BackgroundLung transplantation is a therapeutic option for end‐stage pediatric pulmonary hyperten... more BackgroundLung transplantation is a therapeutic option for end‐stage pediatric pulmonary hypertension (PH). Right ventricular (RV) recovery post‐lung transplant in children with PH has not been well‐described, and questions persist about the peri‐operative course and post‐transplant cardiac function after lung transplantation in medically refractory PH patients with baseline RV dysfunction.MethodsA single‐center chart review identified patients with childhood PH who subsequently underwent bilateral orthotopic lung transplantation between 2000 and 2020. Twenty‐six patients met criteria; three were excluded due to echocardiograms not available for digital review. RV fractional area change (FAC) and left ventricular eccentricity index (LVEI) were determined prior to transplantation, and at 1, 3, 6, and 12‐month post‐transplantation.ResultsFourteen of 23 patients had baseline RV dysfunction. The median age at transplantation was 16.5 years and 13.9 years for those with and without baseline RV dysfunction, respectively. Of the 14 with baseline RV dysfunction, 12 (86%) were alive 1‐year post‐transplantation. All patients with baseline RV dysfunction had increased RV‐FAC post‐transplantation with normalization of RV‐FAC in 70% at 3 months and 100% of patients by 12‐month post‐transplantation. Duration of ventilation (p = .4), intensive care unit (p = .5), or hospital stay (p = .9) was not associated with pre‐transplant RV function.ConclusionsAmong pediatric patients with PH and RV dysfunction, pre‐transplantation RV function was not associated with short‐term outcomes. All patients with baseline RV dysfunction had improvement in RV function, justifying consideration of lung transplantation among pediatric patients with end‐stage PH and RV dysfunction.
Background:Infection with rhinovirus (HRV) occurs following pediatric lung transplantation. Prosp... more Background:Infection with rhinovirus (HRV) occurs following pediatric lung transplantation. Prospective studies documenting frequencies, persistence, and progression of HRV in this at-risk population are lacking.Methods:In the Clinical Trials in Organ Transplant in Children prospective observational study, we followed 61 lung transplant recipients for 2 years. We quantified molecular subtypes of HRV in serially collected nasopharyngeal (NP) and bronchoalveolar lavage (BAL) samples and correlated them with clinical characteristics.Results:We identified 135 community acquired respiratory infections (CARV) from 397 BAL and 480 NP samples. We detected 93 HRV events in 42 (68.8%) patients, 22 of which (23.4%) were symptomatic. HRV events were contiguous with different genotypes identified in 23 cases but symptoms were not preferentially associated with any particular species. Nine (9.7%) HRV events persisted over multiple successive samples for a median of 36 days (range 18 – 408 days). Three persistent HRV were symptomatic. When we serially measured forced expiratory volume in one second (FEV1) in 23 subjects with events, we did not observe significant decreases in lung function over 12 months post-HRV.Conclusion:In conjunction with our previous reports, our prospectively collected data indicate that molecularly heterogeneous HRV infections occur commonly following pediatric lung transplantation, but these infections do not negatively impact clinical outcomes.
Rapamycin inhibits the development and progression of vascular disease. We previously showed that... more Rapamycin inhibits the development and progression of vascular disease. We previously showed that rapamycin induces the cytoprotective protein, heme oxygenase-1 (HO-1), and more importantly, chemically inhibiting HO-1 blocked the antiproliferative actions of rapamycin. In this study, we evaluated whether HO-1 is required for the vascular protective effects of rapamycin in vivo using a rat monocrotaline-induced pulmonary hypertension model. Rats were exposed to monocrotaline with or without rapamycin and HO activity was altered using the chemical inhibitor, tin protoporphyrin or the inducer, cobalt protoporphyrin. We also evaluated possible mechanisms of rapamycin-dependent induction of HO-1, and how HO-1 mediates growth factor-dependent antiproliferative actions of rapamycin. Proliferation and cell cycle progression were examined in smooth muscle cells derived from both wild-type and HO-1 knockout (HO-1 À/À) mice in response to growth factors and rapamycin. Similar to our previous findings in vitro, rapamycin induced HO-1 in rat lung. Rapamycin also inhibited the development of monocrotaline-induced pulmonary hypertension, and this protective effect was blocked with the addition of tin protoporphyrin. In addition, treatment with cobalt protoporphyrin resulted in a substantial protection in this model of pulmonary hypertension. Rapamycin induction of HO-1 was dependent upon a transcriptional event; however, it was not mediated through an altered redox state or mammalian targets of rapamycin inhibition. Unlike wild-type cells, the growth of HO-1 À/À mouse aortic smooth muscle cells was not inhibited or cell cycle arrested in G1 in response to rapamycin. This study demonstrates that HO-1 is critical for the antiproliferative and vascular protective effects of rapamycin in vitro and in vivo in monocrotaline-induced pulmonary hypertension.
