for authorship. M.S.M. Olympus America: Consulting; Serpex Medical: Medical Advisory Board; UpToDate: Royalties for authorship. The remaining author has no conflict of interest or other disclosures., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been shown to have a high diagnostic yield for mediastinal and hilar lymph node sampling, particularly in diagnosing and staging non-small cell lung cancer. However, the diagnostic yield is lower in patients with granulomatous and lymphoproliferative disorders. We prospectively compared the feasibility, safety, and diagnostic yield of EBUS-guided lymph node forceps biopsy (EBUS-TBFB) with electrocautery knife compared to EBUS-TBNA of lymph nodes in patients with suspected granulomatous and lymphoproliferative disease., Methods: Patients over 18 years of age with mediastinal/hilar lymph node >10 mm in size in short axis (on CT chest) who had suspected sarcoidosis/lymphoma radiologically/clinically were included in the study. Patients had EBUS-TBNA first with 21 or 22G needles which were followed by biopsy of the node with small forceps (EBUS-TBFB) through the same aspiration site to obtain samples. Electrocautery knife at 20W was used in patients where mucosal penetration was difficult, followed by passage of forceps through that site., Results: A total of 30 patients were enrolled in the study, of which 25 patients underwent EBUS-TBFB. Eight patients had a history of lymphoma, one patient had history of squamous cell carcinoma, and one patient had history of chronic lymphocytic leukemia. A 22 gauge needle was used for aspiration in all the cases that were performed, and 1.5 mm or 1.8 mm forceps were used for the biopsy. The use of electrocautery knife at 20W (Olympus America Inc.) was required in 10/25 patients. The EC knife allowed all 10 of those to have successful entry of forceps into the lymph node. The cytology (aspiration from EBUS needle) and histopathology (from forceps) were concordant in 17 patients while it was discordant in eight patients. One patient developed pneumomediastinum after needle and forceps biopsy that required no intervention., Conclusion: EBUS-guided forceps biopsy is a safe procedure. EC knife did successfully allow forceps entry into the lymph node in all EC knife procedures. The diagnostic yield was 73% (22/30) which improved to 86% (26/30) when both techniques were combined (TBNA and TBFB)., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Pathak et al.)

Background: Bronchoscopic spray cryotherapy (SCT) is utilized in the field of interventional pulmonology for treating benign and malignant airway stenosis as a standard tool to maintain airway patency. Stent-related complications include tumor overgrowth, granulation tissue, and epithelialization. Thermal ablation can have a limited role in such scenarios due to the risk of airway fire and damage to the existing stent. SCT is a potential therapy using ultra-low temperatures that can allow stents to remain in place during treatment. However, there has been no study demonstrating the safety of SCT on the integrity and physical properties of tracheobronchial stents. We report the results of the first study demonstrating the safety of SCT utilized to treat stent-associated granulation or malignant airway disease. The aim of this study was to demonstrate the effects of SCT on the physical properties of airway stents in an ex vivo environment., Methods: Various types of airway stents were subjected to multiple intervals of SCT for up to 30 seconds, and then the cycle was repeated 3 times. After every cycle, we compressed the stents to 60% of their original size, and compression and expansion force data was collected immediately after, at 3-minute and 5-minute intervals, and compared with the baseline readings., Results: There was no significant change in the association between diameter and compression/expansion force, including any derangement in returning to the original diameter or any physical damage to any of the stents even after 3 prolonged SCT sessions of 30 seconds., Conclusion: Our study provides the first evidence that the use of SCT in conjunction with existing