Retransplantation for COVID-19-related lung graft failure: A case report of successful outcome in a critically ill lung transplant recipient.

End-stage lung disease from nonrecovered COVID-19 acute respiratory distress syndrome has become an increasingly frequent indication for lung transplant. Although reports of lung transplant recipients (LTRs) with COVID-19 suggest an increased risk for hospitalization, respiratory failure, and death, little is known about retransplant for COVID-19-related lung graft failure. In this manuscript, we present a 49-year-old man who received bilateral lung retransplantation for COVID-19-related lung graft failure, 7½ years after his initial transplant for idiopathic pulmonary fibrosis. Our case suggests that retransplantation may be a viable option for critically ill LTRs with COVID-19-related graft failure, even in the presence of other organ dysfunction, provided that they are in good condition and have an immunologically favorable donor.

Lung Transplant After a Heart Transplant: A Case Report.

A heart-lung transplant is considered in patients with end-stage heart and lung disease. However, there is no report of a patient receiving a staged heart transplant followed by a lung transplant. Our case report describes a successful left single lung transplant for idiopathic pulmonary fibrosis 6 years after a heart transplant. This case illustrates that this approach can avoid significantly increased wait time until transplant, and it shows that early interstitial lung disease may not be a contraindication for the heart transplant.

Early clinical experience of bacteriophage therapy in 3 lung transplant recipients.

Bacteriophage therapy (BT) uses bacteriophages to treat pathogenic bacteria and is an emerging strategy against multidrug-resistant (MDR) infections. Experience in solid organ transplant is limited. We describe BT in 3 lung transplant recipients (LTR) with life-threatening MDR infections caused by Pseudomonas aeruginosa (n = 2) and Burkholderia dolosa (n = 1). For each patient, lytic bacteriophages were selected against their bacterial isolates. BT was administered for variable durations under emergency Investigational New Drug applications and with patient informed consent. Safety was assessed using clinical/laboratory parameters and observed clinical improvements described, as appropriate. All patients received concurrent antibiotics. Two ventilator-dependent LTR with large airway complications and refractory MDR P. aeruginosa pneumonia received BT. Both responded clinically and were discharged from the hospital off ventilator support. A third patient had recurrent B. dolosa infection following transplant. Following BT initiation, consolidative opacities improved and ventilator weaning was begun. However, infection relapsed on BT and the patient died. No BT-related adverse events were identified in the 3 cases. BT was well tolerated and associated with clinical improvement in LTRs with MDR bacterial infection not responsive to antibiotics alone. BT may be a viable adjunct to antibiotics for patients with MDR infections.

Overview of Lung Transplantation, Heart-Lung Transplantation, Liver-Lung Transplantation, and Combined Hematopoietic Stem Cell Transplantation and Lung Transplantation.

Lung transplantation (LTx) has evolved to represent the therapy of choice for many patients with end-stage lung diseases. Appropriate candidate selection for LTx is an important determinant of a positive outcome from transplantation. Posttransplantation survival has steadily improved, but long-term survival continues to be a challenge with a median survival of 5.8 years. Similarly, combined heart-lung transplantation and simultaneous liver-lung transplantation has been performed successfully in select patients who are not expected to survive either organ transplant alone. Moreover, LTx has been performed in patients who develop end-stage pulmonary complications following hematopoietic stem cell transplantation.

Flaxseed modulates inflammatory and oxidative stress biomarkers in cystic fibrosis: a pilot study.

