Impact of the COVID-19 pandemic on care disruptions, outcomes, and costs in patients receiving pulmonary arterial hypertension-specific therapy in the United States of America: An observational study.

Regular expert follow-up, risk assessment, and early therapeutic intervention minimize worsening of pulmonary arterial hypertension (PAH). COVID-19 lockdown measures were challenging for chronic disease management. This retrospective, longitudinal analysis used US claims data (January 12, 2016 to September 11, 2021) for patients treated with PAH-specific medication to compare in-person outpatient and specialist visits, telemedicine visits, and PAH-related tests during 6-month assessment periods pre- and immediately post-COVID-19. Hospitalizations, costs, and outcomes were compared in patients with and without care disruptions (no in-person or telemedicine outpatient visits in immediate post-COVID-19 period). Patients in the immediate post-COVID-19 (N = 599) versus the pre-COVID-19 period (N = 598) had fewer in-person outpatient visits (mean 1.27 vs. 2.12) and in-person specialist visits (pulmonologist, 22.9% vs. 37.0% of patients; cardiologist, 27.5% vs. 33.8%); and more telemedicine visits (mean 0.45 vs. 0.02). In the immediate post-COVID-19 period, patients were less likely to have a PAH-related test versus the pre-COVID-19 period (incidence rate ratio: 0.700; 95% confidence interval: 0.615-0.797), including electrocardiograms (41.7% vs. 54.2%) and 6-minute walk distance tests (16.2% vs. 24.9%). In the immediate post-COVID-19 period, 48 patients had care disruptions and, in the following year, required more hospital days than those without care disruptions (N = 240) (median 10 vs. 5 days in total) and had higher overall hospitalization costs (median US$34,755 vs. US$20,090). Our findings support the need for minimizing care disruptions to potentially avoid incremental post-disruption healthcare utilization and costs among patients with serious chronic diseases such as PAH.

Small sequence variations between two mammalian paralogs of the small GTPase SAR1 underlie functional differences in coat protein complex II assembly.

Vesicles that are coated by coat protein complex II (COPII) are the primary mediators of vesicular traffic from the endoplasmic reticulum to the Golgi apparatus. Secretion-associated Ras-related GTPase 1 (SAR1) is a small GTPase that is part of COPII and, upon GTP binding, recruits the other COPII proteins to the endoplasmic reticulum membrane. Mammals have two SAR1 paralogs that genetic data suggest may have distinct physiological roles, e.g. in lipoprotein secretion in the case of SAR1B. Here we identified two amino acid clusters that have conserved SAR1 paralog-specific sequences. We observed that one cluster is adjacent to the SAR1 GTP-binding pocket and alters the kinetics of GTP exchange. The other cluster is adjacent to the binding site for two COPII components, SEC31 homolog A COPII coat complex component (SEC31) and SEC23. We found that the latter cluster confers to SAR1B a binding preference for SEC23A that is stronger than that of SAR1A for SEC23A. Unlike SAR1B, SAR1A was prone to oligomerize on a membrane surface. SAR1B knockdown caused loss of lipoprotein secretion, overexpression of SAR1B but not of SAR1A could restore secretion, and a divergent cluster adjacent to the SEC31/SEC23-binding site was critical for this SAR1B function. These results highlight that small primary sequence differences between the two mammalian SAR1 paralogs lead to pronounced biochemical differences that significantly affect COPII assembly and identify a specific function for SAR1B in lipoprotein secretion, providing insights into the mechanisms of large cargo secretion that may be relevant for COPII-related diseases.

Retrospective Database Analysis of Treatment Patterns Among Patients with Pulmonary Arterial Hypertension.