Lung and heart–lung transplantation are established therapies for children with end-stage lung or... more Lung and heart–lung transplantation are established therapies for children with end-stage lung or congenital heart disease (CHD)/pulmonary vascular disease (PVD) in which there are no other therapeutic options. The most common indications for transplantation differ by age group. Cystic fibrosis is the most common overall indication of the lung recipients for the 12–17-year age group. In children younger than 1 year, the most common indications are CHD/PVD and diffuse lung disease from surfactant abnormalities. Additional diagnoses include transplant and nontransplant bronchiolitis obliterans and pulmonary fibrosis/interstitial pneumonitis. This chapter reviews pretransplant, donor, and posttransplant imaging evaluation.
BACKGROUND Long-term survival after lung transplantation (LTx) is limited by chronic lung allogra... more BACKGROUND Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD). METHODS We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients. RESULTS Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival. CONCLUSIONS Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.
The International Pediatric Transplant Association (IPTA) convened an expert consensus conference... more The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post‐transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre‐emptive strategies. While the group made a strong recommendation for pre‐emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre‐emptive strategy, largely due to insufficient or conflicting evidence. Current gaps and future research priorities are highlighted.
Pulmonary endothelial dysfunction induced by inflammation and inflammation-associated reactive ox... more Pulmonary endothelial dysfunction induced by inflammation and inflammation-associated reactive oxygen species is a central component in the pathophysiology of lung transplant ischemia-reperfusion (IR) injury. Indoleamine-2,3-dioxygenase (IDO) is a unique cytosolic enzyme possessing both immune modulating and antioxidant properties. This study investigated whether enhanced pulmonary endothelial IDO activity by a targeted nonviral gene transfer approach ameliorates lung IR injury. Orthotopic syngeneic lung transplants were performed in Lewis rats. A human IDO (hIDO)-expressing plasmid driven by an endothelial cell-specific endothelin-1 promoter was generated and intravenously delivered to donor lung using cationic polymer polyethylenimine. This nonviral gene transfer approach augmented hIDO expression specifically in endothelial cells within lung grafts. Importantly, enhanced IDO activity induced by the hIDO transgene prevented endothelial cell apoptosis, reduced vascular permeability and leukocyte extravasation, and consequently improved graft function and histologic appearance. Furthermore, our in vitro studies showed that increased IDO activity in endothelial cells protected its mitochondrial function and ultrastructure from oxidative stress through stabilization of intracellular redox status. The approach used in these experiments has properties that could eliminate the inherent side effects associated with viral vectors and/or antibody-directed targeted therapy, and thus may represent a potential therapeutic strategy against lung IR injury in patients.
International Journal of Pediatric Otorhinolaryngology, Mar 1, 2020
Objective:To describe a multidisciplinary approach for the treatment of plastic bronchitis (PB) i... more Objective:To describe a multidisciplinary approach for the treatment of plastic bronchitis (PB) in children.Methods:Retrospective chart review of children with PB between 1997 and 2017. Data regarding clinical presentation, diagnosis, management, and outcomes were analyzed.Results:Of 34 patients presenting with PB, 24 had single ventricle (SV) heart disease, 9 had pulmonary disease, and one had no underlying disease. Median (IQR: interquartile range) age at the time of PB diagnosis was 5.5 years (IQR: 9.0). Presenting symptoms included cough productive of casts (n=27, 79%), wheezing (n=5, 15%), dyspnea (n=18, 53%), hypoxia (n=31, 91%), and respiratory failure (n=9, 26%). Diagnosis was made based on clinical evaluation, bronchoscopy findings, and/or pathology of casts. Treatment methods included bronchoscopy for cast removal (25% of SV patients, 91% of non-SV patients), chest physiotherapy (SV: 92%, non-SV: 45%), albuterol (SV: 79%, non-SV: 73%), inhaled steroids (SV: 75%, non-SV: 18%), nebulized hypertonic saline (SV: 29%, non-SV: 9%), nebulized heparin (SV: 8%, non-SV: 55%), nebulized tissue plasminogen activator (tPA; SV: 33%, non-SV: 9%), inhaled Dornase Alfa (SV: 54%, non-SV: 9%), antibiotics (SV: 46%, non-SV: 45%), systemic steroids (SV: 13%, non-SV: 45%), and lymphatic embolization (SV: 8%, non-SV: 45%). Of SV patients, 11 had no recurrence, 5 underwent heart transplantation, one awaits transplant, and 3 died due to cardiac disease. Three patients with respiratory disease had recurrent PB and one died from MRSA pneumonia.Conclusion:PB is a highly morbid disease with limited treatment options. Bronchoscopy and chest physiotherapy for airway clearance are among the most-utilized therapies.
