Interventions for increasing immunosuppressant medication adherence in solid organ transplant recipients.

BACKGROUND: Non-adherence to immunosuppressant therapy is a significant concern following a solid organ transplant, given its association with graft failure. Adherence to immunosuppressant therapy is a modifiable patient behaviour, and different approaches to increasing adherence have emerged, including multi-component interventions. There has been limited exploration of the effectiveness of interventions to increase adherence to immunosuppressant therapy. OBJECTIVES: This review aimed to look at the benefits and harms of using interventions for increasing adherence to immunosuppressant therapies in solid organ transplant recipients, including adults and children with a heart, lung, kidney, liver and pancreas transplant. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 14 October 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs), quasi-RCTs, and cluster RCTs examining interventions to increase immunosuppressant adherence following a solid organ transplant (heart, lung, kidney, liver, pancreas) were included. There were no restrictions on language or publication type. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts of identified records, evaluated study quality and assessed the quality of the evidence using the GRADE approach. The risk of bias was assessed using the Cochrane tool. The ABC taxonomy for measuring medication adherence provided the analysis framework, and the primary outcomes were immunosuppressant medication initiation, implementation (taking adherence, dosing adherence, timing adherence, drug holidays) and persistence. Secondary outcomes were surrogate markers of adherence, including self-reported adherence, trough concentration levels of immunosuppressant medication, acute graft rejection, graft loss, death, hospital readmission and health-related quality of life (HRQoL). Meta-analysis was conducted where possible, and narrative synthesis was carried out for the remainder of the results. MAIN RESULTS: Forty studies involving 3896 randomised participants (3718 adults and 178 adolescents) were included. Studies were heterogeneous in terms of the type of intervention and outcomes assessed. The majority of studies (80%) were conducted in kidney transplant recipients. Two studies examined paediatric solid organ transplant recipients. The risk of bias was generally high or unclear, leading to lower certainty in the results. Initiation of immunosuppression was not measured by the included studies. There is uncertain evidence of an association between immunosuppressant medication adherence interventions and the proportion of participants classified as adherent to taking immunosuppressant medication (4 studies, 445 participants: RR 1.09, 95% CI 0.95 to 1.20; I² = 78%). There was very marked heterogeneity in treatment effects between the four studies evaluating taking adherence, which may have been due to the different types of interventions used. There was evidence of increasing dosing adherence in the intervention group (8 studies, 713 participants: RR 1.14, 95% CI 1.03 to 1.26, I² = 61%).  There was very marked heterogeneity in treatment effects between the eight studies evaluating dosing adherence, which may have been due to the different types of interventions used. It was uncertain if an intervention to increase immunosuppressant adherence had an effect on timing adherence or drug holidays. There was limited evidence that an intervention to increase immunosuppressant adherence had an effect on persistence. There was limited evidence that an intervention to increase immunosuppressant adherence had an effect on secondary outcomes. For self-reported adherence, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the proportion of participants classified as medically adherent to immunosuppressant therapy (9 studies, 755 participants: RR 1.21, 95% CI 0.99 to 1.49; I² = 74%; very low certainty evidence). Similarly, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the mean adherence score on self-reported adherence measures (5 studies, 471 participants: SMD 0.65, 95% CI -0.31 to 1.60; I² = 96%; very low certainty evidence). For immunosuppressant trough concentration levels, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the proportion of participants who reach target immunosuppressant trough concentration levels (4 studies, 348 participants: RR 0.98, 95% CI 0.68 to 1.40; I² = 40%; very low certainty evidence). It is uncertain whether an intervention to increase adherence to immunosuppressant medication may reduce hospitalisations (5 studies, 460 participants: RR 0.67, 95% CI 0.44 to 1.02; I² = 64%; low certainty evidence). There were limited, low certainty effects on patient-reported health outcomes such as HRQoL. There was no clear evidence to determine the effect of interventions on secondary outcomes, including acute graft rejection, graft loss and death. No harms from intervention participation were reported. AUTHORS' CONCLUSIONS: Interventions to increase taking and dosing adherence to immunosuppressant therapy may be effective; however, our findings suggest that current evidence in support of interventions to increase adherence to immunosuppressant therapy is overall of low methodological quality, attributable to small sample sizes, and heterogeneity identified for the types of interventions. Twenty-four studies are currently ongoing or awaiting assessment (3248 proposed participants); therefore, it is possible that findings may change with the inclusion of these large ongoing studies in future updates.