silicone/metal stents is feasible and does not cause any physical damage to the stents or alters their ability to maintain the original diameter., Competing Interests: Disclosure: R.W.S. received consulting fees from COOK Medical, royalties from UpToDate, grant funding from Spiration (Olympus). D.S. received consulting fees from Merit Medical. L.K. declares that there is no conflict of interest or other disclosures., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although thoracentesis can offer considerable symptomatic relief to the patient, its physiologic impact on oxygen saturation has not been well established in the literature. This study aimed to evaluate the impact of thoracentesis on postprocedure pulse oximetry (SpO2) in an inpatient population., Methods: A retrospective study of patients undergoing thoracentesis from January 2012 to November 2017 was performed. Inclusion criteria were age above 18 and thoracentesis performed in an inpatient setting. Records were reviewed for patient demographics, procedure reports, and laboratory values. SpO2 and FiO2 values were collected before and 6 and 24 hours postprocedure. Multivariable linear regression models were used to evaluate for changes in SpO2 and SpO2/FiO2. Analyses were adjusted for age, sex, serum hemoglobin, effusion etiology, volume removed, nonexpandable lung physiology and procedural complications and FiO2., Results: A total of 502 patients were included. The mean (SD) age was 60 (14) years, and 53.4% of the patients were male. The most common cause of pleural effusion was malignant effusion (37%). The median (interquartile range) volume of fluid removed was 1400 (1000 to 2000) mL and nonexpandable lung physiology was noted in 35%. There was no significant within-subject difference in 24 hours postprocedure SpO2 compared with preprocedure SpO2. In multivariable analysis, there was a small increase in 24-hour postprocedure SpO2 [β=0.31, 95% confidence interval (0.22, 0.41), P<0.01] and a similar small increase in 24-hour postprocedure SpO2/FiO2 [β=0.84, 95% confidence interval: (0.68, 1.01), P<0.01)., Conclusion: Among inpatients undergoing thoracentesis, there is no clinically significant change in SpO2 or SpO2/FiO2 at 24-hours post-procedure compared to pre-procedural SpO2 or SpO2/FiO2., Competing Interests: Disclosure: There is no conflict of interest or other disclosures., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite increased use of rigid bronchoscopy (RB) for therapeutic indications and recommendations from professional societies to use performance-based competency, an assessment tool has not been utilized to measure the competency of trainees to perform RB in clinical settings., Objectives: The aim of the study was to evaluate a previously developed assessment tool - Rigid Bronchoscopy Tool for Assessment of Skills and Competence (RIGID-TASC) - for determining the RB learning curve of interventional pulmonary (IP) trainees in the clinical setting and explore the variability of learning curve of trainees., Methods: IP fellows at 4 institutions were enrolled. After preclinical simulation training, all RBs performed in patients were scored by faculty using RIGID-TASC until competency threshold was achieved. Competency threshold was defined as unassisted RB intubation and navigation through the central airways on 3 consecutive patients at the first attempt with a minimum score of 89. A regression-based model was devised to construct and compare the learning curves., Results: Twelve IP fellows performed 178 RBs. Trainees reached the competency threshold between 5 and 24 RBs, with a median of 15 RBs (95% CI, 6-21). There were differences among trainees in learning curve parameters including starting point, slope, and inflection point, as demonstrated by the curve-fitting model. Subtasks that required the highest number of procedures (median = 10) to gain competency included ability to intubate at the first attempt and intubation time of <60 s., Conclusions: Trainees acquire RB skills at a variable pace, and RIGID-TASC can be used to assess learning curve of IP trainees in clinical settings., (© 2021 S. Karger AG, Basel.)

