scholarly journals Increased Incidence of Clonal Hematopoiesis in Lung Transplant Recipients Involves DNA Damage Response Genes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2163-2163
Author(s):  
Laneshia Tague ◽  
Karolyn A. Oetjen ◽  
Anirudh Mahadev ◽  
Daniel C. Link ◽  
Andrew E Gelman
Keyword(s):  
Lung Transplant ◽  
Healthy Controls ◽  
Transplant Recipients ◽  
Azathioprine Therapy ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Fitness Advantage ◽  
Significant Difference ◽  
Damage Response ◽  
Lung Transplant Recipients

Abstract Lung transplant recipients receive lifelong immunosuppression that includes a calcineurin inhibitor (tacrolimus or cyclosporine), an anti-proliferative agent (mycophenolate or azathioprine) and corticosteroids. They are also known to be at increased risk for a broad spectrum of adverse hematologic events. This includes relatively common complications such as neutropenia and other cytopenias, which occur in over half of patients, as well as rarer events such as de novo hematopoietic malignancy. Certain patterns of clonal hematopoiesis, the expansion of unique somatic clones in hematopoietic stem cells, are known to be associated with cytotoxic therapy and the development of hematologic malignancies. We hypothesized that the stress of transplantation and subsequent immunosuppression provides an environment whereby a unique pattern of clonal hematopoiesis emerges. To evaluate this hypothesis, we designed a custom panel of 59 genes using an error-corrected sequencing assay capable of detecting variant allele frequency (VAF) as low as 0.01. We characterized the overall burden and distribution of clonal hematopoiesis and compared differences among lung transplant recipients (n=73) and age-matched healthy controls (n=19). Clonal hematopoiesis was identified in 51/73 (69.9%) of lung transplant recipients. This was significantly higher than the frequency in the age-matched healthy controls (6/19,31.6% p=0.0071). Additionally, 27/51 (52.9%) of patients with clonal hematopoiesis had multiple variants. The increase in clonal hematopoiesis was mainly due to mutations in DNA damage response (DDR) genes (ATM, PPM1D, SRCAP or TP53), with 29/73 (39.7%) of lung transplant recipients carrying one or more mutation compared with 1/19 (5.3%) of age-matched healthy controls (5.3%, p=0.029). No significant difference in the frequency of clonal hematopoiesis due to non-DDR genes was also observed (48% vs. 26.3%, p=0.121). We first evaluated the relationship between clonal hematopoiesis and lung transplant indication. This is relevant, since interstitial lung disease (ILD), a common indication for lung transplantation, is associated with telomeropathies which are also linked to bone marrow failure and clonal hematopoiesis. However, the frequency of DDR clonal hematopoiesis in ILD patients (17/39, 44%) was similar to that observed in patients with COPD (9/20, 45%). We next investigated the association of immunosuppression with clonal hematopoiesis. Overall, 30/48 patients on mycophenolate (MPA) and 13/19 patients on azathioprine (AZA) had at least 1 clonal hematopoiesis mutation. We found no significant difference in overall clonal hematopoiesis frequency among patients on MPA vs. AZA. However, the frequency of DDR clonal hematopoiesis was significantly higher in patients on AZA (OR 4.04, 95% CI 1.22-13.38, p=0.022) than in patients on MPA. Moreover, when we assessed clonal hematopoiesis burden via Poisson regression, it was increased in patients receiving AZA (1.68, 95% CI 1.08-2.59, p=0.020) when compared to patients on MPA. All lung transplant recipients were maintained on tacrolimus but one, so associations with type of calcineurin inhibitor could not be assessed. Finally, we assessed clonal hematopoiesis in recipients who developed neutropenia (n=24) and found no significant association. To the best of our knowledge, we report the first evidence of increased clonal hematopoiesis in a solid organ transplant population. Our data indicate that azathioprine therapy is associated with the expansion of hematopoietic clones carrying variants in DDR genes. However, azathioprine therapy often represents a failure of MPA therapy, typically due to either hematologic or gastrointestinal toxicity. Therefore, the association noted might reflect MPA intolerance rather than azathioprine therapy. Nevertheless, prior studies show that treatment with genotoxic agents, such as chemotherapy or radiation therapy, provide a fitness advantage to hematopoietic stem/progenitor cells carrying DDR gene variants. Whether azathioprine vs. MPA therapy confers a similar fitness advantage is currently under investigation. Further investigation also is warranted to determine if the presence of clonal hematopoiesis influences lung transplant outcomes. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Retrospective Review of Calcineurin Inhibitors’ Impact on Cytomegalovirus Infections in Lung Transplant Recipients