Diagnostic performance of endobronchial ultrasound-guided mediastinal lymph node sampling in early stage non-small cell lung cancer: A prospective study.

BACKGROUND AND OBJECTIVE: Standard nodal staging of lung cancer consists of positron emission tomography/computed tomography (PET/CT), followed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) if PET/CT shows mediastinal lymphadenopathy. Sensitivity of EBUS-TBNA in patients with N0/N1 disease by PET/CT is unclear and largely based on retrospective studies. We assessed the sensitivity of EBUS-TBNA in this setting. METHODS: We enrolled patients with proven or suspected lung cancer staged as N0/N1 by PET/CT and without metastatic disease (M0), who underwent staging EBUS-TBNA. Primary outcome was sensitivity of EBUS-TBNA compared with a composite reference standard of surgical stage or EBUS-TBNA stage if EBUS demonstrated N2/N3 disease. RESULTS: Seventy-five patients were included in the analysis. Mean tumour size was 3.52 cm (±1.63). Fifteen of 75 patients (20%) had N2 disease. EBUS-TBNA identified six while nine were only identified at surgery. Sensitivity of EBUS-TBNA for N2 disease was 40% (95% CI: 16.3-67.7%). CONCLUSION: A significant proportion of patients with N0/N1 disease by PET/CT had N2 disease (20%) and EBUS-TBNA identified a substantial fraction of these patients, thus improving diagnostic accuracy compared with PET/CT alone. Sensitivity of EBUS-TBNA however appears lower compared with historical data from patients with larger volume mediastinal disease. Therefore, strategies to improve EBUS-TBNA accuracy in this population should be further explored.

A Prediction Model to Help with the Assessment of Adenopathy in Lung Cancer: HAL.

RATIONALE: Estimating the probability of finding N2 or N3 (prN2/3) malignant nodal disease on endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in patients with non-small cell lung cancer (NSCLC) can facilitate the selection of subsequent management strategies. OBJECTIVES: To develop a clinical prediction model for estimating the prN2/3. METHODS: We used the AQuIRE (American College of Chest Physicians Quality Improvement Registry, Evaluation, and Education) registry to identify patients with NSCLC with clinical radiographic stage T1-3, N0-3, M0 disease that had EBUS-TBNA for staging. The dependent variable was the presence of N2 or N3 disease (vs. N0 or N1) as assessed by EBUS-TBNA. Univariate followed by multivariable logistic regression analysis was used to develop a parsimonious clinical prediction model to estimate prN2/3. External validation was performed using data from three other hospitals. MEASUREMENTS AND MAIN RESULTS: The model derivation cohort (n = 633) had a 25% prevalence of malignant N2 or N3 disease. Younger age, central location, adenocarcinoma histology, and higher positron emission tomography-computed tomography N stage were associated with a higher prN2/3. Area under the receiver operating characteristic curve was 0.85 (95% confidence interval, 0.82-0.89), model fit was acceptable (Hosmer-Lemeshow, P = 0.62; Brier score, 0.125). We externally validated the model in 722 patients. Area under the receiver operating characteristic curve was 0.88 (95% confidence interval, 0.85-0.90). Calibration using the general calibration model method resulted in acceptable goodness of fit (Hosmer-Lemeshow test, P = 0.54; Brier score, 0.132). CONCLUSIONS: Our prediction rule can be used to estimate prN2/3 in patients with NSCLC. The model has the potential to facilitate clinical decision making in the staging of NSCLC.

FEV1 Variability Predicts Lung Transplant or Mortality in Cystic Fibrosis Patients in the US.

