Kurt R. Schumacher

Social Media Methods for Studying Rare Diseases

For pediatric rare diseases, the number of patients available to support traditional research methods is often inadequate. However, patients who have similar diseases cluster “virtually” online via social media. This study aimed to (1) determine whether patients who have the rare diseases Fontan-associated protein losing enteropathy (PLE) and plastic bronchitis (PB) would participate in online research, and (2) explore response patterns to examine social media’s role in participation compared with other referral modalities. A novel, internet-based survey querying details of potential pathogenesis, course, and treatment of PLE and PB was created. The study was available online via web and Facebook portals for 1 year. Apart from 2 study-initiated posts on patient-run Facebook pages at the study initiation, all recruitment was driven by study respondents only. Response patterns and referral sources were tracked. A total of 671 respondents with a Fontan palliation completed a valid survey, including 76 who had PLE and 46 who had PB. Responses over time demonstrated periodic, marked increases as new online populations of Fontan patients were reached. Of the responses, 574 (86%) were from the United States and 97 (14%) were international. The leading referral sources were Facebook, internet forums, and traditional websites. Overall, social media outlets referred 84% of all responses, making it the dominant modality for recruiting the largest reported contemporary cohort of Fontan patients and patients who have PLE and PB. The methodology and response patterns from this study can be used to design research applications for other rare diseases.

Fontan-Associated Protein-Losing Enteropathy and Plastic Bronchitis

OBJECTIVE To characterize the medical history, disease progression, and treatment of current-era patients with the rare diseases Fontan-associated protein-losing enteropathy (PLE) and plastic bronchitis. STUDY DESIGN A novel survey that queried demographics, medical details, and treatment information was piloted and placed online via a Facebook portal, allowing social media to power the study. Participation regardless of PLE or plastic bronchitis diagnosis was allowed. Case control analyses compared patients with PLE and plastic bronchitis with uncomplicated control patients receiving the Fontan procedure. RESULTS The survey was completed by 671 subjects, including 76 with PLE, 46 with plastic bronchitis, and 7 with both. Median PLE diagnosis was 2.5 years post-Fontan. Hospitalization for PLE occurred in 71% with 41% hospitalized ≥ 3 times. Therapy varied significantly. Patients with PLE more commonly had hypoplastic left ventricle (62% vs 44% control; OR 2.81, 95% CI 1.43-5.53), chylothorax (66% vs 41%; OR 2.96, CI 1.65-5.31), and cardiothoracic surgery in addition to staged palliation (17% vs 5%; OR 4.27, CI 1.63-11.20). Median plastic bronchitis diagnosis was 2 years post-Fontan. Hospitalization for plastic bronchitis occurred in 91% with 61% hospitalized ≥ 3 times. Therapy was very diverse. Patients with plastic bronchitis more commonly had chylothorax at any surgery (72% vs 51%; OR 2.47, CI 1.20-5.08) and seasonal allergies (52% vs 36%; OR 1.98, CI 1.01-3.89). CONCLUSIONS Patient-specific factors are associated with diagnoses of PLE or plastic bronchitis. Treatment strategies are diverse without clear patterns. These results provide a foundation upon which to design future therapeutic studies and identify a clear need for forming consensus approaches to treatment.

Predicting Graft Loss by 1 Year in Pediatric Heart Transplantation Candidates An Analysis of the Pediatric Heart Transplant Study Database

