Anti-fibrotic therapy and lung transplant outcomes in patients with idiopathic pulmonary fibrosis.

BACKGROUND: It is unclear whether continuing anti-fibrotic therapy until the time of lung transplant increases the risk of complications in patients with idiopathic pulmonary fibrosis. OBJECTIVES: To investigate whether the time between discontinuation of anti-fibrotic therapy and lung transplant in patients with idiopathic pulmonary fibrosis affects the risk of complications. METHODS: We assessed intra-operative and post-transplant complications among patients with idiopathic pulmonary fibrosis who underwent lung transplant and had been treated with nintedanib or pirfenidone continuously for ⩾ 90 days at listing. Patients were grouped according to whether they had a shorter (⩽ 5 medication half-lives) or longer (> 5 medication half-lives) time between discontinuation of anti-fibrotic medication and transplant. Five half-lives corresponded to 2 days for nintedanib and 1 day for pirfenidone. RESULTS: Among patients taking nintedanib (n = 107) or pirfenidone (n = 190), 211 (71.0%) had discontinued anti-fibrotic therapy ⩽ 5 medication half-lives before transplant. Anastomotic and sternal dehiscence occurred only in this group (anastomotic: 11 patients [5.2%], p = 0.031 vs patients with longer time between discontinuation of anti-fibrotic medication and transplant; sternal: 12 patients [5.7%], p = 0.024). No differences were observed in surgical wound dehiscence, length of hospital stay, or survival to discharge between groups with a shorter versus longer time between discontinuation of anti-fibrotic therapy and transplant. CONCLUSION: Anastomotic and sternal dehiscence only occurred in patients with idiopathic pulmonary fibrosis who discontinued anti-fibrotic therapy < 5 medication half-lives before transplant. The frequency of other intra-operative and post-transplant complications did not appear to differ depending on when anti-fibrotic therapy was discontinued. REGISTRATION: clinicaltrials.gov NCT04316780: https://clinicaltrials.gov/ct2/show/NCT04316780.

The microfluidic artificial lung: Mimicking nature's blood path design to solve the biocompatibility paradox.

The increasing prevalence of chronic lung disease worldwide, combined with the emergence of multiple pandemics arising from respiratory viruses over the past century, highlights the need for safer and efficacious means for providing artificial lung support. Mechanical ventilation is currently used for the vast majority of patients suffering from acute and chronic lung failure, but risks further injury or infection to the patient's already compromised lung function. Extracorporeal membrane oxygenation (ECMO) has emerged as a means of providing direct gas exchange with the blood, but limited access to the technology and the complexity of the blood circuit have prevented the broader expansion of its use. A promising avenue toward simplifying and minimizing complications arising from the blood circuit, microfluidics-based artificial organ support, has emerged over the past decade as an opportunity to overcome many of the fundamental limitations of the current standard for ECMO cartridges, hollow fiber membrane oxygenators. The power of microfluidics technology for this application stems from its ability to recapitulate key aspects of physiological microcirculation, including the small dimensions of blood vessel structures and gas transfer membranes. An even greater advantage of microfluidics, the ability to configure blood flow patterns that mimic the smooth, branching nature of vascular networks, holds the potential to reduce the incidence of clotting and bleeding and to minimize reliance on anticoagulants. Here, we summarize recent progress and address future directions and goals for this potentially transformative approach to artificial lung support.

Factors Related to Survival in Low-Glomerular Filtration Rate Cohorts Undergoing Lung Transplant.