RATIONALE: Declines in percent predicted Forced Expiratory Volume in 1 Second (ppFEV1) are an important marker of clinical progression of Cystic Fibrosis (CF). OBJECTIVES: We examined ppFEV1 variability on a combined outcome of lung transplant or death. METHODS: We estimated the association between ppFEV1 variability and the combined outcome of lung transplant or death. We included children ages 8 years and above with CF and two prior years of ppFEV1 data before baseline between 2005 and 2021. We defined ppFEV1 increased variability as any relative increase or decrease of at least 10% in ppFEV1 from a two-year averaged baseline. A marginal structural Cox proportional hazards model was used. We examined a cumulative measure of ppFEV1 variability, defined as the cumulative proportion of visits with ppFEV1 variability at each visit. Kaplan-Meier survival curves were generated based upon quartiles of the cumulative distribution of ppFEV1 variability. MEASUREMENTS AND MAIN RESULTS: We included 9,706 CF patients in our cohort. Median age at cohort entry was 8.3 (IQR 8.2 - 8.4) years, 50% of patients were female, 94% white, and median baseline ppFEV1 was 94.4 (IQR 81.6 - 106.1). The unadjusted HR for increased ppFEV1 variability on lung transplant/mortality was 4.13 (95% CI 3.48 - 4.90) and the weighted HR was 1.49 (95% CI 1.19 - 1.86). Survival curves stratified by quartile of cumulative variability demonstrated an increased hazard of lung transplant/mortality as the proportion of cumulative ppFEV1 variability increased. CONCLUSIONS: We found a strong association between ppFEV1 variability and lung transplant or mortality in a cohort of people with CF in the US.

Nebulized hypertonic saline via positive expiratory pressure versus via jet nebulizer in patients with severe cystic fibrosis.

BACKGROUND: Nebulized hypertonic saline is a highly effective therapy for patients with cystic fibrosis (CF), yet 10% of patients are intolerant of hypertonic saline administered via jet nebulizer. Positive expiratory pressure (PEP) nebulizers splint open the airways and offers a more controlled rate of nebulization. METHODS: In 4 consecutive adult CF patients who were intolerant of hypertonic saline via jet nebulizer, we nebulized 6% hypertonic saline via a PEP nebulizer. We measured the number of days the patients required intravenous antibiotics from enrollment to study end, compared to an equal period before PEP, and the mean time between the patients' 3 most recent infective pulmonary exacerbation episodes before PEP to their next exacerbation after PEP. Patients also completed a Likert-scale adverse-effects questionnaire on hypertonic saline via PEP versus jet nebulizer. RESULTS: The 4 patients had severe CF pulmonary disease and all fully tolerated hypertonic saline via PEP, for 77, 92, 128, and 137 days, respectively until the study end date. There were fewer days of antibiotics in 3 of the 4 patients, from 45 to 20 days, 66 to 14 days, and 28 to 0 days (mean relative risk reduction 53%, P = .11). The other patient had 63 days of antibiotics during both the PEP and the jet nebulizer periods. There was a mean 3.6-fold longer time to next infective pulmonary exacerbation during the PEP period (P = .07). Adverse effects were less with PEP: chest tightness 68% (P = .04), bad taste 62% (P = .06), cough 47% (P = .10), and sore throat 50% (P = .20). CONCLUSIONS: Hypertonic saline via PEP nebulizer benefits CF patients who do not tolerate hypertonic saline via jet nebulizer.

Post-transplant diabetes mellitus associated with heart and lung transplant.

BACKGROUND: The incidence of post-transplant diabetes (PTDM) is variable primarily due to a lack of standardised diagnostic criteria. AIM: This study aimed to assess the incidence of PTDM in heart and lung transplant (HLT) patients and to review if the management of these patients is in accordance with the 2014 American Society of Transplantation guidelines. METHODS: This was a retrospective study in the Mater Misericordiae University Hospital, Dublin, Ireland. Data was collected from the patients who had undergone HLT. RESULTS: All patients who had a heart and/or lung transplant between 2005 and 2017 were identified. The majority of our patients had lung 111 (53.9%), heart 94 (45.6%) and combined heart/lung 1(0.5%) transplants. A total of 174 (84.5%) patients were screened for diabetes pre-transplantation. Two hundred five (99.9%) patients were screened for PTDM post-surgery. The cumulative incidence for PTDM was 19.4% (40/206). All patients with PTDM were on prednisolone, 32 (80%) on tacrolimus and 4 (10%) on cyclosporine. CONCLUSIONS: The cumulative incidence of post-transplant diabetes in our cohort was 19.4%. The majority of the patients were screened before and after transplant for glucose abnormality. The authors recommend that all patients should be managed in a multidisciplinary setting including transplant physicians, endocrinlogist, diabetes nurse specialists, transplant nurses and dietitians.