Background— Pediatric data on the impact of pre–heart transplantation (HTx) risk factors on early post-HTx outcomes remain inconclusive. Thus, among patients with previous congenital heart disease or cardiomyopathy, disease-specific risk models for graft loss were developed with the use pre-HTx recipient and donor characteristics. Methods and Results— Patients enrolled in the Pediatric Heart Transplant Study (PHTS) from 1996 to 2006 were stratified by pre-HTx diagnosis into cardiomyopathy and congenital heart disease cohorts. Logistic regression identified independent, pre-HTx risk factors. Risk models were constructed for 1-year post-HTx graft loss. Donor factors were added for model refinement. The models were validated with the use of patients transplanted from 2007 to 2009. Risk factors for graft loss were identified in patients with cardiomyopathy (n=896) and congenital heart disease (n=965). For cardiomyopathy, independent risk factors were earlier year of transplantation, nonwhite race, female sex, diagnosis other than dilated cardiomyopathy, higher blood urea nitrogen, and panel reactive antibody >10%. The recipient characteristic risk model had good accuracy in the validation cohort, with predicted versus actual survival of 97.5% versus 95.3% (C statistic, 0.73). For patients with congenital heart disease, independent risk factors were nonwhite race, history of Fontan, ventilator dependence, higher blood urea nitrogen, panel reactive antibody >10%, and lower body surface area. The risk model was less accurate, with 86.6% predicted versus 92.4% actual survival, in the validation cohort (C statistic, 0.63). Donor characteristics did not enhance model precision. Conclusions— Risk factors for 1-year post-HTx graft loss differ on the basis of pre-HTx cardiac diagnosis. Modeling effectively stratifies the risk of graft loss in patients with cardiomyopathy and may be an adjunctive tool in allocation policies and center performance metrics. # CLINICAL PERSPECTIVE {#article-title-28}Background— Pediatric data on the impact of pre–heart transplantation (HTx) risk factors on early post-HTx outcomes remain inconclusive. Thus, among patients with previous congenital heart disease or cardiomyopathy, disease-specific risk models for graft loss were developed with the use pre-HTx recipient and donor characteristics. Methods and Results— Patients enrolled in the Pediatric Heart Transplant Study (PHTS) from 1996 to 2006 were stratified by pre-HTx diagnosis into cardiomyopathy and congenital heart disease cohorts. Logistic regression identified independent, pre-HTx risk factors. Risk models were constructed for 1-year post-HTx graft loss. Donor factors were added for model refinement. The models were validated with the use of patients transplanted from 2007 to 2009. Risk factors for graft loss were identified in patients with cardiomyopathy (n=896) and congenital heart disease (n=965). For cardiomyopathy, independent risk factors were earlier year of transplantation, nonwhite race, female sex, diagnosis other than dilated cardiomyopathy, higher blood urea nitrogen, and panel reactive antibody >10%. The recipient characteristic risk model had good accuracy in the validation cohort, with predicted versus actual survival of 97.5% versus 95.3% (C statistic, 0.73). For patients with congenital heart disease, independent risk factors were nonwhite race, history of Fontan, ventilator dependence, higher blood urea nitrogen, panel reactive antibody >10%, and lower body surface area. The risk model was less accurate, with 86.6% predicted versus 92.4% actual survival, in the validation cohort (C statistic, 0.63). Donor characteristics did not enhance model precision. Conclusions— Risk factors for 1-year post-HTx graft loss differ on the basis of pre-HTx cardiac diagnosis. Modeling effectively stratifies the risk of graft loss in patients with cardiomyopathy and may be an adjunctive tool in allocation policies and center performance metrics.

Fontan-associated protein-losing enteropathy and heart transplant: A Pediatric Heart Transplant Study analysis

BACKGROUND Post-Fontan protein-losing enteropathy (PLE) is associated with significant morbidity and mortality. Although heart transplantation (HTx) can be curative, PLE may increase the risk of morbidity before and after HTx. This study analyzed the influence of PLE influence on waiting list and post-HTx outcomes in a pediatric cohort. METHODS Fontan patients listed for HTx and enrolled in the Pediatric Heart Transplant Study from 1999 to 2012 were stratified by a diagnosis of PLE, and the association of PLE with waiting list and post-HTx mortality, rejection, and infection was analyzed. RESULTS Compared with non-PLE Fontan patients (n = 260), PLE patients listed for HTx (n = 96) were older (11.9 years vs 7.6 years; p = 0.003), had a larger body surface area (1.1 m(2) vs 0.9 m(2); p = 0.0001), had lower serum bilirubin (0.5 vs 0.9 mg/dl; p = 0.01), lower B-type natriuretic peptide (59 vs 227 pg/ml; p = 0.006), and were less likely to be on a ventilator (3% vs 13%; p = 0.006). PLE patients had lower waiting list mortality than non-PLE Fontan patients (p < 0.0001). There were no intergroup differences for post-HTx survival or times to the first infection or rejection. PLE was not independently associated with increased post-HTx mortality at any time point. CONCLUSIONS In this multicenter cohort, the diagnosis of PLE alone was not associated with increased waiting list mortality or post-HTx morbidity or mortality. Given the limitations of our data, this analysis suggests that PLE patients in the pediatric age group have outcomes similar to their non-PLE counterparts. Additional multicenter studies of PLE patients with targeted collection of PLE-specific information will be necessary to fully delineate the risks conferred by PLE for HTx.