BackgroundLung transplantation is a therapeutic option for end‐stage pediatric pulmonary hyperten... more BackgroundLung transplantation is a therapeutic option for end‐stage pediatric pulmonary hypertension (PH). Right ventricular (RV) recovery post‐lung transplant in children with PH has not been well‐described, and questions persist about the peri‐operative course and post‐transplant cardiac function after lung transplantation in medically refractory PH patients with baseline RV dysfunction.MethodsA single‐center chart review identified patients with childhood PH who subsequently underwent bilateral orthotopic lung transplantation between 2000 and 2020. Twenty‐six patients met criteria; three were excluded due to echocardiograms not available for digital review. RV fractional area change (FAC) and left ventricular eccentricity index (LVEI) were determined prior to transplantation, and at 1, 3, 6, and 12‐month post‐transplantation.ResultsFourteen of 23 patients had baseline RV dysfunction. The median age at transplantation was 16.5 years and 13.9 years for those with and without baseline RV dysfunction, respectively. Of the 14 with baseline RV dysfunction, 12 (86%) were alive 1‐year post‐transplantation. All patients with baseline RV dysfunction had increased RV‐FAC post‐transplantation with normalization of RV‐FAC in 70% at 3 months and 100% of patients by 12‐month post‐transplantation. Duration of ventilation (p = .4), intensive care unit (p = .5), or hospital stay (p = .9) was not associated with pre‐transplant RV function.ConclusionsAmong pediatric patients with PH and RV dysfunction, pre‐transplantation RV function was not associated with short‐term outcomes. All patients with baseline RV dysfunction had improvement in RV function, justifying consideration of lung transplantation among pediatric patients with end‐stage PH and RV dysfunction.
Background:Infection with rhinovirus (HRV) occurs following pediatric lung transplantation. Prosp... more Background:Infection with rhinovirus (HRV) occurs following pediatric lung transplantation. Prospective studies documenting frequencies, persistence, and progression of HRV in this at-risk population are lacking.Methods:In the Clinical Trials in Organ Transplant in Children prospective observational study, we followed 61 lung transplant recipients for 2 years. We quantified molecular subtypes of HRV in serially collected nasopharyngeal (NP) and bronchoalveolar lavage (BAL) samples and correlated them with clinical characteristics.Results:We identified 135 community acquired respiratory infections (CARV) from 397 BAL and 480 NP samples. We detected 93 HRV events in 42 (68.8%) patients, 22 of which (23.4%) were symptomatic. HRV events were contiguous with different genotypes identified in 23 cases but symptoms were not preferentially associated with any particular species. Nine (9.7%) HRV events persisted over multiple successive samples for a median of 36 days (range 18 – 408 days). Three persistent HRV were symptomatic. When we serially measured forced expiratory volume in one second (FEV1) in 23 subjects with events, we did not observe significant decreases in lung function over 12 months post-HRV.Conclusion:In conjunction with our previous reports, our prospectively collected data indicate that molecularly heterogeneous HRV infections occur commonly following pediatric lung transplantation, but these infections do not negatively impact clinical outcomes.
Rapamycin inhibits the development and progression of vascular disease. We previously showed that... more Rapamycin inhibits the development and progression of vascular disease. We previously showed that rapamycin induces the cytoprotective protein, heme oxygenase-1 (HO-1), and more importantly, chemically inhibiting HO-1 blocked the antiproliferative actions of rapamycin. In this study, we evaluated whether HO-1 is required for the vascular protective effects of rapamycin in vivo using a rat monocrotaline-induced pulmonary hypertension model. Rats were exposed to monocrotaline with or without rapamycin and HO activity was altered using the chemical inhibitor, tin protoporphyrin or the inducer, cobalt protoporphyrin. We also evaluated possible mechanisms of rapamycin-dependent induction of HO-1, and how HO-1 mediates growth factor-dependent antiproliferative actions of rapamycin. Proliferation and cell cycle progression were examined in smooth muscle cells derived from both wild-type and HO-1 knockout (HO-1 À/À) mice in response to growth factors and rapamycin. Similar to our previous findings in vitro, rapamycin induced HO-1 in rat lung. Rapamycin also inhibited the development of monocrotaline-induced pulmonary hypertension, and this protective effect was blocked with the addition of tin protoporphyrin. In addition, treatment with cobalt protoporphyrin resulted in a substantial protection in this model of pulmonary hypertension. Rapamycin induction of HO-1 was dependent upon a transcriptional event; however, it was not mediated through an altered redox state or mammalian targets of rapamycin inhibition. Unlike wild-type cells, the growth of HO-1 À/À mouse aortic smooth muscle cells was not inhibited or cell cycle arrested in G1 in response to rapamycin. This study demonstrates that HO-1 is critical for the antiproliferative and vascular protective effects of rapamycin in vitro and in vivo in monocrotaline-induced pulmonary hypertension.