Interventional Procedures in Patients With Pulmonary Vascular Obstruction.

A 21-year-old patient presented with a short history of fatigue and dyspnea on a background of double-lung transplantation for cystic fibrosis and preexisting chronic superior vena cava obstruction. Computed tomography of the chest demonstrated a 3-cm mass occluding the right pulmonary veins, with associated right upper and lower lobe pulmonary parenchymal infiltrates. Two invasive procedures were performed, with similar complications in both procedures.

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in the Nodal Staging of Stereotactic Ablative Body Radiotherapy Patients.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) being evaluated for stereotactic ablative body radiotherapy (SABR) are typically staged noninvasively with positron emission tomography/computed tomography (PET/CT). Incorporating endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) into the staging workup of these patients has not been evaluated. Our primary objective was to compare the performance of PET/CT with EBUS-TBNA for intrathoracic nodal assessment among SABR-eligible patients. METHODS: This was a retrospective study consisting of two parts. First, we assessed the concordance for nodal metastasis of PET/CT and EBUS-TBNA. Second, we evaluated clinical outcomes among patients who underwent SABR with and without a prior EBUS-TBNA. RESULTS: We identified 246 eligible patients. Compared with PET/CT, EBUS-TBNA led to a stage shift in 48 of 246 patients (19%). Of 174 N0 patients by PET/CT, 6 (3.4%) had nodal metastasis on EBUS-TBNA. Among 72 clinical N1 patients, 36 (50%) were downstaged to N0 after EBUS-TBNA, therefore becoming eligible for SABR. Concordance between PET/CT and EBUS-TBNA for nodal metastasis was 83% (κ = 0.53). Clinical outcomes of patients who underwent SABR with or without a prior EBUS-TBNA did not differ significantly. CONCLUSIONS: Concordance of PET/CT and EBUS-TBNA for nodal disease was only moderate. Incorporating EBUS-TBNA into the staging workup was beneficial in identifying occult nodal metastasis that would otherwise be left untreated with SABR and in expanding the pool of potentially SABR-eligible patients.

Intrapleural Fibrinolytic Therapy in Patients With Nondraining Indwelling Pleural Catheters.

BACKGROUND: Tissue plasminogen activator (tPA) has been successfully used to relieve obstruction of dysfunctional devices, including vascular catheters. Intrapleural tPA is used by some centers to restore flow of nondraining indwelling pleural catheters (IPCs) in symptomatic patients with malignant pleural effusions (MPEs). Because few studies have evaluated its safety and effectiveness, we conducted a retrospective cohort study of outcomes after tPA treatment during a 10-year period at our institution. METHODS: We studied 97 patients with MPE and a nondraining IPC in the setting of persistent pleural fluid who were treated with intrapleural tPA. The primary outcome was restoration of flow after treatment. Secondary outcomes included complication rates and the need for further pleural interventions. Symptomatic relief was assessed using the Borg perceived scale. RESULTS: We identified 97 patients with MPE and a nondraining IPC who were treated with tPA. Flow was restored after 1 tPA dose in 83 of 97 patients (86%; 95% confidence interval, 77%-92%). Reocclusion after 1 dose was seen in 27 of 83 patients (32%), and 22 (81%) of these patients were treated with a second tPA dose. Among these 22, flow was restored in 16 (72%; 95% confidence interval, 44%-84%). Borg score improvement was only seen in patients who had restored flow (P=0.024). This finding was independent of the size of the effusion upon chest x-ray. There were 5 complications: 2 hemothoraxes and 3 infectious complications. CONCLUSION: On the basis of our finding of successful flow restoration with few complications, we recommend intrapleural tPA treatment for symptomatic patients with nondraining IPCs in the setting of persistent pleural fluid.

