IDIOPATHIC MULTICENTRIC CASTLEMAN DISEASE (IMCD) AS A MANIFESTATION OF POST-COVID-19 INFLAMMATORY SYNDROME

SESSION TITLE: Pulmonary Manifestations of Infections SESSION TYPE: Case Reports PRESENTED ON: 10/17/2022 03:15 pm - 04:15 pm INTRODUCTION: Post-acute COVID-19 inflammatory syndrome is defined as persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms of original infection (1). These can manifest in various ways, but pulmonary, cardiac, and renal complications are the most common (1), with IL-6 thought to be an important mediator (2). We report what we believe to be the first case of Idiopathic Multicentric Castleman's Disease (iMCD) as a manifestation of post-acute COVID-19 inflammatory syndrome. CASE PRESENTATION: A 36-year old male with history of hypertension and childhood asthma (not on current therapy), and recently resolved COVID-19 from 4 weeks prior, is admitted to the hospital with progressive shortness of breath, cough, fevers and significant fatigue. Prior COVID-19 symptoms included fevers, cough, and shortness of breath, which improved after 2 weeks without treatment. Symptoms returned 2 weeks later and worsened. On admission, he was tachycardic to 108 with temp of 37.8C, and otherwise stable vitals. Pertinent labs included WBC 17 (neutrophil predominant), Hgb 11.6, Cr 2.52, Na 126 and albumin 2.7 (normal baselines). SARS-CoV2 PCR was negative. CT chest with PE protocol showed no PE but moderate bilateral pleural effusions and extensive mediastinal lymphadenopathy. 1.2L clear fluid (transudative with lymphocyte predominance) was removed via thoracentesis. Microbiology, flow cytometry and cytology were unremarkable. Renal and mediastinal lymph node biopsies were taken. Lymph node sampling was non-diagnostic x2, but renal biopsy showed acute microangiopathy without thrombi, concerning for acute glomerulonephritis. Serologic vasculitis and CTD workup were entirely negative. He was treated with a course of prednisone and improved, however as outpatient, had recurrence of all these issues. Repeat thoracentesis x3 was unrevealing. He was again admitted and had an excisional inguinal node biopsy, showing findings consistent with hyaline vascular Castleman Disease. Further heme/onc evaluation and discussion showed diagnosis meeting criteria for iMCD. DISCUSSION: Multicentric Castleman's Disease is most often associated with HHV-8 infection in the setting of HIV. If HHV-8 is negative, the disease is termed idiopathic (iMCD). In these cases, disease is mediated predominantly by IL-6, but the direct cause is unknown, though existing theories include non-specific viral infections, malignancy and autoimmune diseases (3). Our patient had no evidence of malignancy or autoimmune phenomena. Thus COVID-19 illness was the most plausible explanation, especially given known IL-6 activity in COVID-19 inflammatory syndromes. CONCLUSIONS: Post-acute COVID-19 inflammatory syndromes are extensive and can affect any organ system. iMCD is another possible manifestation, and must be diagnosed with excisional lymph node biopsy. High index of suspicion should be maintained to make this diagnosis. Reference #1: Nalbandian, Ani et al. "Post-acute COVID-19 syndrome." Nature medicine vol. 27,4 (2021): 601-615. Reference #2: Phetsouphanh, Chansavath et al. "Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection.” Nature immunology vol. 23,2 (2022): 210-216. Reference #3: Dispenzieri, Angela, and David C Fajgenbaum. "Overview of Castleman disease." Blood vol. 135,16 (2020): 1353-1364. DISCLOSURES: No relevant relationships by Kyle Halligan No relevant relationships by Chris Yan