BACKGROUND: Historically, a glomerular filtration rate (GFR) of less than 50 mL/min per 1.73 m2 has been considered a contraindication to lung transplantation. Combined or sequential lung-kidney transplantation is an option for those with a GFR less than 30 mL/min per 1.73 m2. Patients with a GFR of 30 to 50 mL/min per 1.73 m2 are provided with no options for transplantation. This study explores factors associated with improved survival in patients who undergo isolated lung transplantation with a GFR of 30 to 50 mL/min per 1.73 m2. METHODS: The United Network for Organ Sharing database was queried for adult patients undergoing primary isolated lung transplantation between January 2007 and March 2018. Regression models were used to identify factors associated with improved survival in lung recipients with a preoperative GFR of 30 to 50 mL/min per 1.73 m2. The propensity score method was used to match highly performing patients (outpatient recipients aged less than 60 years) with a GFR of 30 to 50 mL/min per 1.73 m2 with patients who had a GFR greater than 50 mL/min per 1.73 m2. Kaplan-Meier, Cox, and logistic regression analyses compared outcomes in matched populations. RESULTS: A total of 21,282 lung transplantations were performed during the study period. Compared with patients with a GFR greater than 50 mL/min per 1.73 m2, survival was significantly worse for patients with a GFR of 30 to 50 mL/min per 1.73 m2. Multivariate analysis of patients with a GFR of 30 to 50 mL/min per 1.73 m2 demonstrated outpatient status and age less than 60 years to be predictive of superior survival. After propensity matching, survival of this highly performing subset with a GFR of 30 to 50 mL/min per 1.73 m2 was no different from that of patients with a normal GFR. CONCLUSIONS: Outpatient recipients aged less than 60 years represent an optimal subset of patients with a GFR of 30 to 50 mL/min per 1.73 m2. Lung transplant listing should not be declined based only on a GFR less than 50 mL/min per 1.73 m2.

Clinical management and outcomes of patients with Hermansky-Pudlak syndrome pulmonary fibrosis evaluated for lung transplantation.

Pulmonary fibrosis is a progressive, fatal manifestation of Hermansky-Pudlak syndrome (HPS). Some patients with advanced HPS pulmonary fibrosis undergo lung transplantation despite their disease-associated bleeding tendency; others die while awaiting donor organs. The objective of this study is to determine the clinical management and outcomes of a cohort with advanced HPS pulmonary fibrosis who were evaluated for lung transplantation. Six patients with HPS-1 pulmonary fibrosis were evaluated at the National Institutes of Health Clinical Center and one of two regional lung transplant centers. Their median age was 41.5 years pre-transplant. Three of six patients died without receiving a lung transplant. One of these was referred with end-stage pulmonary fibrosis and died before a donor organ became available, and donor organs were not identified for two other patients sensitized from prior blood product transfusions. Three of six patients received bilateral lung transplants; they did not have a history of excessive bleeding. One patient received peri-operative desmopressin, one was transfused with intra-operative platelets, and one received extracorporeal membrane oxygenation and intra-operative prothrombin complex concentrate, platelet transfusion, and desmopressin. One transplant recipient experienced acute rejection that responded to pulsed steroids. No evidence of chronic lung allograft dysfunction or recurrence of HPS pulmonary fibrosis was detected up to 6 years post-transplant in these three lung transplant recipients. In conclusion, lung transplantation and extracorporeal membrane oxygenation are viable options for patients with HPS pulmonary fibrosis. Alloimmunization in HPS patients is an important and potentially preventable barrier to lung transplantation; interventions to limit alloimmunization should be implemented in HPS patients at risk of pulmonary fibrosis to optimize their candidacy for future lung transplants.

Bilateral lung transplantation in a patient with humoral immune deficiency: a case report with review of the literature.

Humoral immune deficiencies have been associated with noninfectious disease complications including autoimmune cytopenias and pulmonary disease. Herein we present a patient who underwent splenectomy for autoimmune cytopenias and subsequently was diagnosed with humoral immune deficiency in the context of recurrent infections. Immunoglobulin analysis prior to initiation of intravenous immunoglobulin (IVIG) therapy was notable for low age-matched serum levels of IgA (11 mg/dL), IgG2 (14 mg/L), and IgG4 (5 mg/L) with a preserved total level of IgG. Flow cytometry was remarkable for B cell maturation arrest at the IgM+/IgD+ stage. Selective screening for known primary immune deficiency-causing genetic defects was negative. The disease course was uniquely complicated by the development of pulmonary arteriovenous malformations (AVMs), ultimately requiring bilateral lung transplantation in 2012. This is a patient with humoral immune deficiency that became apparent only after splenectomy, which argues for routine immunologic evaluation prior to vaccination and splenectomy. Lung transplantation is a rare therapeutic endpoint and to our knowledge has never before been described in a patient with humoral immune deficiency for the indication of pulmonary AVMs.