Adalimumab-induced lupus serositis.

A 61-year-old man presented with a 1-month history of breathlessness, chest pain and lethargy. He had been taking adalimumab for ankylosing spondylitis for 2 years. Pleural and pericardial effusions were both found. A video-assisted thorascopic (VATS) pleural and lung biopsy were performed. The pleural pathology showed eosinophils, acute inflammatory cells and lymphoid aggregates. The patient was positive for antinuclear, antidouble-stranded and antihistone antibodies consistent with drug-induced lupus due to adalimumab. His serositis resolved on withdrawal of the drug. Drug-induced lupus can occur as a consequence of anti-TNF-α agents from induction of autoimmunity in a predisposed host.

Biomarkers to identify ILD and predict lung function decline in scleroderma lung disease or idiopathic pulmonary fibrosis.

BACKGROUND: SSc-ILD and IPF demonstrate significant morbidity and mortality. Predicting disease progression is challenging in both diseases. OBJECTIVES: We sought a serum biomarker that could identify patients with SSc-ILD or IPF and prospectively predict short-term decline in lung function in these patients. METHODS: 10 healthy controls, 5 SSc w/o ILD, 6 SSc-ILD and 13 IPF patients underwent venesection. An array of cytokines including KL-6, SP-D and MMP7 were measured. PFTs were obtained at baseline and six months. Cytokine measurements were correlated with PFTs. RESULTS: KL-6 in IPF patients (633 ng/ml, IQR 492-1675) was significantly elevated compared to controls (198 ng/ml, IQR 52-360, p<0.01) and SSc w/o ILD patients (192 ng/ml, IQR 0-524, p<0.05); KL-6 in SSc-ILD patients (836 ng/ml, IQR 431-1303) was significantly higher than in controls (p<0.05). SP-D was significantly higher in IPF patients (542 ng/ml, IQR 305-577) compared to controls (137 ng/ml, IQR 97-284, p<0.01) or to SSc w/o ILD patients (169 ng/ml, IQR 137-219, p<0.05). In comparison with controls (0.0 ng/ml, IQR 0.0-0.6), MMP7 was significantly higher in both IPF patients (2.85 ng/ml, IQR 1.5-3.6, p<0.05) and SSc-ILD patients (5.41 ng/ml, IQR 2.6-7.2, p<0.001). Using a cut-off level of 459ng/ml for KL-6 and of 1.28 ng/ml for MMP7, 18 out of 19 patients with ILD had a serum value of either KL-6 or MMP7 above these thresholds. For all ILD patients, baseline serum SP-D correlated with ΔFVC %pred over six months (r=-0.63, p=0.005, 95% CI -0.85 to -0.24). CONCLUSIONS: Combining KL-6 with MMP7 may be a useful screening tool for patients at risk of ILD. SP-D may predict short-term decline in lung function.

Microbiota and metabolite profiling reveal specific alterations in bacterial community structure and environment in the cystic fibrosis airway during exacerbation.

Chronic polymicrobial infections of the lung are the foremost cause of morbidity and mortality in cystic fibrosis (CF) patients. The composition of the microbial flora of the airway alters considerably during infection, particularly during patient exacerbation. An understanding of which organisms are growing, their environment and their behaviour in the airway is of importance for designing antibiotic treatment regimes and for patient prognosis. To this end, we have analysed sputum samples taken from separate cohorts of CF and non-CF subjects for metabolites and in parallel, and we have examined both isolated DNA and RNA for the presence of 16S rRNA genes and transcripts by high-throughput sequencing of amplicon or cDNA libraries. This analysis revealed that although the population size of all dominant orders of bacteria as measured by DNA- and RNA- based methods are similar, greater discrepancies are seen with less prevalent organisms, some of which we associated with CF for the first time. Additionally, we identified a strong relationship between the abundance of specific anaerobes and fluctuations in several metabolites including lactate and putrescine during patient exacerbation. This study has hence identified organisms whose occurrence within the CF microbiome has been hitherto unreported and has revealed potential metabolic biomarkers for exacerbation.