BACKGROUND: Cystic fibrosis (CF) leads to advanced lung disease despite aggressive care. Persistent inflammation and oxidative stress contribute to exacerbations and disease progression. Flaxseed (FS), a dietary botanical supplement with high fiber, lignan phenolics, and omega-3 fatty acids has anti-inflammatory and antioxidant properties in murine models of acute and chronic lung injury. This pilot study was designed to determine whether CF patients could tolerate FS, evaluate circulating FS metabolites, and study biomarkers of lung damage, as a prelude to studying clinical outcomes. METHODS: 10 CF patients and 5 healthy volunteers consumed 40 g of FS daily for 4 weeks with safety and tolerability being assessed. Urine was evaluated for systemic oxidative stress and plasma for FS metabolites (enterolignans) and cytokine levels. Buccal swabs were analyzed for gene expression of Nrf2-regulated antioxidant enzymes including Heme Oxygenase-1 (HO-1) and NAD(P)H Quinone Oxidoreductase 1 (NQO1). RESULTS: All subjects completed the study without serious adverse events. Plasma levels of enterolignans were detectable in both healthy controls and CF volunteers. CF patients were stratified based on plasma enterolignan levels after 2 weeks of FS administration into high- (174 to 535 nM ED and 232 to 1841 nM EL) and low- (0 to 32 nM ED and 0 to 40 nM EL) plasma lignan cohorts. The low enterolignan level cohort experienced a statistically significant drop in urinary inflammatory IsoP and plasma TNFα levels, while demonstrating higher average NQO1 mRNA levels in buccal epithelium compared to high-lignan patients. CONCLUSIONS: This pilot study demonstrated that FS is tolerated by CF patients. FS metabolites could be detected in the plasma. Future studies will assess appropriate dosing and target populations for FS, while exploring clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02014181 .

Oxidative Lung Damage Resulting from Repeated Exposure to Radiation and Hyperoxia Associated with Space Exploration.

BACKGROUND: Spaceflight missions may require crewmembers to conduct Extravehicular Activities (EVA) for repair, maintenance or scientific purposes. Pre-breathe protocols in preparation for an EVA entail 100% hyperoxia exposure that may last for a few hours (5-8 hours), and may be repeated 2-3 times weekly. Each EVA is associated with additional challenges such as low levels of total body cosmic/galactic radiation exposure that may present a threat to crewmember health and therefore, pose a threat to the success of the mission. We have developed a murine model of combined, hyperoxia and radiation exposure (double-hit) in the context of evaluating countermeasures to oxidative lung damage associated with space flight. In the current study, our objective was to characterize the early and chronic effects of repeated single and double-hit challenge on lung tissue using a novel murine model of repeated exposure to low-level total body radiation and hyperoxia. This is the first study of its kind evaluating lung damage relevant to space exploration in a rodent model. METHODS: Mouse cohorts (n=5-15/group) were exposed to repeated: a) normoxia; b) >95% O2 (O2); c) 0.25Gy single fraction gamma radiation (IR); or d) a combination of O2 and IR (O2+IR) given 3 times per week for 4 weeks. Lungs were evaluated for oxidative damage, active TGFß1 levels, cell apoptosis, inflammation, injury, and fibrosis at 1, 2, 4, 8, 12, 16, and 20 weeks post-initiation of exposure. RESULTS: Mouse cohorts exposed to all challenge conditions displayed decreased bodyweight compared to untreated controls at 4 and 8 weeks post-challenge initiation. Chronic oxidative lung damage to lipids (malondialdehyde levels), DNA (TUNEL, cleaved Caspase 3, cleaved PARP positivity) leading to apoptotic cell death and to proteins (nitrotyrosine levels) was elevated all treatment groups. Importantly, significant systemic oxidative stress was also noted at the late phase in mouse plasma, BAL fluid, and urine. Importantly, however, late oxidative damage across all parameters that we measured was significantly higher than controls in all cohorts but was exacerbated by the combined exposure to O2 and IR. Additionally, impaired levels of arterial blood oxygenation were noted in all exposure cohorts. Significant but transient elevation of lung tissue fibrosis (p<0.05), determined by lung hydroxyproline content, was detected as early as 2 week in mice exposed to challenge conditions and persisted for 4-8 weeks only. Interestingly, active TGFß1 levels in +BAL fluid was also transiently elevated during the exposure time only (1-4 weeks). Inflammation and lung edema/lung injury was also significantly elevated in all groups at both early and late time points, especially the double-hit group. CONCLUSION: We have characterized significant, early and chronic lung changes consistent with oxidative tissue damage in our murine model of repeated radiation and hyperoxia exposure relevant to space travel. Lung tissue changes, detectable several months after the original exposure, include significant oxidative lung damage (lipid peroxidation, DNA damage and protein nitrosative stress) and increased pulmonary fibrosis. These findings, along with increased oxidative stress in diverse body fluids and the observed decreases in blood oxygenation levels in all challenge conditions (whether single or in combination), lead us to conclude that in our model of repeated exposure to oxidative stressors, chronic tissue changes are detected that persist even months after the exposure to the stressor has ended. This data will provide useful information in the design of countermeasures to tissue oxidative damage associated with space exploration.