HLA desensitization in pediatric heart transplant candidates: Efficacy of rituximab and IVIg

Purpose: Pre-transplant (HTx) HLA-sensitization is associated with increased risk of post-HTx humoral rejection via donor-specific HLA antibodies (DSA). No universally accepted desensitizing protocol exists. This study details our 8-year experience using IVIg and Rituximab. Methods and Materials: The degree of HLA-sensitization was determined using ELISA or single-antigen bead Luminex assay with results expressed as median fluorescence intensity (MFI). Significantly sensitized patients were treated with one dose IVIg and serial Rituximab infusions. Serial HLA antibody measurement via calculated panel reactive antibody tests (CPRA) assessed treatment response. Paired t-tests compared the first and last CPRAs before HTx, death, or last follow-up. Results: Median follow-up was 5 2.8 months after the last Rituximab dose. 8/14 patients had a sustained (median 4 CPRAs/patient) decrease in circulating antibody assessed by ELISA or Luminex with reduction in class I and II CPRA from 50 25 to 17 36; p 0.009, and 61 26 to 17 38; p 0.045, respectively. Between responders and non-responders, there was no difference in median number of Rituximab doses (3 1.4 each) or patient age. However, 6/8 responders received 2 Rituximab doses before a significant PRA reduction was noted. Of the 14 patients, 1 died, 5 were delisted, and the remaining 8 (5 responders) underwent HTx using virtual crossmatching. One recipient made low-level DSA which cleared by 6 months post-HTx. Primary graft failure caused 2 post-HTx deaths; no patient had humoral rejection. Conclusions: Though not universal, a majority of allosensitized patients in this study experienced a significant reduction in HLA antibody after receipt of IVIg and Rituximab. For responders, this therapy increases the prospective donor pool through reduction in unacceptable antigens when using a virtual crossmatch process and may decrease waitlist mortality as well as post-HTx humoral rejection risk. IVIg and Rituximab appears to be a useful desensitization therapy and larger patient-base study is warranted.

Pediatric Coronary Allograft Vasculopathy—A Review of Pathogenesis and Risk Factors

Coronary allograft vasculopathy is the current leading cause for late graft loss following cardiac transplantation. Its pathogenesis is multifactorial, including immune, constitutional and genetic factors, metabolism, infection, as well as potential injury from routine immunosuppressive therapy. Children represent a patient group with unique differences: their pretransplant history rarely includes ischemic heart disease and risk factors for atherosclerotic heart disease, but many are presensitized from use of allograft material during reconstructive cardiac surgeries. Compared with older children and adults, infants and young children show significantly lower rates of graft vasculopathy that may be related to the relative immaturity of their immune system. This review summarizes the current concepts of coronary allograft vasculopathy derived mainly from animal models and adult clinical observations. It provides an overview of confirmed risk factors and explains their interactions. The characteristics and unique clinical findings among pediatric transplant recipients will be explored within the context of recent, albeit limited, scientific investigations.

Risk Factors and Outcome of Fontan-Associated Plastic Bronchitis: A Case-Control Study

Background The onset of plastic bronchitis (PB) can be debilitating in survivors of Fontan surgery. The rarity of this complication makes designing studies to understand risk factors for PB challenging. This 2‐center case‐control study aimed to describe patient outcomes and to assess the association of antecedent patient factors with PB development. Methods and Results Using center registries, PB patients (n=25) were matched 1:2 to non‐PB Fontans (n=43) by date of Fontan surgery and center. The groups were compared for baseline characteristics. Association of patient characteristics with PB was assessed using logistic regression and of potential risk factors with onset of PB using time‐to‐event analyses. The median time from Fontan to PB diagnosis was 2.5 years. Overall, 12/25 PB patients died or underwent heart transplant; the median transplant‐free survival was 8.3 years after diagnosis. Factors associated with developing PB included post‐surgical chylothorax (44% PB versus 10% control; odds ratio [OR] 7.3; P=0.003), chest tube (CT) duration at stage 2 (P=0.04) and Fontan (P=0.004), and postoperative ascites (36% PB versus 12% control; OR 4.2; P=0.003). CT drainage >13 days at Fontan was associated with earlier PB onset (P=0.04). Early‐onset PB was associated with an increased risk of death (OR 5.0; P=0.002). Conclusions PB is a life‐threatening disorder. A longer duration of CT drainage after surgery, chylothorax, and development of ascites are all associated with developing PB. Understanding the pathophysiology of peri‐operative complications in individual patients and using targeted interventions may delay the onset of the PB phenotype.

