Improvement of idiopathic pulmonary fibrosis through a combination of Astragalus radix and Angelica sinensis radix via mammalian target of rapamycin signaling pathway-induced autophagy in rat.

Background: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF) in clinic. Astragalus radix (AR; Huangqi) and Angelica sinensis radix (AS; Danggui) have been frequently used in the treatment of IPF. This study aimed to reveal the pharmacological effects and the mechanisms of the action of an AR-AS combination in treating IPF. Methods: Sprague-Dawley rats were randomly divided into six groups (n=5): control, bleomycin (BLM) model, AR, AS, AR + AS, and prednisone (PDN) groups. A transforming growth factor-ß1 (TGF-ß1)-induced MRC-5 cell model were also used. Pulmonary fibrosis, inflammation, oxidative stress, and autophagy were evaluated by performing hematoxylin and eosin (H&E) staining, Masson staining, immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and hydroxyproline assay following the treatment of AR, AS, and the AR-AS herb pair. Results: Rats administered the AR-AS herb pair had lower α-smooth muscle actin (α-SMA), collagen I, fibronectin, and vimentin levels in lung tissues, and lower inflammatory cytokine levels in rat serum. In addition, the AR-AS herb pair induced mammalian target of rapamycin (mTOR)-mediated autophagy and reduced oxidative stress in BLM-induced rats. The effects of the AR and AS combination were confirmed in MRC-5 cells treated with TGF-ß1. Specifically, the combination of AR and AS attenuated MRC-5 cell fibrosis, inflammation, and oxidative stress while inducing autophagy. Conclusions: The combination of AR and AS protects against IPF by inducing autophagy via inhibiting the mTOR signaling pathway. The synergistic action of AR and AS is superior to that of either AR or AS alone.

Using HCV-viremic organs for lung transplantation does not confer higher rejection rates compared to HCV-negative organs.

BACKGROUND: National data demonstrate that hepatitis C virus (HCV)-infected organ donors are increasingly being used in the US, including for lung transplantation. We aimed to assess whether there were any differences in the acute or chronic rejection rates at 1 year following lung transplantation from HCV-viremic versus uninfected donors. METHODS: We retrospectively reviewed all lung transplant recipients at our institution from April 1, 2017 to October 1, 2020 and then assessed various outcomes between those who received a transplant from HCV-viremic donors versus HCV-negative donors. Primary outcome was to determine if there was a higher incidence of acute and/or chronic allograft rejection when using HCV NAT+ lung donation. We carried out univariate and multivariate analyses. RESULTS: We transplanted 135 patients during the study period, including 18 from HCV-viremic donors. Standard induction therapy with basiliximab and maintenance triple drug immunosuppression was utilized per UC San Diego protocol. All 17 patients receiving HCV-viremic organs developed acute HCV infection and were treated in the postoperative period with 12 weeks of direct acting antivirals (DAA). HCV genotypes included 1, 2, and 3. DAA used included glecaprevir/pibrentasvir (12), sofosbuvir/velpatasvir (1), and ledipasvir/sofosbuvir (2) with drug choice determined by patient's medical insurance coverage. Sustained virological response at 12 weeks after end of DAA therapy (SVR12), indicative of a cure, was achieved in all (100%) recipients. No recipient had a serious adverse event related to HCV infection. The lung transplant recipient (LTR) HCV-viremic donors had lower rates of clinically significant rejection (5.9% vs. 11% LTR HCV-nonviremic donors), and no chronic lung allograft dysfunction at 1 year (vs. 5.9% LTR HCV-nonviremic donors). One-year survival was 100% in the LTR HCV-viremic donors compared to 95.8% in the LTR HCV-nonviremic donors. CONCLUSIONS: We demonstrate the feasibility and success of using HCV NAT + donors with excellent results and without a higher incidence of rejection. Longer term follow-up and a larger sample size are needed to allow this to be a more widely accepted practice for lung transplant programs and payors.

Difference in immunosuppressant dose requirement when transitioning to isavuconazole from other azoles in thoracic transplant recipients.