2021 ◽  
Vol 2 (4) ◽  
pp. 478-490
Author(s):  
Rita Nogueiras-Álvarez ◽  
Víctor Manuel Mora-Cuesta ◽  
José Manuel Cifrián Martínez ◽  
María Ángeles de Cos Cossío ◽  
María del Mar García Sáiz
Keyword(s):  
Retrospective Review ◽  
Allograft Rejection ◽  
Lung Transplant ◽  
Calcineurin Inhibitors ◽  
Blood Levels ◽  
Transplant Recipients ◽  
Cmv Infection ◽  
Related Factors ◽  
Significant Difference ◽  
Lung Transplant Recipients

Immunosuppressive therapy reduces the risk for allograft rejection but leaves recipients susceptible to infections. Cytomegalovirus (CMV) is one of the most frequent causes for infection after transplantation and increases the risk for allograft rejection. As lung transplant recipients (LTRs) need to be under immunosuppression for life, they are a vulnerable group. To determine the potential association between the development of CMV infection and the calcineurin inhibitor (CNI) blood levels within previous 90 days, a retrospective review of LTRs was performed. Data from recipients who underwent a lung transplantation (LTx) at our center from January 2011 to December 2018 were collected. The studied recipients, after case/control matching, included 128 CMV-infection cases. The median time from the transplant to the first positive CMV viral load was 291.5 days. In our study, more patients were treated with tacrolimus (91.9%) than with cyclosporine (8.1%). Drug blood levels at selected timepoints showed no statistically significant difference between cases and controls. However, we found that CMV infection was more frequent in the donor-seropositive/recipient-seronegative group, interstitial lung disease (ILD) recipients, LTRs who underwent basiliximab induction, cyclosporine treated recipients, and LTRs with lymphopenia (at the time of CMV infection and 90 days before). In this review of LTRs, no association between the CNI blood level and CMV infection was seen, although other immunity-related factors were found to be influencing, i.e., basiliximab induction, cyclosporine treatment, and lymphopenia.

scholarly journals 2640. Aerosol vs. Oral Ribavirin for the Treatment of Community-Acquired Respiratory Virus Infections in Lung Transplant Recipients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S923-S923
Author(s):  
Emily Mui ◽  
Marisa Holubar ◽  
Roy Lee ◽  
Danielle Pham ◽  
Lina Meng ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Lung Transplant ◽  
Respiratory Virus ◽  
Graft Loss ◽  
Transplant Recipients ◽  
Organ Rejection ◽  
Increased Risk ◽  
Significant Difference ◽  
Lung Transplant Recipients ◽  
Overall Mortality

Abstract Background Community-acquired respiratory virus (CARV) infections are associated with an increased risk of chronic lung allograft dysfunction (CLAD) and graft loss in lung transplant recipients (LTR). Administration of ribavirin by aerosol was the standard of care at Stanford Health Care in the management of CARV infections. Given the sparse evidence of benefit with aerosol ribavirin (AR) and its increasing cost and teratogenic risk for exposed healthcare personnel, AR was restricted to the treatment of respiratory syncytial virus (RSV) in 2016 and was ultimately removed from formulary in 2017. Oral (PO) ribavirin was used at the discretion of the transplant team. The objective of this study was to evaluate the clinical outcomes of AR compared with PO ribavirin in lung transplant recipients. Methods We performed a retrospective cohort analysis of adult lung transplant recipients diagnosed with CARV (metapneumovirus, parainfluenza virus, and RSV) infections treated with either AR or PO ribavirin. The analysis included the first treatment course of ribavirin by either route and patients were excluded if they received ribavirin in the prior 12 months. The primary outcome was the development/progression of CLAD, acute organ rejection, and overall mortality. Results Of 85 patients, 41 received AR and 44 received PO ribavirin. There was no significant difference in the following clinical outcomes with AR and oral ribavirin, respectively: development or progression of CLAD (30 days: 9.7% vs. 4.5%, P = 0.4227; 90 days: 14.6% vs. 6.8%, P = 0.303; 6 months: 17% vs. 9%, P = 0.3413; 12 months: 24% vs. 15.9%, P = 0.4188), acute organ rejection (90 days: 7.3% vs. 4.5%, P = 0.6689; 6 months: 12.1% vs. 9%, P = 0.7329; 12 months: 19.5% vs. 13.6%, P = 0.5635), and overall mortality (30 days: 0% vs. 4.5%, P = 0.4947; 90 days: 7.3% vs. 4.5%, P = 0.6689; 6 months: 7.3% vs. 9%, P = 1.0; 12 months: 7.3% vs. 13.6%, P = 0.4858). There was no observable difference in reported adverse effects between AR and PO ribavirin. Conclusion Lung transplant recipients with CARV infections had similar outcomes when treated with AR or PO ribavirin. Oral ribavirin is a less costly treatment than AR, but the efficacy of ribavirin by any route remains questionable. Disclosures All authors: No reported disclosures.