INTRODUCTION: Release of the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines put increased emphasis on using combination therapy, either as upfront or sequential therapy among patients with pulmonary arterial hypertension (PAH). However, with these recommendations and the therapy advances made in the last several years, little is known on the real-world treatment patterns among patients with PAH, particularly before and after publication of the 2015 ESC/ERS guidelines. METHODS: This was a retrospective study of adult commercial and Medicare Advantage with Part D (MAPD) enrollees with at least one claim for a PAH-related medication from January 01, 2012 to March 31, 2017, at least one medical claim with a pulmonary hypertension diagnosis, and continuous health plan enrollment at least 6 months prior to and at least 12 months following the date of the first pharmacy claim for PAH-related therapy (index date). Patients were divided into cohorts based on prescription of monotherapy or combination therapy and index date category (2012-2013, January 2014-July 2015, and August 2015-March 2017). RESULTS: Out of 1878 patients, 90.8% initiated with monotherapy and 9.2% initiated with combination therapy. The percentage of patients with index combination therapy increased from 5.7% in 2012-2013 to 13.0% in August 2015-March 2017. Patients with index combination therapy had better persistence (11.6 months versus 10.3 months) and adherence (0.95 versus 0.85). Overall, the discontinuation rate was 40% and was higher in monotherapy versus combination therapy patients (42.8% versus 12.2%). Approximately 30.2% of patients had a second regimen, of which 50% were combination regimens. The time to combination therapy initiation decreased from 10.5 months in 2012-2013 to 3.4 months in August 2015-March 2017. CONCLUSIONS: The majority of patients initiated monotherapy treatment for PAH, most often a phosphodiesterase 5 inhibitor (PDE5i). Patients with upfront combination therapy increased following publication of the 2015 ESC/ERS guidelines, indicating that physicians responded to the guideline's option of prescribing upfront combination therapy.

Dimethyl Fumarate Disrupts Human Innate Immune Signaling by Targeting the IRAK4-MyD88 Complex.

Dimethyl fumarate (DMF) is a prescribed treatment for multiple sclerosis and has also been used to treat psoriasis. The electrophilicity of DMF suggests that its immunosuppressive activity is related to the covalent modification of cysteine residues in the human proteome. Nonetheless, our understanding of the proteins modified by DMF in human immune cells and the functional consequences of these reactions remains incomplete. In this study, we report that DMF inhibits human plasmacytoid dendritic cell function through a mechanism of action that is independent of the major electrophile sensor NRF2. Using chemical proteomics, we instead identify cysteine 13 of the innate immune kinase IRAK4 as a principal cellular target of DMF. We show that DMF blocks IRAK4-MyD88 interactions and IRAK4-mediated cytokine production in a cysteine 13-dependent manner. Our studies thus identify a proteomic hotspot for DMF action that constitutes a druggable protein-protein interface crucial for initiating innate immune responses.

Treatment patterns, healthcare resource utilization, and healthcare costs among patients with pulmonary arterial hypertension in a real-world US database.

Several new medications for pulmonary arterial hypertension (PAH) have recently been introduced; however, current real-world data regarding US patients with PAH are limited. We conducted a retrospective administrative claims study to examine PAH treatment patterns and summarize healthcare utilization and costs among patients with newly diagnosed PAH treated in US clinical practice. Patients newly treated for PAH from 1 January 2010 to 31 March 2015 were followed for ≥12 months. Patient characteristics, treatment patterns, healthcare resource utilization, and costs were described. Adherence (proportion of days covered), persistence (months until therapy discontinuation/modification), and the probability of continuing the index regimen were analyzed by index regimen cohort (monotherapy versus combination therapy). Of 1637 eligible patients, 93.8% initiated treatment with monotherapy and 6.2% with combination therapy. The most common index regimen was phosphodiesterase type 5 inhibitor (PDE-5I) monotherapy (70.0% of patients). A total of 581 patients (35.5%) modified their index regimen during the study. Most patients (55.4%) who began combination therapy did so on or within six months of the index date. Endothelin receptor agonists (ERAs) and combination therapies were associated with higher adherence than PDE-5Is and monotherapies, respectively. Healthcare utilization was substantial across the study population, with costs in the combination therapy cohort more than doubling from baseline to follow-up. The majority of patients were treated with monotherapies (most often, PDE-5Is), despite combination therapies and ERAs being associated with higher medication adherence. Index regimen adjustments occurred early and in a substantial proportion of patients, suggesting that inadequate clinical response to monotherapies may not be uncommon.