The triazole antifungal isavuconazole (ISAVU) is used for prevention and treatment of fungal infections in solid organ transplant (SOT). SOT recipients commonly need to transition from one azole to another due to breakthrough infection, toxicity, or other reasons. The purpose of our study was to evaluate the effect of ISAVU on immunosuppressant concentrations in thoracic transplant recipients when ISAVU was started de novo or transitioned from another azole. We conducted a single-center retrospective cohort study including 68 patients (51 lung, 14 heart, and 3 heart/lung transplant). Concentration to dosage ratios (C/D) of immunosuppressants were assessed at baseline, day 3, and weekly for 9 weeks. When starting ISAVU de novo, we observed a temporary doubling of tacrolimus exposure. Cyclosporine and sirolimus required dose decreases. Tacrolimus C/D increased by 110% at day 3 in patients started on ISAVU de novo then returned to baseline C/D ± 17% weeks 2-9 (n = 8). One cyclosporine patient started on ISAVU de novo had variable C/D, and C/D increased by 219% ± 72% in 2 sirolimus patients. When transitioning from other azoles, tacrolimus and cyclosporine required about twice the initial dose. After week 1, tacrolimus C/D decreased by 53% ± 6% in patients transitioned from posaconazole (n = 33), voriconazole (n = 14), or fluconazole (n = 2). Cyclosporine C/D decreased by 45% ± 16% in patients transitioning from other azoles (posaconazole [n = 2], voriconazole [n = 2], fluconazole [n = 1]). Sirolimus C/D decreased by 73% ± 13% in patients transitioned from posaconazole (n = 7). Aside from the initial loading phase, ISAVU had a lesser degree of interaction with immunosuppressants than other azoles in loading phase, ISAVU had a lesser degree of interaction with immunosuppressants than other azoles in adjustments for the 4-week period after initiating antifungal therapy with ISAVU or switching from another agent.

Outcomes following lung transplantation for American Indians/Alaska Natives in the United States.

Limited data is available for American Indians/Alaska Natives (AI/AN) undergoing lung transplant. The goal of our study was to assess outcomes for AI/AN lung transplant recipients (LTR). A retrospective review of data from the Organ Procurement and Transplant Network was performed comparing AI/AN (n = 88) and Caucasian (n = 22,767) LTRs between May 4, 2005 and October 31, 2019. AI/AN LTRs had worse functional parameters prior to transplantation but had similar post-transplant outcomes compared to Caucasians LTRs.

An Unexpected Cause of Lung Disease Identified After Lung Transplantation.

CASE PRESENTATION: A 54-year-old woman with systemic lupus erythematosus with associated interstitial lung disease (ILD) presented to the lung transplant clinic for assessment of candidacy for transplantation. She was initially diagnosed with ILD based on clinical and radiographic features (never underwent lung biopsy). In addition, she had associated mixed group I/III pulmonary arterial hypertension. The patient had no family history of pulmonary disease and had never used tobacco and did not have a history of illicit drug use. She was maintained on systemic immunosuppression with hydroxychloroquine, mycophenolate mofetil, and nintedanib for ILD as well as inhaled treprostinil, sildenafil, and macitentan for pulmonary arterial hypertension. Given her progressive symptoms on maximal medical therapy, she was referred for consideration to undergo lung transplantation.

Sirolimus Long-Term Tolerability and Impact on Kidney Function in Lung Transplantation: A Single-Center Experience.

BACKGROUND: After lung transplant, 2 common complications are calcineurin inhibitor (CNI) induced nephrotoxicity and bronchiolitis obliterans syndrome. The objective of this study was to investigate the long-term effects of sirolimus conversion after lung transplantation. METHODS: This was a retrospective cohort study of patients who had undergone lung transplantation at a single center from June 2003 to December 2016. We compared patients converted to a sirolimus-based regimen to those maintained on our standard tacrolimus-based regimen. Kidney function, pulmonary function, and immunosuppression concentrations were compared between the groups. Additionally, indications, toxicity monitoring parameters, and discontinuation rates for sirolimus were collected. RESULTS: During the study period, 176 of the 205 patients who underwent lung transplants were converted to a sirolimus-containing regimen (86%). The most common reason for sirolimus initiation was impairment of kidney function or CNI-associated neurotoxicity. Sirolimus was initiated at a median of 150 days post-transplantation and continued for a medium time of 5.02 (2.27-7.85) years. Of those patients converted to sirolimus, 39 (22%) had sirolimus subsequently discontinued secondary to an adverse event. No difference in pulmonary function was found between the groups at 1- and 3-years post-transplantation. In the sirolimus group, the median estimated glomerular filtration rate improved by 8.6 mL/min/1.73 m2 at 3 months post-conversion (P < .001), which was maintained at both 1 and 3 years (P = .014 and .025, respectively). CONCLUSION: Sirolimus is a viable immunosuppressant option after lung transplant, which successfully allows for the reduction or withdrawal of the CNI, resulting in sustained improvement in kidney function.

Tolerability and Feasibility of the Upper Esophageal Sphincter Assist Device in Preventing Acute and Chronic Allograft Rejection Among Lung Transplant Recipients.