CNE Article: Pain After Lung Transplant: High-Frequency Chest Wall Oscillation vs Chest Physiotherapy

2013 ◽  
Vol 22 (2) ◽  
pp. 115-124 ◽  
Author(s):  
Angeli Esguerra-Gonzalez ◽  
Monina Ilagan-Honorio ◽  
Stephanie Fraschilla ◽  
Priscilla Kehoe ◽  
Ai Jin Lee ◽  
...  
Keyword(s):  
Chest Wall ◽  
High Frequency ◽  
Repeated Measures ◽  
Lung Transplant ◽  
Chest Physiotherapy ◽  
Transplant Recipients ◽  
Pain Scores ◽  
Significant Difference ◽  
Wall Oscillation ◽  
Lung Transplant Recipients

Background Chest physiotherapy and high-frequency chest wall oscillation (HFCWO) are routinely used after lung transplant to facilitate removal of secretions. To date, no studies have been done to investigate which therapy is more comfortable and preferred by lung transplant recipients. Patients who have less pain may mobilize secretions, heal, and recover faster. Objectives To compare effects of HFCWO versus chest physiotherapy on pain and preference in lung transplant recipients. Methods In a 2-group experimental, repeated-measures design, 45 lung transplant recipients (27 single lung, 18 bilateral) were randomized to chest physiotherapy (10 AM, 2 PM) followed by HFCWO (6 PM, 10 PM; group 1, n=22) or vice versa (group 2, n=23) on postoperative day 3. A verbal numeric rating scale was used to measure pain before and after treatment. At the end of the treatment sequence, a 4-item patient survey was administered to assess treatment preference, pain, and effectiveness. Data were analyzed with χ2 and t tests and repeated-measures analysis of variance. Results A significant interaction was found between mean difference in pain scores from before to after treatment and treatment method; pain scores decreased more when HFCWO was done at 10 AM and 6 PM (P =.04). Bilateral transplant recipients showed a significant preference for HFCWO over chest physiotherapy (11 [85%] vs 2 [15%], P=.01). However, single lung recipients showed no significant difference in preference between the 2 treatments (11 [42%] vs 14 [54%]). Conclusions HFCWO seems to provide greater decreases in pain scores than does chest physiotherapy. Bilateral lung transplant recipients preferred HFCWO to chest physiotherapy. HFCWO may be an effective, feasible alternative to chest physiotherapy. (American Journal of Critical Care. 2013;22:115–125)

scholarly journals Vaccine serologic responses among transplant patients associate with COVID-19 infection and T peripheral helper cells

2021 ◽  
Author(s):  
Jacob E. Lemieux ◽  
Amy Li ◽  
Matteo Gentili ◽  
Cory A. Perugino ◽  
Zoe F. Weiss ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd4 T Cells ◽  
Lung Transplant ◽  
T Cell Subsets ◽  
Healthy Controls ◽  
Transplant Recipients ◽  
Vaccine Response ◽  
Lung Transplant Recipients

Background: Therapeutically immunosuppressed transplant recipients exhibit attenuated responses to COVID-19 vaccines. To better understand the immune alterations that determined poor vaccine response, we correlated quantities of circulating T and B cell subsets at baseline with longitudinal serologic responses to SARS-CoV-2 mRNA vaccination in heart and lung transplant recipients. Methods: Samples at baseline and at approximately 8 and 30 days after each vaccine dose for 22 heart and lung transplant recipients with no history of COVID-19, four heart and lung transplant recipients with prior COVID-19 infection, and 12 healthy controls undergoing vaccination were analyzed. Anti-spike protein receptor binding domain (RBD) IgG and pseudovirus neutralization activity were measured. Proportions of B and T cell subsets at baseline were comprehensively quantitated. Results: At 8-30 days post vaccination, healthy controls displayed robust anti-RBD IgG responses, whereas heart and lung transplant recipients showed minimally increased responses. A parallel absence of activity was observed in pseudovirus neutralization. In contrast, three of four (75%) transplant recipients with prior COVID-19 infection displayed robust responses at levels comparable to controls. Baseline levels of activated PD-1+ HLA-DR+ CXCR5- CD4+ T cells (also known as T peripheral helper [TPH] cells) and CD4+ T cells strongly predicted the ability to mount a response. Conclusions: Immunosuppressed patients have defective vaccine responses but can be induced to generate neutralizing antibodies after SARS-CoV-2 infection. Strong correlations of vaccine responsiveness with baseline TPH and CD4+ T cell numbers highlights a role for T helper activity in B cell differentiation into antibody secreting cells during vaccine response.