Rationale: Less invasive, nonsurgical approaches are needed to treat severe emphysema. Objectives: To evaluate the effectiveness and safety of the Spiration Valve System (SVS) versus optimal medical management. Methods: In this multicenter, open-label, randomized, controlled trial, subjects aged 40 years or older with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control). Measurements and Main Results: The primary efficacy outcome was the difference in mean FEV 1 from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV 1 responder rates, target lobe volume reduction, hyperinflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic serious adverse events. All analyses were conducted by determining the 95% Bayesian credible intervals (BCIs) for the difference between treatment and control arms. Between October 2013 and May 2017, 172 participants (53.5% male; mean age, 67.4 yr) were randomized to treatment ( n  = 113) or control ( n  = 59). Mean FEV 1 showed statistically significant improvements between the treatment and control groups-between-group difference at 6 and 12 months, respectively, of 0.101 L (95% BCI, 0.060-0.141) and 0.099 L (95% BCI, 0.048-0.151). At 6 months, the treatment group had statistically significant improvements in all secondary endpoints except 6-minute-walk distance. Composite thoracic serious adverse event incidence through 6 months was greater in the treatment group (31.0% vs. 11.9%), primarily due to a 12.4% incidence of serious pneumothorax. Conclusions: In patients with severe heterogeneous emphysema, the SVS shows significant improvement in multiple efficacy outcomes, with an acceptable safety profile.Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

Central airway involvement is a common manifestation of lung cancer during the disease course. Some patients will require bronchoscopic therapeutic interventions to palliate symptoms, or less commonly to provide more definitive therapy of airway involvement. We describe an overview specifically of bronchoscopic ablative techniques that are available for use in malignant airway obstruction. Techniques that are more commonly used include bronchoscopic application of laser, electrocautery, argon plasma coagulation (APC), cryotherapy and mechanical debulking techniques. Less commonly employed are brachytherapy and photodynamic therapy. These techniques may be applied via flexible or rigid bronchoscopy depending upon the clinical scenario. The choice of technique depends on available tools and expertise, the urgency of the clinical scenario, and whether the lesion is predominately endobronchial, extrinsic compression, or a combination of both. Malignant airway obstruction is a common finding in lung cancer and there are a number of effective bronchoscopic ablative techniques that may be employed safely to palliate patients with a significant symptom burden., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Cystic fibrosis liver disease (CFLD) in children causes progressive fibrosis leading to biliary cirrhosis; however, its cause(s) and early pathogenesis are unclear. We hypothesized that a bile acid-induced ductular reaction (DR) drives fibrogenesis. The DR was evaluated by cytokeratin-7 immunohistochemistry in liver biopsies, staged for fibrosis, from 60 children with CFLD, and it demonstrated that the DR was significantly correlated with hepatic fibrosis stage and biliary taurocholate levels. To examine the mechanisms involved in DR induction, liver progenitor cells (LPCs) were treated with taurocholate, and key events in DR evolution were assessed: LPC proliferation, LPC biliary differentiation, and hepatic stellate cell (HSC) chemotaxis. Taurocholate induced a time-dependent increase in LPC proliferation and expression of genes associated with cholangiocyte differentiation (cytokeratin 19, connexin 43, integrin β4, and γ-glutamyltranspeptidase), whereas the hepatocyte specification marker HNF4α was suppressed. Functional cholangiocyte differentiation was demonstrated via increased acetylated α-tubulin and SOX9 proteins, the number of primary cilia + LPCs, and increased active γ-glutamyltranspeptidase enzyme secretion. Taurocholate induced LPCs to release MCP-1, MIP1α, and RANTES into conditioned medium causing HSC chemotaxis, which was inhibited by anti-MIP1α. Immunofluorescence confirmed chemokine expression localized to CK7 + DR and LPCs in CFLD liver biopsies. This study suggests that taurocholate is involved in initiating functional LPC biliary differentiation and the development of the DR, with subsequent induction of chemokines that drive HSC recruitment in CFLD., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Pleural biopsy is often obtained in patients with undiagnosed exudative pleural effusion during pleuroscopy. Standard forceps have been traditionally used for the biopsy. Cryoprobes are being increasingly used for transbronchial lung biopsy as they obtain larger specimens and have less crush artifact. However, the safety and feasibility of cryoprobe biopsy compared to standard forceps for pleural biopsy has not been fully assessed., Objectives: The objective of this study was to demonstrate the safety and feasibility of cryoprobe biopsy in the pleural space using semi-rigid pleuroscopy., Methods: Patients with idiopathic exudative pleural effusions underwent pleuroscopy. The procedure was done in the endoscopy suite with full barrier precautions and moderate sedation. Pleural biopsies were initially taken with a 2.0-mm saw-toothed forceps followed by a 2.4-mm cryoprobe (ERBECRYO, ERBE, US). The freeze time for each biopsy was 3 s., Results: There were a total of ten patients, five males and five females. The mean age was 69 years (SD ± 11 years). The mean number of biopsies taken from the parietal pleura using forceps was 4.5 (SD ± 1.5) vs. 3.7 (SD ± 1.4) using cryoprobe. The mean cumulative tissue volume with forceps biopsy was 80 cu. mm; the mean cumulative tissue volume with cryobiopsy was 320 cu. mm, p = 0.007. The diagnostic yields were similar in both the groups. There was no increased incidence of bleeding, chest wall injury, or pain using cryoprobe in any of the patients., Conclusion: The use of cryoprobe for parietal pleural biopsy via semi-rigid pleuroscopy was feasible and safe in this small pilot study.