GOALS: We aimed to evaluate a novel upper esophageal sphincter (UES) assist device loaner program for the prevention of acute cellular rejection and chronic lung allograft dysfunction among lung transplant (LTx) recipients. BACKGROUND: Laryngopharyngeal reflux can lead to chronic microaspiration and LTx rejection. The UES assist device applies external pressure at the level of UES to decrease reflux. STUDY: We prospectively enrolled and issued UES assist devices to consecutive transplant patients referred for gastrointestinal motility testing from 2016 to 2020. Device tolerability was defined by successful utilization as a bridge to ambulatory pH monitoring and/or antireflux procedure, or as permanent therapy. Incidence of rejection was analyzed before, during, and after device implementation. RESULTS: Twenty-six participants were issued devices (15 pathologic, 5 physiological, 6 unknown reflux status), none of whom developed acute rejection episodes or chronic lung allograft dysfunction while using the device. Thirteen adopted the device promptly after transplantation (mean 1.7 mo) and remained free of rejection episodes over a mean 24.7 months of follow-up. Among those with pathologic reflux, lag time to device adoption strongly correlated with the development of rejection ( r =0.8, P =0.0006). There was no such correlation among those with physiological reflux. Five developed acute rejection after device return. CONCLUSIONS: The device was tolerated by a majority of LTx patients and appears feasible as a barrier measure in the prevention of rejection. Delayed treatment of laryngopharyngeal reflux may lead to early allograft failure; therefore, the UES assist device should be given important consideration in transplant protection.

Development of Host Immune Response to Bacteriophage in a Lung Transplant Recipient on Adjunctive Phage Therapy for a Multidrug-Resistant Pneumonia.

Bacteriophage therapy is the use of viruses to kill bacteria for the treatment of antibiotic-resistant infections. Little is known about the human immune response following phage therapy. We report the development of phage-specific CD4 T cells alongside rising phage-specific immunoglobulin G and neutralizing antibodies in response to adjunctive bacteriophage therapy used to treat a multidrug-resistant Pseudomonas aeruginosa pneumonia in a lung transplant recipient. Clinically, treatment was considered a success despite the development phage-specific immune responses.

A Pilot Trial for Prevention of Hepatitis C Virus Transmission From Donor to Organ Transplant Recipient With Short-Course Glecaprevir/Pibrentasvir.

A 7-day course of glecaprevir/pibrentasvir started in the preoperative period prevented transmission of hepatitis C virus (HCV) from viremic donors to 10 HCV-negative recipients (2 heart, 1 lung, 6 kidney, 1 heart/kidney) with 100% sustained virological response at 12 weeks.

Heart and Lung Transplant for Mixed Connective Tissue Disease: A Case Report and Implications for Pretransplant Testing.

We present a case of end-stage lung disease secondary to mixed connective tissue disease (MCTD) with concomitant myocarditis found on explant at time of transplant. The patient is a 37-year-old man who was first diagnosed with interstitial lung disease secondary to MCTD at 30 years of age. He underwent en bloc heart-lung transplant for progressive decline in left ventricular ejection fraction and severe pulmonary fibrosis despite immunosuppression with hydroxychloroquine, mycophenolate, and azathioprine. Cardiac MRI failed to demonstrate findings suggestive of myocarditis; however, explant demonstrated significant lymphocytic infiltrate with myocyte damage and areas of fibrosis with myocyte hypertrophy. In patients presenting with unexplained systolic dysfunction in the setting of MCTD, fluorodeoxyglucose-positron emission tomography may be a screening tool and if myocardial inflammation is noted, there may be a role for increased immunosuppression. While this strategy was not employed in our patient, his improvement in left ventricular ejection fraction while on mycophenolate mofetil as compared with HCQ and explant histology suggests a process that may have been further responsive to escalation of immunosuppression.

Alpha 1 "Hereditary Emphysema" Experience: A Patient-Physician Perspective.

This article is co-authored by a patient living with alpha-1 antitrypsin deficiency, and her treating physician. The commentary article describes the patient's experience of the diagnosis and treatment process. The physician then discusses alpha-1 antitrypsin deficiency diagnosis and management in the context of the patient's experiences.

Heart-lung vs. double-lung transplantation for idiopathic pulmonary arterial hypertension.

Patients with idiopathic pulmonary arterial hypertension (IPAH) have improved survival after heart-lung transplantation (HLT) and double-lung transplantation (DLT). However, the optimal procedure for patients with IPAH undergoing transplantation remains unclear. We hypothesized that critically ill IPAH patients, defined by admission to the intensive care units (ICU), would demonstrate improved survival with HLT vs. DLT. All adult IPAH patients (>18 yr) in the Scientific Registry of Transplant Recipients (SRTR) database, who underwent either HLT or DLT between 1987 and 2012, were included. Baseline characteristics, survival, and adjusted survival were compared between the HLT and DLT groups. Similar analyses were performed for the subgroups as defined by the recipients' hospitalization status. A total of 928 IPAH patients (667 DLT, 261 HLT) were included in this analysis. The HLT recipients were younger, more likely to be admitted to the ICU, and have had their transplant in previous eras. Overall, the adjusted survivals after HLT or DLT were similar. For recipients who were hospitalized in the ICU, DLT was associated with worse outcomes (HR 1.827; 95% CI 1.018-3.279). In IPAH patients, the overall survival after HLT or DLT is comparable. HLT may provide improved outcomes in critically ill IPAH patients admitted to the ICU at time of transplantation.