scholarly journals Long-term outcomes of metallic endobronchial stents in lung transplant recipients are not affected by bacterial colonization

2020 ◽  
Vol 32 (1) ◽  
pp. 47-54
Author(s):  
Shimon Izhakian ◽  
Walter G Wasser ◽  
Baruch Vainshelboim ◽  
Barak Pertzov ◽  
Oleg Gorelik ◽  
...  
Keyword(s):  
Lung Transplant ◽  
Bacterial Colonization ◽  
Statistical Significance ◽  
Intervention Group ◽  
Control Group ◽  
Stent Insertion ◽  
Transplant Recipients ◽  
Significant Difference ◽  
Lung Transplant Recipients

Abstract OBJECTIVES We evaluated associations of endobronchial stenting with airway bacterial colonization, the antimicrobial resistance profile, hospitalizations for pneumonia and survival in lung transplant recipients. METHODS This is a retrospective single-centre study of 582 recipients of lung transplant during 2002–2018. We compared outcomes of 57 patients (9.7%) who received endobronchial stents (intervention group) to a control group of 57 patients without stents who were matched one to one for age, sex, year of transplantation, unilateral/bilateral transplantation and underlying disease. RESULTS For the intervention compared to the control group, airway colonization was more common for Pseudomonas (86% vs 35%, P < 0.001), Acinetobacter (21% vs 7%, P = 0.05), Klebsiella (21% vs 5%, P = 0.02) and Staphylococcus species (11% vs 0%, P = 0.02). The respective proportions of patients with positive bronchoalveolar lavage cultures on the third post-transplantation day, the day of stent insertion and 6-month post-stent insertion were 47.4%, 50.9% and 65.4% for Pseudomonas sp.; 15.8%, 12.3% and 3.8% for Klebsiella sp.; and 8.8%, 5.3% and 5.8% for Acinetobacter sp. The mean number of hospitalizations for pneumonia per patient was higher, without statistical significance, in the intervention than the control group (1.5 ± 1.7 vs 0.9 ± 1.5, P = 0.1). Kaplan–Meier survival curves did not show a statistically significant difference between the intervention group and the entire group without endobronchial stents (n = 525) (P = 0.4). CONCLUSIONS Lung transplant recipients with endobronchial stents were more likely to be colonized with pathologic bacteria and having pneumonia; however, stent placement was not associated with increased long-term mortality with appropriate stent maintenance.

scholarly journals Cytomegalovirus (CMV) Disease Despite Weekly Preemptive CMV Strategy for Recipients of Solid Organ and Hematopoietic Stem Cell Transplantation

2018 ◽  
Vol 5 (5) ◽  
Author(s):  
I P Lodding ◽  
C da Cunha Bang ◽  
S S Sørensen ◽  
F Gustafsson ◽  
M Iversen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Lung Transplant ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Hematopoietic Stem ◽  
Screening Intervals ◽  
Lung Transplant Recipients ◽  
Cmv Disease ◽  
Cmv Dnaemia

Abstract Background Transplant recipients presenting with cytomegalovirus (CMV) disease at the time of diagnosis of CMV DNAemia pose a challenge to a preemptive CMV management strategy. However, the rate and risk factors of such failure remain uncertain. Methods Solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) recipients with a first episode of CMV polymerase chain reaction (PCR) DNAemia within the first year posttransplantation were evaluated (n = 335). Patient records were reviewed for presence of CMV disease at the time of CMV DNAemia diagnosis. The distribution and prevalence of CMV disease were estimated, and the odds ratio (OR) of CMV disease was modeled using logistic regression. Results The prevalence of CMV disease increased for both SOT and HSCT with increasing diagnostic CMV PCR load and with screening intervals >14 days. The only independent risk factor in multivariate analysis was increasing CMV DNAemia load of the diagnostic CMV PCR (OR = 6.16; 95% confidence interval, 2.09–18.11). Among recipients receiving weekly screening (n = 147), 16 (10.8%) had CMV disease at the time of diagnosis of CMV DNAemia (median DNAemia load 628 IU/mL; interquartile range, 432–1274); 93.8% of these cases were HSCT and lung transplant recipients. Conclusions Despite application of weekly screening intervals, HSCT and lung transplant recipients in particular presented with CMV disease at the time of diagnosis of CMV DNAemia. Additional research to improve the management of patients at risk of presenting with CMV disease at low levels of CMV DNAemia and despite weekly screening is warranted.

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