Lung and heart–lung transplantation are established therapies for children with end-stage lung or... more Lung and heart–lung transplantation are established therapies for children with end-stage lung or congenital heart disease (CHD)/pulmonary vascular disease (PVD) in which there are no other therapeutic options. The most common indications for transplantation differ by age group. Cystic fibrosis is the most common overall indication of the lung recipients for the 12–17-year age group. In children younger than 1 year, the most common indications are CHD/PVD and diffuse lung disease from surfactant abnormalities. Additional diagnoses include transplant and nontransplant bronchiolitis obliterans and pulmonary fibrosis/interstitial pneumonitis. This chapter reviews pretransplant, donor, and posttransplant imaging evaluation.
BACKGROUND Long-term survival after lung transplantation (LTx) is limited by chronic lung allogra... more BACKGROUND Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD). METHODS We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients. RESULTS Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival. CONCLUSIONS Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.
The International Pediatric Transplant Association (IPTA) convened an expert consensus conference... more The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post‐transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre‐emptive strategies. While the group made a strong recommendation for pre‐emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre‐emptive strategy, largely due to insufficient or conflicting evidence. Current gaps and future research priorities are highlighted.
Pulmonary endothelial dysfunction induced by inflammation and inflammation-associated reactive ox... more Pulmonary endothelial dysfunction induced by inflammation and inflammation-associated reactive oxygen species is a central component in the pathophysiology of lung transplant ischemia-reperfusion (IR) injury. Indoleamine-2,3-dioxygenase (IDO) is a unique cytosolic enzyme possessing both immune modulating and antioxidant properties. This study investigated whether enhanced pulmonary endothelial IDO activity by a targeted nonviral gene transfer approach ameliorates lung IR injury. Orthotopic syngeneic lung transplants were performed in Lewis rats. A human IDO (hIDO)-expressing plasmid driven by an endothelial cell-specific endothelin-1 promoter was generated and intravenously delivered to donor lung using cationic polymer polyethylenimine. This nonviral gene transfer approach augmented hIDO expression specifically in endothelial cells within lung grafts. Importantly, enhanced IDO activity induced by the hIDO transgene prevented endothelial cell apoptosis, reduced vascular permeability and leukocyte extravasation, and consequently improved graft function and histologic appearance. Furthermore, our in vitro studies showed that increased IDO activity in endothelial cells protected its mitochondrial function and ultrastructure from oxidative stress through stabilization of intracellular redox status. The approach used in these experiments has properties that could eliminate the inherent side effects associated with viral vectors and/or antibody-directed targeted therapy, and thus may represent a potential therapeutic strategy against lung IR injury in patients.
International Journal of Pediatric Otorhinolaryngology, Mar 1, 2020
Objective:To describe a multidisciplinary approach for the treatment of plastic bronchitis (PB) i... more Objective:To describe a multidisciplinary approach for the treatment of plastic bronchitis (PB) in children.Methods:Retrospective chart review of children with PB between 1997 and 2017. Data regarding clinical presentation, diagnosis, management, and outcomes were analyzed.Results:Of 34 patients presenting with PB, 24 had single ventricle (SV) heart disease, 9 had pulmonary disease, and one had no underlying disease. Median (IQR: interquartile range) age at the time of PB diagnosis was 5.5 years (IQR: 9.0). Presenting symptoms included cough productive of casts (n=27, 79%), wheezing (n=5, 15%), dyspnea (n=18, 53%), hypoxia (n=31, 91%), and respiratory failure (n=9, 26%). Diagnosis was made based on clinical evaluation, bronchoscopy findings, and/or pathology of casts. Treatment methods included bronchoscopy for cast removal (25% of SV patients, 91% of non-SV patients), chest physiotherapy (SV: 92%, non-SV: 45%), albuterol (SV: 79%, non-SV: 73%), inhaled steroids (SV: 75%, non-SV: 18%), nebulized hypertonic saline (SV: 29%, non-SV: 9%), nebulized heparin (SV: 8%, non-SV: 55%), nebulized tissue plasminogen activator (tPA; SV: 33%, non-SV: 9%), inhaled Dornase Alfa (SV: 54%, non-SV: 9%), antibiotics (SV: 46%, non-SV: 45%), systemic steroids (SV: 13%, non-SV: 45%), and lymphatic embolization (SV: 8%, non-SV: 45%). Of SV patients, 11 had no recurrence, 5 underwent heart transplantation, one awaits transplant, and 3 died due to cardiac disease. Three patients with respiratory disease had recurrent PB and one died from MRSA pneumonia.Conclusion:PB is a highly morbid disease with limited treatment options. Bronchoscopy and chest physiotherapy for airway clearance are among the most-utilized therapies.
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Papers by Gary Visner