Rationale: Patients with malignant pleural effusions have significant dyspnea and shortened life expectancy. Indwelling pleural catheters allow patients to drain pleural fluid at home and can lead to autopleurodesis. The optimal drainage frequency to achieve autopleurodesis and freedom from catheter has not been determined., Objectives: To determine whether an aggressive daily drainage strategy is superior to the current standard every other day drainage of pleural fluid in achieving autopleurodesis., Methods: Patients were randomized to either an aggressive drainage (daily drainage; n = 73) or standard drainage (every other day drainage; n = 76) of pleural fluid via a tunneled pleural catheter., Measurements and Main Results: The primary outcome was the incidence of autopleurodesis following the placement of the indwelling pleural catheters. The rate of autopleurodesis, defined as complete or partial response based on symptomatic and radiographic changes, was greater in the aggressive drainage arm than the standard drainage arm (47% vs. 24%, respectively; P = 0.003). Median time to autopleurodesis was shorter in the aggressive arm (54 d; 95% confidence interval, 34-83) as compared with the standard arm (90 d; 95% confidence interval, 70 to nonestimable). Rate of adverse events, quality of life, and patient satisfaction were not significantly different between the two arms., Conclusions: Among patients with malignant pleural effusion, daily drainage of pleural fluid via an indwelling pleural catheter led to a higher rate of autopleurodesis and faster time to liberty from catheter. Clinical trial registered with www.clinicaltrials.gov (NCT 00978939).

Tracheobronchial tuberculosis (TBTB) is reported in approximately 10% to 39% of the patients with pulmonary tuberculosis. It is defined as the tubercle infection of the trachea and or bronchi. Due to its non-specific presentation, insidious onset and normal chest radiography in about 10-20% of the patients, the diagnosis is delayed. Bronchoscopy is the most definite method of diagnosis which provides adequate specimens for microbiological and histopathological diagnosis. Tracheobronchial stenosis is one of the most common long term complications of TBTB resulting in significant morbidity. It is estimated that 90% of patients with TBTB have some degree of tracheal and or bronchial stenosis. In this review article, we will discuss the pathogenesis, symptoms, imaging, bronchoscopic findings, and treatment of TBTB and management of tracheobronchial stenosis., Competing Interests: The authors have no conflicts of interest to declare.

Iatrogenic tracheal laceration is a known complication of emergent endotracheal intubation. Patients with tracheal laceration present a therapeutic challenge. There is no established standard treatment approach in this patient population. Interventions reported include conservative management, stent placement, or surgery. We present our experience of tracheal tears in patients with respiratory failure successfully managed with polyurethane-covered nitinol stent, including three cases of postintubation and one case of postsurgical tracheostomy tracheal injury.