Zika Virus Preparedness and Response Efforts Through the Collaboration Between a Health Care Delivery System and a Local Public Health Department.

ABSTRACTThe Zika virus was largely unknown to many health care systems before the outbreak of 2015. The unique public health threat posed by the Zika virus and the evolving understanding of its pathology required continuous communication between a health care delivery system and a local public health department. By leveraging an existing relationship, NYC Health+Hospitals worked closely with New York City Department of Health and Mental Hygiene to ensure that Zika-related processes and procedures within NYC Health+Hospitals facilities aligned with the most current Zika virus guidance. Support given by the public health department included prenatal clinical and laboratory support and the sharing of data on NYC Health+Hospitals Zika virus screening and testing rates, thus enabling this health care delivery system to make informed decisions and practices. The close coordination, collaboration, and communication between the health care delivery system and the local public health department examined in this article demonstrate the importance of working together to combat a complex public health emergency and how this relationship can serve as a guide for other jurisdictions to optimize collaboration between external partners during major outbreaks, emerging threats, and disasters that affect public health. (Disaster Med Public Health Preparedness. 2018;12:689-691).

Considerations for optimal management of patients with pulmonary arterial hypertension: a multi-stakeholder roundtable discussion.

A roundtable panel of national and regional managed care decision makers and providers met to discuss pulmonary arterial hypertension (PAH) and strategies for management. As a rare, complex disease with high economic costs and potentially devastating outcomes, PAH necessitates that managed care providers balance optimal care with efficient use of healthcare resources. PAH specialists are recognized by health plans as knowledgeable experts and integral partners in managing patients and resources. The diagnosis of PAH must be confirmed by a right heart catheterization. Available therapies are indicated almost exclusively for patients with PAH (riociguat is also indicated in chronic thromboembolic pulmonary hypertension) and target 1 of 3 pathways: endothelin receptor antagonists for the endothelin pathway; phosphodiesterase type-5 inhibitors and soluble guanylate cyclase stimulators for the nitric oxide pathway; and prostanoids as well as a prostacyclin receptor agonist for the prostacyclin pathway, with combination therapy becoming more common. Even in the modern treatment era, as shown in the REVEAL and French registries, PAH is often diagnosed years after symptoms first appear, which leads to a poor prognosis and increased burden on the healthcare system. Facilitating treatment of patients with PAH through centers of excellence, and coordinating care management between health plans and providers with evidence-based approaches can lead to both better results for patients and lower healthcare costs. When PAH experts have access to the right treatments for the right patients at the right time, they can work with insurers to improve the health of patients with PAH while helping to reduce the impact on the healthcare system.

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification.

Blunting immunopathology without abolishing host defense is the foundation for safe and effective modulation of infectious and autoimmune diseases. Sphingosine 1-phosphate receptor 1 (S1PR1) agonists are effective in treating infectious and multiple autoimmune pathologies; however, mechanisms underlying their clinical efficacy are yet to be fully elucidated. Here, we uncover an unexpected mechanism of convergence between S1PR1 and interferon alpha receptor 1 (IFNAR1) signaling pathways. Activation of S1PR1 signaling by pharmacological tools or endogenous ligand sphingosine-1 phosphate (S1P) inhibits type 1 IFN responses that exacerbate numerous pathogenic conditions. Mechanistically, S1PR1 selectively suppresses the type I IFN autoamplification loop in plasmacytoid dendritic cells (pDCs), a specialized DC subset, for robust type I IFN release. S1PR1 agonist suppression is pertussis toxin-resistant, but inhibited by an S1PR1 C-terminal-derived transactivating transcriptional activator (Tat)-fusion peptide that blocks receptor internalization. S1PR1 agonist treatment accelerates turnover of IFNAR1, suppresses signal transducer and activator of transcription 1 (STAT1) phosphorylation, and down-modulates total STAT1 levels, thereby inactivating the autoamplification loop. Inhibition of S1P-S1PR1 signaling in vivo using the selective antagonist Ex26 significantly elevates IFN-α production in response to CpG-A. Thus, multiple lines of evidence demonstrate that S1PR1 signaling sets the sensitivity of pDC amplification of IFN responses, thereby blunting pathogenic immune responses. These data illustrate a lipid G-protein coupled receptor (GPCR)-IFNAR1 regulatory loop that balances effective and detrimental immune responses and elevated endogenous S1PR1 signaling. This mechanism will likely be advantageous in individuals subject to a range of inflammatory conditions.