Comprehensive evaluation of lung allograft function in infants after lung and heart-lung transplantation.

BACKGROUND: Limited data exist on methods to evaluate allograft function in infant recipients of lung and heart-lung transplants. At our institution, we developed a procedural protocol in coordination with pediatric anesthesia where infants were sedated to perform infant pulmonary function testing, computed tomography imaging of the chest, and flexible fiberoptic bronchoscopy with transbronchial biopsies. METHODS: A retrospective review was performed of children aged younger than 1 year who underwent lung or heart-lung transplantation at our institution to assess the effect of this procedural protocol in the evaluation of infant lung allografts. RESULTS: Since 2005, 5 infants have undergone thoracic transplantation (3 heart-lung, 2 lung). At time of transplant, the mean ± standard deviation age was 7.2 ± 2.8 months (range, 3-11 months). Of 24 procedural sessions performed to evaluate lung allografts, 83% (20 of 24) were considered surveillance where the patients were completely asymptomatic. Of the surveillance procedures, 80% were performed as an outpatient, whereas 20% were done as inpatients during the lung or heart-lung transplant post-operative period before discharge home. Sedation was performed with propofol alone (23 of 24) or in addition to ketamine (1 of 24) infusion; mean sedation time was 141 ± 39 minutes (range, 70-214) minutes. Of the 16 outpatient procedures, patients were discharged after 14 (88%) on the same day, and after 2 (12%) were admitted for observation, with 1 being due to transportation issues and the other due to fever during the observation period. CONCLUSIONS: A comprehensive procedural protocol to evaluate allograft function in infant lung and heart-lung transplant recipients was performed safely as an outpatient.

Surveillance transbronchial biopsies in infant lung and heart-lung transplant recipients.

There are limited published data on surveillance TBB for the identification of allograft rejection in infants after lung or heart-lung transplantation. We performed a retrospective review of children under one yr of age who underwent lung or heart-lung transplant at our institution. Since 2005, four infants were transplanted (three heart-lung and one lung). The mean age (±s.d.) at the time of transplant was 5.5 ± 2.4 (range 3-8) months. A total of 16 surveillance TBB procedures were completed in both inpatient and outpatient settings, with a range of 3-7 performed per patient. A minimum of five acceptable tissue pieces with expanded alveoli were obtained in 81% (13/16) of TBB procedures and a minimum of three pieces in 88% (14/16). There was no evidence of acute allograft rejection in 88% (14/16) of TBB procedures. One TBB procedure yielded two tissue specimens demonstrating A2 acute allograft rejection. One TBB procedure failed to yield tissue with sufficient alveoli. Additionally, B-grade assessment identified B0 in 50% (8/16), B1R in 12% (2/16), and BX (ungradeable or insufficient sample) in 38% (6/16) of biopsy procedures, respectively. In conclusion, TBB may be safely performed as an inpatient and outpatient procedure in infant lung and heart-lung transplant recipients and may provide adequate tissue for detecting acute allograft rejection and small airway inflammation.

Aggressive coronary artery vasculopathy after combined heart-lung transplantation.

Combined heart-lung transplantation remains as a treatment option for patients with cardiopulmonary failure. There is speculation that lung grafts protect the heart from developing graft vasculopathy after combined heart-lung transplantation. This protective mechanism is more likely, at best, a delay in the onset of coronary artery vasculopathy. We present our experiences in two cases of an aggressive form of cardiac allograft vasculopathy after combined heart-lung transplantation that resulted in the death of both patients.

ICP22 is required for wild-type composition and infectivity of herpes simplex virus type 1 virions.