Radiation mitigating properties of the lignan component in flaxseed.

BACKGROUND: Wholegrain flaxseed (FS), and its lignan component (FLC) consisting mainly of secoisolariciresinol diglucoside (SDG), have potent lung radioprotective properties while not abrogating the efficacy of radiotherapy. However, while the whole grain was recently shown to also have potent mitigating properties in a thoracic radiation pneumonopathy model, the bioactive component in the grain responsible for the mitigation of lung damage was never identified. Lungs may be exposed to radiation therapeutically for thoracic malignancies or incidentally following detonation of a radiological dispersion device. This could potentially lead to pulmonary inflammation, oxidative tissue injury, and fibrosis. This study aimed to evaluate the radiation mitigating effects of FLC in a mouse model of radiation pneumonopathy. METHODS: We evaluated FLC-supplemented diets containing SDG lignan levels comparable to those in 10% and 20% whole grain diets. 10% or 20% FLC diets as compared to an isocaloric control diet (0% FLC) were given to mice (C57/BL6) (n=15-30 mice/group) at 24, 48, or 72-hours after single-dose (13.5 Gy) thoracic x-ray treatment (XRT). Mice were evaluated 4 months post-XRT for blood oxygenation, lung inflammation, fibrosis, cytokine and oxidative damage levels, and survival. RESULTS: FLC significantly mitigated radiation-related animal death. Specifically, mice fed 0% FLC demonstrated 36.7% survival 4 months post-XRT compared to 60-73.3% survival in mice fed 10%-20% FLC initiated 24-72 hours post-XRT. FLC also mitigated radiation-induced lung fibrosis whereby 10% FLC initiated 24-hours post-XRT significantly decreased fibrosis as compared to mice fed control diet while the corresponding TGF-beta1 levels detected immunohistochemically were also decreased. Additionally, 10-20% FLC initiated at any time point post radiation exposure, mitigated radiation-induced lung injury evidenced by decreased bronchoalveolar lavage (BAL) protein and inflammatory cytokine/chemokine release at 16 weeks post-XRT. Importantly, neutrophilic and overall inflammatory cell infiltrate in airways and levels of nitrotyrosine and malondialdehyde (protein and lipid oxidation, respectively) were also mitigated by the lignan diet. CONCLUSIONS: Dietary FLC given early post-XRT mitigated radiation effects by decreasing inflammation, lung injury and eventual fibrosis while improving survival. FLC may be a useful agent, mitigating adverse effects of radiation in individuals exposed to incidental radiation, inhaled radioisotopes or even after the initiation of radiation therapy to treat malignancy.

Dietary Flaxseed in Non-Small Cell Lung Cancer Patients Receiving Chemoradiation.

PURPOSE: The standard of care in Locally-Advanced Non-Small Cell Lung Cancer (LA-NSCLC) is chemotherapy and radiation; however, Radiation-Induced Lung Injury (RILI), which may be prevented by the anti-inflammatory and anti-oxidant properties of Flaxseed (FS), impedes its maximum benefit. MATERIALS AND METHODS: Patients with LA-NSCLC requiring definitive RT were randomized to one FS or control muffin daily from start to 2 weeks after RT. Blood and urine were collected to quantify plasma FS metabolites, Enterodione (ED) and Enterolactone (EL), and urinary oxidative stress biomarkers, 8, 12-iso-iPF2a-VI (isoprostane) and 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxo-dGuo). Tolerability was defined as consuming ≥ 75% of the intended muffins and no ≥ grade 3 gastrointestinal toxicities. RESULTS: Fourteen patients (control,7; FS,7) were enrolled. The tolerability rates were 42.9 versus 71.4% (p=0.59) for FS and control, respectively. Mean percentages of intended number of muffins consumed were 37% versus 73% (p=0.12). ED and EL increased at onset of FS and decreased with discontinuation, confirming bioavailability. Isoprostane and 8-oxo-dGuo were detectable. There was a trend towards decreased rates of pneumonitis in FS. CONCLUSIONS: This is the first study to report FS bioavailability and quantify oxidative stress markers in NSCLC patients. FS in the administered muffin formulation did not meet tolerability criteria. Given the promising mechanism of FS as a radioprotectant, further investigations should focus on the optimal method for administration of FS.