Prognostic factors associated with adverse outcome among critically ill elderly patients admitted to the intensive care unit.

INTRODUCTION: Despite concerns over the appropriateness and quality of care provided in the intensive care unit (ICU) at the end of life, the number of elderly patients who receive critical care is increasing. Despite this, many physicians have doubts as to whether elderly patients are good candidates for ICU care because of the apparently poor outcome during and after critical care in this population. The objective of the present study was to describe the clinical characteristics and outcome of a geriatric population admitted to the ICU. MATERIALS AND METHODS: A single-center, prospective, observational study was carried out among geriatric patients, aged 75 years or older, admitted to ICU. RESULTS: A total of 71 patients were admitted to ICU during the study period. Their mean age was 83 years (range 75-98 years), with a mean Acute Physiology and Chronic Health Evaluation-II score of 21.8 (range 8-39) on admission to ICU. A total of 48 patients (68%) required mechanical ventilation, and 39 (55%) received at least one vasoactive drug. The mean ICU length of stay was 4.6 days (range 1-18 days), and it was similar for ICU survivors and non-survivors (4.7 vs 4.5). A total of 14 patients (19.7%) were admitted after cardiac arrest, and eight (57.1%) of them died in ICU. A total of 28 patients (39.4%) died in the hospital, and 18 (25.4%) died in ICU. CONCLUSION: Advanced age, critical illness, cardiopulmonary resuscitation, and needs for mechanical ventilation and/or vasopressor therapy are independent risk factors associated with adverse outcome in elderly patients admitted to ICU. Alternatives for ICU admission should be considered in geriatric patients with severe critical illnesses.

Clinical trial designs in PAH: shifting from functional measurements to long-term clinical outcomes.

Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary vasculature that leads to right ventricular dysfunction, right ventricular failure, and premature death. There are a number of medications already on the market, representing different therapeutic classes and possessing multiple mechanisms of action. Three new agents were approved by the US Food and Drug Administration in 2013, and others are currently in development. Recent advancements in PAH have resulted in increased survival and improved quality of life; however, no therapy provides a cure. Experts in the field are now utilizing clinical trial designs and end points that better reflect the disease progression among patients with this chronic disease. Although randomized placebo-controlled monotherapy trials are considered the strongest design, ethical and practical considerations have led to an increasing number of randomized trials designed to compare a PAH-specific treatment with placebo as an add-on to standard therapy. As many patients who enroll in clinical trials are already being treated for their condition, it may be unethical to withdraw or delay lifesaving therapies. The most widely used primary end point for PAH trials, change in 6-minute walk distance (6MWD) from baseline, has substantial limitations. Although it is generally reproducible, inexpensive, and relatively easy to conduct, the 6MWD is not designed to assess disease progression. Recent data have shown that 6MWD has inconsistent correlation with key indicators of disease progression such as hospitalization due to PAH, worsening right-sided heart failure, and death. The Task Force on End Points and Clinical Trial Design that met at the 4th World Symposium on Pulmonary Hypertension (WSPH) in 2008 in Dana Point, California, questioned the clinical relevance of the 6MWD as a primary end point and recommended the use of a composite end point--time to clinical worsening (TTCW)--in phase 3 or pivotal trials. TTCW may include time from randomization to PAH-related hospitalization, need for interventional procedures (ie, lung transplantation or balloon atrial septostomy), and mortality. More recently, at the 5th WSPH, held in 2013 in Nice, France, experts reiterated these recommendations. They further noted that, as clinical trials increasingly allow background therapies and are longer in duration, it may be more meaningful to use primary end points that measure "clinical worsening" rather than 6MWD. This paradigm shift will not only lead to a clearer demonstration of efficacy and safety as new agents come on the market, but will provide important information on long-term benefits (ie, the effects of drugs on clinical deterioration) that can assist payers as they strive to make value-based formulary decisions and provide cost-effective high-quality care.