The immediate-early regulatory protein ICP22 is required for efficient replication of herpes simplex virus type 1 in some cell types (permissive) but not in others (restrictive). In mice infected via the ocular route, the pathogenesis of an ICP22- virus, 22/n199, was altered relative to that of wild-type virus. Specifically, tear film titers of 22/n199-infected mice were significantly reduced at 3 h postinfection relative to those of mice infected with wild-type virus. Further, 22/n199 virus titers were below the level of detection in trigeminal ganglia (TG) during the first 9 days postinfection. On day 30 postinfection, TG from 22/n199-infected mice contained reduced viral genome loads and exhibited reduced expression of latency-associated transcripts and reduced reactivation efficiency relative to TG from wild-type virus-infected mice. Notably, the first detectable alteration in the pathogenesis of 22/n199 in these tests occurred in the eye prior to the onset of nascent virus production. Thus, ICP22- virions appeared to be degraded, cleared, or adsorbed more rapidly than wild-type virions, implying potential differences in the composition of the two virion types. Analysis of the protein composition of purified extracellular virions indicated that ICP22 is not a virion component and that 22/n199 virions sediment at a reduced density relative to wild-type virions. Although similar to wild-type virions morphologically, 22/n199 virions contain reduced amounts of two gamma2 late proteins, US11 and gC, and increased amounts of two immediate-early proteins, ICP0 and ICP4, as well as protein species not detected in wild-type virions. Although ICP22- viruses replicate to near-wild-type levels in permissive cells, the virions produced in these cells are biochemically and physically different from wild-type virions. These virion-specific differences in ICP22- viruses add a new level of complexity to the functional analysis of this immediate-early viral regulatory protein.

The products of the herpes simplex virus type 1 immediate-early US1/US1.5 genes downregulate levels of S-phase-specific cyclins and facilitate virus replication in S-phase Vero cells.

Herpes simplex virus type 1 ICP22-/U(S)1.5- mutants initiate viral gene expression in all cells; however, in most cell types, the replication process stalls due to an inability to express gamma2 late proteins. Although the function of ICP22/U(S)1.5 has not been established, it has been suggested that these proteins activate, induce, or repress the activity of cellular proteins during infection. In this study, we hypothesized that cell cycle-associated proteins are targets of ICP22/U(S)1.5. For this purpose, we first isolated and characterized an ICP22-/U(S)1.5- mutant virus, 22/n199. Like other ICP22-/U(S)1.5- mutants, 22/n199 replicates in a cell-type-specific manner and fails to induce efficient gamma2 late gene expression in restrictive cells. Although synchronization of restrictive human embryonic lung cells in each phase of the cell cycle did not overcome the growth restrictions of 22/n199, synchronization of permissive Vero cells in S phase rendered them less able to support 22/n199 plaque formation and replication. Consistent with this finding, expression of cellular S-phase cyclins was altered in an ICP22/U(S)1.5-dependent manner specifically when S-phase Vero cells were infected. Collectively, these observations support the notion that ICP22/U(S)1.5 deregulates the cell cycle upon infection of S-phase permissive cells by altering expression of key cell cycle regulatory proteins either directly or indirectly.

Pulmonary capillaritis in lung transplant recipients: treatment and effect on allograft function.

The clinical outcomes of lung transplant recipients presenting with post-transplant pulmonary capillaritis have not been well described. We retrospectively reviewed 40 cases of biopsy-proven pulmonary capillaritis in lung transplant recipients. Patients presented with a clinical syndrome characterized by dyspnea, hypoxemia, abnormal chest X-ray, and a decrease in forced expiratory volume in 1 second (FEV1); 25% presented with hemoptysis, and 18% with fulminant respiratory failure. Therapy with intravenous corticosteroids resulted in clinical improvement in 17 cases (43%). A response to plasmapheresis was seen in 12 (67%) of 18 cases refractory to corticosteroids. There were 5 deaths within 3 months of diagnosis. Nine (82%) of 11 lung transplant recipients who presented with capillaritis within 4 weeks post-transplant were alive at 1 year; all but 1 patient achieved expected percent predicted FEV1 values. Only 3 (14%) of 21 who presented with capillaritis > 1 month after transplant had a >20% decrease in the FEV1 after 12 months. These results suggest that post-transplant pulmonary capillaritis is (1) likely a form of acute allograft rejection clinically and histologically distinct from typical acute rejection, (2) less responsive to corticosteroid therapy than typical acute rejection, and (3) not associated with long-term adverse effects on allograft function.