Immunophenotyping and Protein Profiling of Fontan-associated Plastic Bronchitis Airway Casts

RATIONALE Plastic bronchitis (PB) is a rare and deadly condition that is characterized by the formation of airway casts. It most frequently occurs in children with underlying congenital heart disease that has been surgically palliated by the Fontan procedure. The Fontan circulation results in above-normal central venous pressure, and it has been hypothesized that the formation of airway casts is due to lymph leak. Knowledge of plastic bronchitis pathogenesis is poor and stems mostly from published case reports. OBJECTIVES To garner information about cast pathogenesis by characterizing inflammatory cell phenotypes in existing formalin-preserved, paraffin-embedded samples and generating protein and cytokine-chemokine profiles of airway cast homogenates. METHODS We used immunofluorescence confocal microscopy, state-of-the-science proteomics, and a cytokine array assay to immunophenotype cellular content and to generate protein and cytokine profiles of plastic bronchitis airway casts, respectively. MEASUREMENTS AND MAIN RESULTS Neutrophils, eosinophils, macrophages, and B lymphocytes were identified in cast samples; there were notably fewer T lymphocytes. Fibrin(ogen) was an abundant protein in the cast proteome. Histone H4 was also abundant, and immunofluorescence microscopy demonstrated it to be mostly extracellular. The cytokine profile of plastic bronchitis casts was proinflammatory. CONCLUSIONS Plastic bronchitis airway casts from children with Fontan physiology are composed of fibrin and are cellular and inflammatory in nature, providing evidence that their formation cannot be explained simply by lymph leak into the airways. Consequences of cellular necrosis including extracellular histones and the apparent low number of T cells indicate that a derangement in inflammation resolution likely contributes to cast formation.

Differential effect of body mass index on pediatric heart transplant outcomes based on diagnosis

The impact of nutritional status on HTx waitlist mortality in children is unknown, and there are conflicting data regarding the role of nutrition in post‐HTx survival. This study examined the influence of nutrition on waitlist and post‐HTx outcomes in children. Children 2–18 yr listed for HTx from 1997 to 2011 were identified from the OPTN database and stratified by BMI percentile. Multivariable logistic regression evaluated the influence of BMI on waitlist mortality. Cox proportional hazard regression assessed the impact of BMI on post‐HTx mortality. When all 2712 patients were analyzed, BMI did not impact waitlist, one‐, or five‐yr mortality. However, when stratified by diagnosis, BMI > 95% (AOR 1.96; 95% CI 1.24, 3.09) and BMI < 1% (AOR 2.17; 95% CI 1.28, 3.68) were independent risk factors for waitlist mortality in patients with CM. BMI did not impact waitlist mortality in CHD and did not impact post‐HTx outcomes, regardless of diagnosis. BMI > 95% and BMI < 1% are independent risk factors for waitlist mortality in patients with CM, but not CHD. This suggests differing risk factors based on disease etiology, and an individualized approach to risk assessment based on diagnosis may be warranted.

A systematic review of parent and family functioning in pediatric solid organ transplant populations

The process of pediatric solid organ transplantation (SOT) places new and increased stressors on patients and family members. Measures of family functioning may predict psychological and health outcomes for pediatric patients and their families, and provide opportunity for targeted intervention. This systematic review investigated parent and family functioning and factors associated with poorer functioning in the pediatric SOT population. Thirty‐seven studies were identified and reviewed. Studies featured a range of organ populations (eg, heart, liver, kidney, lung, intestine) at various stages in the transplant process. Findings highlighted that parents of pediatric SOT populations commonly report increased stress and mental health symptoms, including posttraumatic stress disorder. Pediatric SOT is also associated with increased family stress and burden throughout the transplant process. Measures of parent and family functioning were associated with several important health‐related factors, such as medication adherence, readiness for discharge, and number of hospitalizations. Overall, findings suggest that family stress and burden persists post‐transplant, and parent and family functioning is associated with health‐related factors in SOT, highlighting family‐level functioning as an important target for future intervention.