S1P signaling: new therapies and opportunities.

Development of sphingosine-1-phosphate receptor 1 (S1P1) modulators to dampen inflammation and its sequelae is becoming increasingly promising for treating medical conditions characterized by significant immunopathology. As shown by the non-selective S1P receptor modulator FTY720 (fingolimod [Gilenya(®)]) in the treatment of relapsing-remitting multiple sclerosis (MS), the ability to use S1P1 modulation to precisely block immune cell traffic-immunomodulation-while maintaining immunosurveillance, has opened therapeutic opportunities in various other immune-derived chronic pathologies, including inflammatory bowel disease (IBD), lupus, psoriasis, as well as, potentially, in early acute viral respiratory infection. Proof-of-concept studies across validated animal models with S1P receptor modulators highly selective for S1P1, such as BAF-312 (Siponimod), KRP-203, ONO-4641 (Ceralifimod), ponesimod and RPC-1063, and emerging clinical trials for safety and efficacy in humans, particularly in MS, ulcerative colitis (UC) and psoriasis, have set the stage for us to consider additional testing in various other autoimmune diseases.

Understanding the impact of pulmonary arterial hypertension on patients' and carers' lives.

Pulmonary arterial hypertension (PAH) is a rare, debilitating and rapidly progressive disease. Although there have been important medical advances in PAH management, the search for a cure continues. Despite an increased understanding of the disease, data on the wider effect of PAH on patients and carers, beyond the clinical symptoms, are still limited. In order to explore this, a large-scale international survey investigated four key areas affected by PAH (physical and practical, emotional, social, and information needs) and provides new insight into patients' and carers' experiences of living with the disease. The results from the survey highlight not only the limited ability of patients to carry out everyday tasks, but also the financial impact and social isolation experienced by both patients and carers. The study confirmed that a decline in a patient's World Health Organization functional class, which indicates an increase in clinical severity of the disease, is associated with greater limitations. Results from the survey demonstrate the need for multidisciplinary PAH management and a comprehensive standard of care to assess and improve all aspects of well-being for both patients and carers. In addition, they underline the need for updated PAH guidelines that address these needs.

The structure of Sec12 implicates potassium ion coordination in Sar1 activation.

Coat protein II (COPII)-coated vesicles transport proteins and lipids from the endoplasmic reticulum to the Golgi. Crucial for the initiation of COPII coat assembly is Sec12, a guanine nucleotide exchange factor responsible for activating the small G protein Sar1. Once activated, Sar1/GTP binds to endoplasmic reticulum membranes and recruits COPII coat components (Sec23/24 and Sec13/31). Here, we report the 1.36 Å resolution crystal structure of the catalytically active, 38-kDa cytoplasmic portion of Saccharomyces cerevisiae Sec12. Sec12 adopts a ß propeller fold. Conserved residues cluster around a loop we term the "K loop," which extends from the N-terminal propeller blade. Structure-guided site-directed mutagenesis, in conjunction with in vitro and in vivo functional studies, reveals that this region of Sec12 is catalytically essential, presumably because it makes direct contact with Sar1. Strikingly, the crystal structure also reveals that a single potassium ion stabilizes the K loop; bound potassium is, moreover, essential for optimum guanine nucleotide exchange activity in vitro. Thus, our results reveal a novel role for a potassium-stabilized loop in catalyzing guanine nucleotide exchange.

World Health Organization Group III pulmonary hypertension.