Future direction of immunosuppression in lung transplantation.

PURPOSE OF REVIEW: Immunosuppression regimens have helped improve rejection episodes following lung transplantation, but long-term outcomes are still not comparable with cardiac, hepatic, or renal transplantation. This review summarizes the immunobiology that contributes to rejection events and future opportunities in outcomes on the basis of providing optimized delivery of the immunosuppression based on immune-monitoring techniques, taking into account individual patient pharmacokinetics and phenotypic variance. RECENT FINDINGS: Drug toxicities, narrow therapeutic drug monitoring windows, and current immunoassays currently do not assist in detecting the global degree of immunosuppression. The currently available randomized control trials for induction therapy or maintenance therapies do not provide additional benefits compared with previously reported retrospective trials. To push beyond the current barriers, transplant teams are focusing on the role of pharmacokinetics, assessing phenotypic variable to potentially modify to quadruple therapy and using extracorporeal photopheresis. SUMMARY: Conventional practice for the choices of immunosuppression is being evaluated on the basis of randomized control trials as opposed to retrospective studies or single-center trials. The future direction of immunosuppression will be continued by dynamic processes taking into consideration measures to improve tolerance, reducing treatment burden, and providing the best level of evidence while accounting for rejection, infections, renal function, and other comorbidities.

Rapidly fatal disseminated acanthamoebiasis in a single lung transplant recipient.

BACKGROUND: Lung transplant recipients are at great risk for developing various infectious complications. These infections portend a significant morbidity and mortality throughout their lifetime following transplantation. At times, cutaneous manifestations are the only clues to systemic infection. CASE REPORT: A 62 year-old man with a history of idiopathic pulmonary fibrosis presented 6 months after receiving bilateral sequential cadaveric lung transplantation for anorexia, early satiety, weight loss, exertional dsypnea, arthralgia, and depression. On exam, two rapidly growing non-painful 1.5-3 centimeter erythematous nodules with purulent draining on the anterior chest wall were noted. On Hospital Day 7, the patent was found to be un-responsive, hypotensive, and febrile. Brain imaging revealed diffuse thick nodular enhancement of leptomeningeal surface and multiple areas of hypodenisty associated with mass effect in the bilateral vermis and cerebellar hemispheres with effacement of the fourth ventricle. CSF PCR analysis showed Acanthamoeba sp. confirmed by the Center for Disease Control. Despite multi-modal therapy, his clinical course deteriorated and resulted in brain death. CONCLUSION: Acanthamoeba infection is extremely rare in thoracic organ recipients. We report the fifth case of progressive disseminated acanthamoebiasis in a lung transplant recipient.

Use of Foscarnet Therapy for EBV Infection following Control of PTLD with Enhancement of Cellular Immunity in a Lung-Transplant Recipient.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation with an annual incidence rate of 3-5% in lung-transplant recipients. Pathogenesis indicates a strong association with functional over-immunosuppression and EBV infection. Clinical improvement is generally observed with reduction in immunosuppression intensity alone. We present a case of a 24-year-old woman with EBV-associated PTLD following lung transplant where decreasing the immunosuppression improved PTLD but was ineffective against controlling the EBV infection. Foscarnet in combination with immunoglobulins was successfully administered to cause a remission of the EBV infection. This is the second case reported of a persistent EBV infection after reducing immunosuppression levels and evidence of PTLD remission that required foscarnet for EBV infection control.

Pericardial constriction after lung transplantation.

Pericardial constriction is extremely rare after lung transplantation. We present a case and review the potential contributing factors for pericardial constriction after lung transplantation. Treatment for this condition, irrespective of the cause, remains pericardiectomy.

Gastric sarcoidosis and review of the literature.

Sarcoidosis is a systemic disease with a 90% predilection for the lungs, but any organ can be involved. Gastrointestinal involvement is rare. Within the gastrointestinal system, gastric involvement is the most common. When this organ system is involved, it can be a feature of systemic disease or an isolated case. Gastrointestinal sarcoid can resemble a broad spectrum of other disease processes; thus, it is important for health care providers to be familiar with the various gastrointestinal manifestations. Patients can have subclinical symptoms or have symptoms of epigastric pain, nausea, vomiting, and hematemesis. We present 2 cases of gastric sarcoid and a MEDLINE search of 44 reported cases of gastric sarcoid based on a compatible history and the demonstration of noncaseating granulomas. We describe the clinical manifestations of symptomatic gastric sarcoid in relation to the endoscopic findings.