Regine L. Caruthers

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.

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.

Pharmacotherapy Challenges of Fontan‐Associated Plastic Bronchitis: A Rare Pediatric Disease

Pediatric pharmacotherapy is often challenging due to the paucity of available clinical data on the safety and efficacy of drugs that are commonly used in children. This quandary is even more prevalent in children with rare diseases. Although extrapolations for dosing and administration are often made from available adult data with similar disease states, this translation becomes even more problematic in rare pediatric diseases. Understanding of rare disease pathophysiology is typically poor, and few, if any, effective therapies have been studied and identified. One condition that illustrates these issues is plastic bronchitis, a rare, most often pediatric disease that is characterized by the production of obstructive bronchial airway casts. This illness primarily occurs in children with congenital heart disease, often after palliative surgery. Plastic bronchitis is a highly clinically relevant and therapeutically challenging problem with a high mortality rate, and, a generally accepted effective pharmacotherapy regimen has yet to be identified. Furthermore, the disease is ill defined, which makes timely identification and treatment of children with plastic bronchitis difficult. The pharmacotherapies currently used to manage this disease are largely anecdotal and vary between the use of macrolide antibiotics, mucolytics, bronchodilators, and inhaled fibrinolytics in a myriad of combinations. The purpose of this review is 2‐fold: first, to highlight the dilemma of treating plastic bronchitis, and second, to bring attention to the continuing need for studies of drug therapies used in children so safe and effective drug regimens can be established, particularly for rare diseases.

Letter by Caruthers and Dorsch Regarding Article, “Dosing of Clopidogrel for Platelet Inhibition in Infants and Young Children: Primary Results of the Platelet Inhibition in Children On cLOpidogrel (PICOLO) Trial”

To the Editor: We appreciate and were excited to read the article by Li et al,1 which evaluated the pharmacodynamics of clopidogrel in children to determine the dose of clopidogrel necessary to achieve a mean 30% to 50% inhibition of 5-μmol/L ADP-induced platelet aggregation. We have concerns, however, about the authors’ conclusion that a uniform clopidogrel dose of 0.2 mg · kg−1 · d−1 in children between 0 and 24 months of age produces …