Pulmonary hypertension in the setting of parenchymal lung disease and conditions associated with chronic hypoxemia is commonly encountered in clinical practice and may adversely affect patients' function and mortality. Diagnosis of this subgroup of pulmonary hypertension has evolved but still requires right heart catheterization for confirmation. The primary treatment goal is optimization of the underlying parenchymal lung or hypoxemia-associated condition prior to consideration of pharmacologic therapy. Limited published experience with pulmonary hypertension-specific medications for treatment of WHO Group 3 pulmonary hypertension suggests symptomatic and functional benefit in selected individuals. The potential for worsening ventilation-perfusion matching must be considered in these cases, however, since there is a paucity of data regarding the optimal approach to treatment selection. Ongoing medication trials and further investigation of mechanisms of hypoxic pulmonary vasoconstriction provide hope for these patients who in the past often had only lung transplantation as a potential treatment option.

The use of an early alert system to improve compliance with sepsis bundles and to assess impact on mortality.

Introduction. Diagnostic and therapeutic guidelines, organized as sepsis bundles, have been shown to improve mortality, but timely and consistent implementation of these can be challenging. Our study examined the use of a screening tool and an early alert system to improve bundle compliance and mortality. Methods. A screening tool was used to identify patients with severe sepsis or septic shock and an overhead alert system known as Code SMART (Sepsis Management Alert Response Team) was activated at the physician's discretion. Data was collected for 6 months and compliance with bundle completion and mortality were compared between the Code SMART and non-Code SMART groups. Results. Fifty eight patients were enrolled -34 Code SMART and 24 non-Code SMART. The Code SMART group achieved greater compliance with timely antibiotic administration (P < 0.001), lactate draw (P < 0.001), and steroid use (P = 0.02). Raw survival and survival adjusted for age, leucopenia, and severity of illness scores, were greater in the Code SMART group (P < 0.05, P = 0.03, and P = 0.01). Conclusions. A screening tool and an alert system can improve compliance with sepsis bundle elements and improve survival from severe sepsis and septic shock.

COPII and the regulation of protein sorting in mammals.

Secretory proteins are transported to the Golgi complex in vesicles that bud from the endoplasmic reticulum. The cytoplasmic coat protein complex II (COPII) is responsible for cargo sorting and vesicle morphogenesis. COPII was first described in Saccharomyces cerevisiae, but its basic function is conserved throughout all eukaryotes. Nevertheless, the COPII coat has adapted to the higher complexity of mammalian physiology, achieving more sophisticated levels of secretory regulation. In this review we cover aspects of mammalian COPII-mediated regulation of secretion, in particular related to the function of COPII paralogues, the spatial organization of cargo export and the role of accessory proteins.

Five-year outcomes with alemtuzumab induction after lung transplantation.

BACKGROUND: Induction therapy with alemtuzumab, followed by lower than conventional intensity post-transplant immunosuppression (eg, tacrolimus monotherapy), has been associated with reduced morbidity and mortality in abdominal and heart transplantation. We examined 5-year outcomes in lung recipients receiving alemtuzumab in conjunction with reduced-intensity post-transplant immunosuppression (early lower-dose tacrolimus; lower-dose steroids, with or without mycophenolate mofetil), compared with lung recipients receiving other induction agents or no induction in association with post-transplant immunosuppression. METHODS: A retrospective analysis was performed using prospectively collected data from a single-site clinical database of 336 lung recipients (aged ≥ 18) who received allografts between 1998 and 2005, classified by induction type: alemtuzumab, 127; Thymoglobulin, 43; daclizumab, 73; and none, 93. Survival analyses examined patient and graft survival, and freedom from acute cellular rejection (ACR), lymphocytic bronchiolitis, obliterative bronchiolitis (OB), bronchiolitis obliterans syndrome (BOS), and post-transplant lymphoproliferative disorder (PTLD). RESULTS: Five-year patient and graft survival differed by group (p = 0.046, p = 0.038, respectively). Alemtuzumab patient/graft survival rates were 59%/59%. Survival rates were 60%/44% for Thymoglobulin, 47%/46% for no induction, and 44%/41% for daclizumab. Freedom from ACR, lymphocytic bronchiolitis, OB, and BOS differed by group (all values, p < 0.008); alemtuzumab recipients showed greater 5-year freedom from each outcome (30%/82%/86%/54%) than Thymoglobulin (20%/54%/62%/27%), daclizumab (19%/55%/70%/43%), and no-induction groups (18%/70%/69%/46%). The groups did not differ in PTLD rates (≥ 94% free of PTLD at 5 years; p = 0.864). Effects were unchanged after controlling for potential covariates. CONCLUSIONS: Alemtuzumab induction may be associated with improved outcomes in lung transplantation. Randomized controlled trials are needed to establish any effects of this agent.