Objectives: Although screening for biliary atresia (BA) is associated with improved outcomes, no screening program currently exists in the United States. In this study, we explore the possibility of a screening strategy based on newborn direct or conjugated bilirubin (DB or CB) measurements. Our objective is to estimate testing's sensitivity and specificity for BA., Methods: Two groups were examined retrospectively. For sensitivity calculations, a BA group consisting of infants born between January 2011 and December 2014, diagnosed with BA, and cared for at a pediatric gastroenterology referral center was examined. For specificity calculations, a non-BA group that comprised of infants born between June 2009 and August 2011 in a hospital with a policy of checking newborn bilirubin concentrations was studied., Results: All 35 infants with newborn DB or CB measurements in the BA group had elevated concentrations, translating to a sensitivity of 100% (95% CI 87.7-100). In the non-BA group, 8936 of 9102 infants had DB concentrations within the laboratory's reference interval, translating to a specificity of 98.2% (95% CI 97.9-98.4). Three methods-calculating direct:total bilirubin ratios, using 99% reference intervals, and repeat testing-changed specificity to different degrees., Conclusions: Newborn DB or CB measurements may have a high sensitivity and specificity for BA. Specificity can be further improved by using 99% reference intervals and/or repeat testing. Our findings can serve as the foundation for larger prospective studies, to determine whether newborn DB or CB measurements can be an effective screening strategy for BA.

Purpose of Review: Peripheral pulmonary lesions (PPL) are being diagnosed with increasing frequency, especially with the increased use of chest computed tomography (CT). Depending on the location and size, these lesions often present a diagnostic challenge in terms of the low yield of traditional bronchoscopic biopsy techniques or the risks of a percutaneous biopsy approach., Recent Findings: Over the last several years, several different image-guided bronchoscopy techniques have emerged, including virtual bronchoscopic navigation, electromagnetic navigation bronchoscopy, radial endobronchial ultrasound, and ultrathin bronchoscopy. These technologies seek to improve both access and the diagnostic yield of PPL compared with traditional bronchoscopy and to perform with a lower complication rate than percutaneous techniques such as CT-guided trans-thoracic needle aspiration., Summary: These advanced bronchoscopic techniques play an increasingly common role in the evaluation and biopsy of PPL. Electromagnetic navigation bronchoscopy and radial endobronchial ultrasound are the most commonly used guided techniques either in isolation or in combination and have the most published data regarding clinical experience and diagnostic yield; however, none of the techniques have consistently matched the yield of CT-guided trans-thoracic needle biopsy for PPL. Overall the complication rate of image-guided bronchoscopy techniques is low with pneumothorax being the most common adverse event.

Background: Endobronchial ultrasound (EBUS) was introduced in the last decade, enabling real-time guidance of transbronchial needle aspiration (TBNA) of mediastinal and hilar structures and parabronchial lung masses. The many publications produced about EBUS-TBNA have led to a better understanding of the performance characteristics of this procedure. The goal of this document was to examine the current literature on the technical aspects of EBUS-TBNA as they relate to patient, technology, and proceduralist factors to provide evidence-based and expert guidance to clinicians., Methods: Rigorous methodology has been applied to provide a trustworthy evidence-based guideline and expert panel report. A group of approved panelists developed key clinical questions by using the PICO (population, intervention, comparator, and outcome) format that addressed specific topics on the technical aspects of EBUS-TBNA. MEDLINE (via PubMed) and the Cochrane Library were systematically searched for relevant literature, which was supplemented by manual searches. References were screened for inclusion, and well-recognized document evaluation tools were used to assess the quality of included studies, to extract meaningful data, and to grade the level of evidence to support each recommendation or suggestion., Results: Our systematic review and critical analysis of