Bacterial cis-2-unsaturated fatty acids found in the cystic fibrosis airway modulate virulence and persistence of Pseudomonas aeruginosa.

There is an increasing appreciation of the polymicrobial nature of many bacterial infections such as those associated with cystic fibrosis (CF) and of the potentially important role for interspecies interactions in influencing both bacterial virulence and response to therapy. Patients with CF are often co-infected with Pseudomonas aeruginosa and other pathogens including Burkholderia cenocepacia and Stenotrophomonas maltophilia. These latter bacteria produce signal molecules of the diffusible signal factor (DSF) family, which are cis-2-unsaturated fatty acids. We have previously shown by in vitro studies that DSF from S. maltophilia leads to altered biofilm formation and increased resistance to antibiotics by P. aeruginosa; these responses of P. aeruginosa require the sensor kinase PA1396. Here we show that DSF signals are present in sputum taken from patients with CF. Presence of these DSF signals was correlated with patient colonization by S. maltophilia and/or B. cenocepacia. Analysis of 50 clinical isolates of P. aeruginosa showed that each responded to the presence of synthetic DSF by increased antibiotic resistance and these strains demonstrated little sequence variation in the PA1396 gene. In animal experiments using CF transmembrane conductance regulator knockout mice, the presence of DSF promoted P. aeruginosa persistence. Furthermore, antibiotic resistance of P. aeruginosa biofilms grown on human airway epithelial cells was enhanced in the presence of DSF. Taken together, these data provide substantial evidence that interspecies DSF-mediated bacterial interactions occur in the CF lung and may influence the efficacy of antibiotic treatment, particularly for chronic infections involving persistence of bacteria.

Radiologic imaging in cystic fibrosis: cumulative effective dose and changing trends over 2 decades.

OBJECTIVE: With the increasing life expectancy for patients with cystic fibrosis (CF), and a known predisposition to certain cancers, cumulative radiation exposure from radiologic imaging is of increasing significance. This study explores the estimated cumulative effective radiation dose over a 17-year period from radiologic procedures and changing trends of imaging modalities over this period. METHODS: Estimated cumulative effective dose (CED) from all thoracic and extrathoracic imaging modalities and interventional radiology procedures for both adult and pediatric patients with CF, exclusively attending a nationally designated CF center between 1992-2009 for > 1 year, was determined. The study period was divided into three equal tertiles, and estimated CED attributable to all radiologic procedures was estimated for each tertile. RESULTS: Two hundred thirty patients met inclusion criteria (2,240 person-years of follow-up; 5,596 radiologic procedures). CED was > 75 mSv for one patient (0.43%), 36 patients (15.6%) had a CED between 20 and 75 mSv, 56 patients (24.3%) had a CED between 5 and 20 mSv, and in 138 patients (60%) the CED was estimated to be between 0 and 5 mSv over the study period. The mean annual CED per patient increased consecutively from 0.39 mSv/y to 0.47 mSv/y to 1.67 mSv/y over the tertiles one to three of the study period, respectively (P < .001). Thoracic imaging accounted for 46.9% of the total CED and abdominopelvic imaging accounted for 42.9% of the CED, respectively. There was an associated 5.9-fold increase in the use of all CT scanning per patient (P < .001). CONCLUSIONS: This study highlights the increasing exposure to ionizing radiation to patients with CF as a result of diagnostic imaging, primarily attributable to CT scanning. Increased awareness of CED and strategies to reduce this exposure are needed.

Idiopathic pulmonary fibrosis: treatment update.

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. Despite multiple recent clinical trials, there is no strong evidence supporting a survival advantage for any agent in the management of patients with IPF. The limited effectiveness of current treatment regimes has led to a search for novel therapies including antifibrotic strategies. This article reviews the evidence supporting the treatments currently used in the management of IPF.