Elevated pulmonary artery pressure is a risk factor for primary graft dysfunction following lung transplantation for idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is often associated with elevations in pulmonary artery pressures. Although primary pulmonary arterial hypertension (PAH) has been associated with primary graft dysfunction (PGD), the role of secondary PAH in mediating PGD risk in patients with IPF is incompletely understood. The purpose of this study was to evaluate the relationship between mean pulmonary artery pressure (mPAP) and PGD among patients with IPF. METHODS: We performed a multicenter prospective cohort study of 126 lung transplant procedures performed for IPF between March 2002 and August 2007. The primary outcome was grade 3 PGD at 72 h after lung transplant. The mPAP was measured as the initial reading following insertion of the right-sided heart catheter during lung transplant. Multivariable logistic regression was used to adjust for confounding variables. RESULTS: The mPAP for patients with PGD was 38.5 ± 16.3 mm Hg vs 29.6 ± 11.5 mm Hg for patients without PGD (mean difference, 8.9 mm Hg [95% CI, 3.6-14.2]; P = .001). The increase in odds of PGD associated with each 10-mm Hg increase in mPAP was 1.64 (95% CI, 1.18-2.26; P = .003). In multivariable models, this relationship was independent of confounding by other clinical variables, although the use of cardiopulmonary bypass partially attenuated the relationship. CONCLUSIONS: Higher mPAP in patients with IPF is associated with the development of PGD.

Intrapulmonary disposition of amphotericin B after aerosolized delivery of amphotericin B lipid complex (Abelcet; ABLC) in lung transplant recipients.

BACKGROUND: Inhaled amphotericin preparations have been used for prophylaxis against invasive aspergillosis in lung transplant recipients. However, no published data exist regarding the pharmacokinetic profile of amphotericin B lipid complex in lung transplant recipients. METHODS: We prospectively determined the concentrations of amphotericin B in the epithelial lining fluid (ELF) and plasma after aerosolized nebulization (AeroEclipse), of amphotericin B lipid complex at 1 mg/kg every 24 hr for 4 days in 35 lung transplant recipients. One brochoalveolar lavage sample and a simultaneous blood sample were collected at various time points after the fourth dose from each subject. High-performance liquid chromatography and high-performance liquid chromatography-MS-MS were used to measure amphotericin B. RESULTS: Concentrations of amphotericin B in ELF (median, 25-75 IQR) were at 4 hr (n=5) 7.20 µg/mL (1.3-17.6), 24 hr (n=6) 8.26 µg/mL (3.9-82.7), 48 hr (n=5) 2.15 µg/mL (1.4-5.5), 72 hr (n=4) 1.25 µg/mL (0.75-5.5), 96 hr (n=6) 0.86 µg/mL (0.55-1.4), 120 hr (n=4) 1.04 µg/mL (0.44-1.6), 144 hr (n=1), 4.25 µg/mL, 168 hr (n=3) 1.14 µg/mL, and 192 hr (n=1) 1 µg/mL. The plasma concentration of the drug remained below 0.08 µg/mL at all time points. During the study, the side effects noted included wheezing, coughing, and 12% decline in forced expiratory volume in 1 sec. CONCLUSIONS: We conclude that administration through aerosolized nebulization of amphotericin B lipid complex every 24 hr for 4 days in lung transplant recipients achieved amphotericin B concentrations in ELF above minimum inhibitory concentration of the Aspergillus nearly at 168 hr after the last inhaled dose and is well tolerated.