the literature on 15 PICO questions related to the technical aspects of EBUS-TBNA resulted in 12 statements: 7 evidence-based graded recommendations and 5 ungraded consensus-based statements. Three questions did not have sufficient evidence to generate a statement., Conclusions: Evidence on the technical aspects of EBUS-TBNA varies in strength but is satisfactory in certain areas to guide clinicians on the best conditions to perform EBUS-guided tissue sampling. Additional research is needed to enhance our knowledge regarding the optimal performance of this effective procedure., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Progressive familial intrahepatic cholestasis type 2 (PFIC-2) is caused by mutations in ABCB11, encoding the bile salt export pump (BSEP). In 2009, we described a child with PFIC-2 who developed PFIC-like symptoms after orthotopic liver transplantation (OLT). BSEP-reactive antibodies were demonstrated to account for disease recurrence. Here, we characterize the nature of this antibody response in 7 more patients with antibody-induced BSEP deficiency (AIBD). Gene sequencing and immunostaining of native liver biopsies indicated absent or strongly reduced BSEP expression in all 7 PFIC-2 patients who suffered from phenotypic disease recurrence post-OLT. Immunofluorescence, western blotting analysis, and transepithelial transport assays demonstrated immunoglobulin (Ig) G-class BSEP-reactive antibodies in these patients. In all cases, the N-terminal half of BSEP was recognized, with reaction against its first extracellular loop (ECL1) in six sera. In five, antibodies reactive against the C-terminal half also were found. Only the sera recognizing ECL1 showed inhibition of transepithelial taurocholate transport. In a vesicle-based functional assay, transport inhibition by anti-BSEP antibodies binding from the cytosolic side was functionally proven as well. Within 2 hours of perfusion with antibodies purified from 1 patient, rat liver showed canalicular IgG staining that was absent after perfusion with control IgG., Conclusions: PFIC-2 patients carrying severe BSEP mutations are at risk of developing BSEP antibodies post-OLT. The antibody response is polyclonal, targeting both extra- and intracellular BSEP domains. ECL1, a unique domain of BSEP, likely is a critical target involved in transport inhibition as demonstrated in several patients with AIBD manifest as cholestasis., (© 2015 by the American Association for the Study of Liver Diseases.)

Unlabelled: Up to 10% of cystic fibrosis (CF) children develop cirrhosis by the first decade. We evaluated the utility of two simple biomarkers, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4, in predicting degree of fibrosis in pediatric CF liver disease (CFLD) validated by liver biopsy. In this retrospective, cross-sectional study, 67 children with CFLD had dual-pass liver biopsies and 104 age- and sex-matched CF children without liver disease (CFnoLD) had serum to calculate APRI and FIB-4 collected at enrollment. CFLD was defined as having two of the following: (1) hepatomegaly±splenomegaly; (2)>6 months elevation of ALT (>1.5× upper limit of normal ULN); or (3) abnormal liver ultrasound findings. Biopsies were staged according to Metavir classification by two blinded pathologists. Receiver operating characteristic (ROC) analysis and continuation ratio logistic regression were performed to assess the predictability of these biomarkers to distinguish CFLD from CFnoLD and determine fibrosis stage-specific cut-off values. The AUC for APRI was better than FIB-4 (0.75 vs. 0.60; P=0.005) for predicting CFLD and severe CFLD (F3-F4) (0.81). An APRI score>0.264 demonstrated a sensitivity (95% confidence interval [CI]) of 73.1% (60.9, 83.2) and specificity of 70.2% (60.4, 78.8) in predicting CFLD. A 50% increase in APRI was associated with a 2.4-fold (95% CI: 1.7, 3.3) increased odds of having CFLD. APRI demonstrated full agreement with histology staging 37% of the time, but was within one stage 73% of the time. Only FIB-4 predicted portal hypertension at diagnosis (area under the receiver operator characteristic curve [AUC 0.91; P<0.001)., Conclusion: This is the first liver biopsy-validated study of APRI and FIB-4 in pediatric CFLD. APRI appears superior to FIB-4 in differentiating CFLD versus CFnoLD. APRI also exhibited a high AUC in predicting severe liver fibrosis with specific cutoffs for lower stages., (© 2015 by the American Association for the Study of Liver Diseases.)