The emergence of SARS-CoV-2/2019 novel coronavirus (COVID-19) has created a global pan-demic with no approved treatments or vaccines. Many treatments have already been administered to COVID-19 patients but have not been systematically evaluated. We performed a systematic literature review to identify all treatments reported to be administered to COVID-19 patients and to assess time to clinically meaningful response for treatments with sufficient data. We searched PubMed, BioRxiv, MedRxiv, and ChinaXiv for articles reporting treatments for COVID-19 patients published between 1 December 2019 and 27 March 2020. Data were analyzed descriptively. Of the 2706 articles identified, 155 studies met the inclusion criteria, comprising 9152 patients. The cohort was 45.4% female and 98.3% hospitalized, David C. Fajgenbaum and Johnson S. Khor contributed equally to this study.

Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti–IL-6 therapy, siltuximab, is the only US Food and Drug Administration–approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8–associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration.

Summary Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure.

8548 Background: Castleman disease (CD) describes a group of lymphoproliferative disorders that share characteristic histopathology. Unicentric CD (UCD) and idiopathic multicentric CD (iMCD) are differentiated by the number of enlarged lymph node (LN) regions: UCD involves 1 region and iMCD involves > 1 region. UCD typically has mild or no symptoms whereas iMCD requires abnormal labs and symptoms for diagnosis and can progress to life-threatening multi-organ failure. Review of an international natural history registry of CD revealed patients across a broad spectrum with regards to number of enlarged LN regions and disease severity. We hypothesize that there is a positive correlation between disease activity and the number of enlarged LNs and that the spectrum of CD is more complex than a binary UCD-iMCD dichotomy. Methods: Herein, enrolled UCD and iMCD patients whose diagnosis was confirmed by an expert-panel were selected for analysis (N = 81). A standardized disease activity score (scale 0-1) was computed for each patient using available diagnostic values of C-reactive protein, hemoglobin, and albumin (CHA score). Results: We looked at the association between number of enlarged LNs and CHA and found a significant positive correlation (R = 0.65, p < 0.0001). Given this, we divided the cohort into groups of mild, moderate, and extensive lymphadenopathy according to the number of regions of enlarged LNs at the time of diagnosis: group 1 (1 enlarged LN region); group 2 (2-4 enlarged LN regions); and group 3 (≥5 enlarged LN regions). We identified 20 patients in group 1, 19 in group 2, and 42 in group 3 with no statistical differences in sex, race, or age at diagnosis. Histopathological subtype differed significantly among groups. Group 1 was 89% hyaline vascular (HV)/ hypervascular (HpV) and 11% mixed (Mx); group 2 was 74% HV/HpV, 21% Mx, and 5% plasmacytic (Pl); and group 3 was 64% HV/HpV, 32% Mx, and 5% Pl. We then looked at CHA score in these groups and found that group 3 patients have a significantly greater CHA score (median [IQR]: 0.46 [0.49]) than both group 2 (0.08 [0.14]) and group 1 (0.0 [0.10]) (adjusted p < 0.001 for both) while there was no difference between groups 1 and 2. Conclusions: These results suggest that disease severity is positively associated with the number of enlarged LNs. The different proportions of histopathological subtypes between the three groups could indicate different pathologic mechanisms are involved. Further work is needed to determine if patients with a few enlarged LNs exhibit disease more closely to UCD or iMCD and to understand long-term outcomes for these patients.