Radioprotective role in lung of the flaxseed lignan complex enriched in the phenolic secoisolariciresinol diglucoside (SDG).

While dietary wholegrain Flaxseed (FS) has potent anti-inflammatory, anti-fibrotic and antioxidant properties in murine models of acute and chronic lung injury, the main bioactive ingredient that contributes to these protective effects remains unknown. This study evaluated the lignan complex of FS (FLC) enriched in secoisolariciresinol diglucoside with respect to lung radioprotective and tumor radiosensitizing efficacy using a mouse model of thoracic radiation-induced pneumonopathy. C57/Bl6 mice were fed 0% FS, 10% FS, 10% FLC or 20% FLC for 3 weeks, then irradiated with a single fraction (13.5 Gy) of X-ray radiation treatment (XRT). Mouse survival was monitored for 4 months after irradiation and inflammatory lung parameters were evaluated in bronchoalveolar lavage (BAL) fluid. Gene and protein levels of protective antioxidant and phase II enzymes were evaluated in lung tissue using qPCR and protein levels were verified by immunoblotting. Prolonged administration of the FLC diet was well tolerated and was not associated with any toxicity. Importantly, comparable to the whole grain 10% FS diet, irradiated mice fed 10% and 20% FLC diets displayed improved survival. Improved hemodynamic measurements were also recorded in irradiated mice fed 10% FS or 10% FLC diet compared to irradiated 0% FS fed mice. Flaxseed lignan complex diet also attenuated polymorphonuclear infiltration and overall lung inflammation to levels comparable to those in nonirradiated mice. Flaxseed lignan complex, similarly to FS, up-regulated gene expression as well as protein levels of protective antioxidant enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Dietary FLC induced radiosensitizing effects in our murine model of metastatic lung cancer. Importantly, protection of normal tissue does not thwart tumor cell death by radiation treatment. The dietary lignan complex of FS, mainly consisting of the phenolic secoisolariciresinol, is protective against radiation pneumonopathy in vivo while not hindering the tumoricidal effects of radiotherapy.

Appropriate goal level for 25-hydroxyvitamin D in cystic fibrosis.

BACKGROUND: Vitamin D deficiency is common in patients with cystic fibrosis (CF), and guidelines recommend 25-hydroxyvitamin D (25OHD) levels ≥ 30 ng/mL. This threshold was selected because serum parathyroid hormone (PTH) rises in healthy individuals when the 25OHD level falls below 30 ng/mL. PTH levels > 50 pg/mL are associated with an increased risk of bone loss. However, the relationship between 25OHD and PTH has not been studied in CF. We sought to determine the appropriate goal 25OHD level in patients with CF by identifying the level below which the risk of PTH > 50 pg/mL begins to increase. METHODS: Levels of 25OHD and PTH in 216 individuals with CF were collected prospectively. Individuals with 25OHD < 30 ng/mL were treated with vitamin D2, and levels were reevaluated. RESULTS: Mean 25OHD level was 25.7 ± 12.4 ng/mL, and mean PTH level was 46.7 ± 25.9 pg/mL. In 63% of individuals, 25OHD level was < 30 ng/mL, and in 38.0% it was ≤ 20 ng/mL. Low 25OHD levels were significantly associated with elevated PTH levels, with a mean PTH of 53.1 ± 29.8 pg/mL for 25OHD level 0 to 19 ng/mL; 51.1 ± 30.7 pg/mL for 25OHD level 20 to 29 ng/mL; 38.4 ± 16.4 pg/mL for 25OHD level 30 to 39 ng/mL; and 37.2 ± 16.4 pg/mL for 25OHD level ≥ 40 ng/mL (P = .006). We assessed the sensitivity of different 25OHD thresholds to identify individuals meeting the goal of a PTH level < 50 pg/mL to reduce the risk of bone loss. To obtain 90% sensitivity, a 25OHD level ≥ 35 ng/mL was required. Strikingly, 23% of individuals with 25OHD levels 30 to 34 ng/mL still had a PTH level > 50 pg/mL. This decreased to 14% for 25OHD level ≥ 35 ng/mL. CONCLUSIONS: Inadequate serum 25OHD levels are common in adults with CF and are associated with elevated PTH levels. Aiming to maintain 25-OHD levels ≥ 35 ng/mL in individuals with CF decreases the risk of having a PTH level associated with secondary hyperparathyroidism and bone loss.