CHEST-WALL CASTLEMAN DISEASE MIMICKING THYMOMA DROP METASTASIS

SESSION TITLE: Amazing Chest Imaging Findings SESSION TYPE: Case Reports PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm INTRODUCTION: Thoracic Castleman disease is challenging to diagnose and can mimic various lymphoproliferative disorders. Herein we present a case of unicentric thoracic castleman disease co-existing with thymoma, mimicking a thymoma drop metastasis. CASE PRESENTATION: A 50-year-old previously healthy Caucasian female presented to the emergency room with COVID-19 related respiratory symptoms. CTA was consistent with COVID-19 pneumonia and incidentally showed a 4.2 x 3.1 cm mass in the right anterosuperior mediastinum abutting the ascending aorta and superior right atrium, and a 3.3 x 2.1 cm mass in right posterior costophrenic sulcus abutting the right 11th rib raising suspicion for thymoma with a "drop metastases.” CT abdomen/pelvis was unrevealing. For proper staging, US guided biopsy of chest wall mass was performed which showed reactive lymphoid tissue. CT guided biopsy of the mediastinal mass revealed a thymoma. Due to ongoing concern for pleural metastases and possible sampling error with prior biopsy of the costophrenic lesion, she underwent surgical resection of the anterior mediastinal mass and chest wall lesion including part of 11th rib. The chest wall lesion was noted to be extrapleural. Surgical biopsy confirmed WHO grade B1 Thymoma and the chest wall lesion showed hyaline vascular Castleman disease. DISCUSSION: Pleural "Drop” metastasis from a thymoma or thymic carcinoma should be considered in patients with an anterior mediastinal mass and pleural based lesions. Imaging shows one or more pleural nodules or masses, which can be smooth, nodular, or diffuse. [1]. In our case, a basilar, discrete, nodular mass was suspicious for a drop metastasis. At the time of surgery, the lesion was noted to be extrapleural. Unicentric Castleman disease is a benign lymphoproliferative disorder which presents as a homogeneous, well-marginated, highly vascularized enhancing mass commonly involving the mediastinum. These lesions can mimic thymoma, lymphoma, sarcoma, hemangiopericytoma, and neural crest derived neoplasms. Pleural Castleman disease can arise from visceral and parietal pleura with extension into the chest wall or lung fissures and can cause pleural effusion. Intercostal disease can resemble other chest wall masses and cause rib erosions [2]. Chest-wall localization is a rare manifestation of Castleman disease often diagnosed due to non-specific thoracic symptoms such as dyspnea, cough, chest-wall pain or generalized malaise.[3] Complete excision of the lesion is generally curative with cure rate of 95-100%, with recurrence reported with partially resected lesions. CONCLUSIONS: Castleman disease located in the chest wall can present diagnostic and management challenges particularly when present in the context of other lesion with metastatic potential. Reference #1: 1.Benveniste, M.F.K., Rosado-de-Christenson, M.L., Sabloff, B.S., Moran, C.A., Swisher, S.G. and Marom, E.M. (2011). Role of Imaging in the Diagnosis, Staging, and Treatment of Thymoma. RadioGraphics, 31(7), pp.1847–1861. Reference #2: 2.Ko, S.-F., Hsieh, M.-J., Ng, S.-H., Lin, J.-W., Wan, Y.-L., Lee, T.-Y., Chen, W.-J. and Chen, M.-C. (2004). Imaging Spectrum of Castleman's Disease. American Journal of Roentgenology, 182(3), pp.769–775 Reference #3: 3. Rena, O., Casadio, C. and Maggi, G. (2001). Castleman's disease: unusual intrathoracic localization. European Journal of Cardio-Thoracic Surgery, 19(4), pp.519–521. DISCLOSURES: No relevant relationships by Peter LaCamera, value=Consulting fee Removed 04/06/2022 by Peter LaCamera No relevant relationships by Peter LaCamera, value=Consulting fee Removed 04/06/2022 by Peter LaCamera No relevant relationships by Alina Wasim

PERSISTENT COVID-19 INFECTION IN A PATIENT WITH CASTLEMAN DISEASE

SESSION TITLE: Rare Pulmonary Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: Castleman's Disease (CD) includes a group of rare and heterogenous lymphoproliferative disorders that share characteristic histopathological features. The etiology of CD is unknown. The condition results in episodic regional lymphadenopathy. Symptoms are driven by episodic cytokine excess. Clinical presentation can include fevers, night sweats, weight loss and fatigue. Life expectancy is not affected, however patients are at risk of developing various other conditions including amyloidosis, cryptogenic organizing pneumonia and lymphoma. COVID-19 is known to have periods of cytokine excess. In severe instances in can lead to cytokine storm, characterized by bilateral pulmonary infiltrates, worsening hypoxemia, and organ failure. We present the case of a 48 year-old female with CD who endured prolonged COVID-19 and cytokine storm. CASE PRESENTATION: A 48-year-old female with CD presented to the emergency department for shortness of breath. Six months prior to admission she had received one dose of the mRNA-1273 (Moderna) vaccine against SARS-CoV-2. Unfortunately, she contracted COVID-19 prior to the second dose. At that time she was hospitalized at a separate institution for COVID-19 and hypoxemia. The patient was treated with systemic glucocorticoids and remdesivir, and subsequently discharged home on supplemental oxygen via nasal cannula at 2 l/min. Unfortunately her respiratory status progressively declined over the following two months. During this time PCR testing for SARS-CoV-2 was positive on multiple occasions. She subsequently presented to our ER for dyspnea and hypoxemia. She once again tested positive by PCR. Inflammatory markers including fibrin degradation products, c-reactive protein and fibrinogen were severely elevated. Chest radiograph revealed bilateral infiltrates. The patient was placed on high flow oxygen and admitted to the ICU. Treatment was initiated with remdesivir, systemic glucocorticoids, and tocilizumab. Unfortunately, she continued to decline and was eventually placed on mechanical ventilation. The patient was then transferred to another institution for evaluation of extracorporeal membrane oxygenation. DISCUSSION: Both CD and COVID-19 are characterized by cytokine excess. Our patient with CD presented with persistent COVID-19. She remained symptomatic for close to six months. Her course was waxing and waning for the first few months and then progressively declined. Multiple PCR tests for SARS-CoV-2 were positive during this interval. We postulate that the proclivity of CD to cytokine excess had a synergistic effect on the inflammatory components of COVID-19 infection. This may have contributed to the protracted infection. CONCLUSIONS: More research is needed in patients with lymphoproliferative disorders and the impact of COVID-19 infection on their outcomes. Reference #1: Van Rhee, Frits, et al. "International, Evidence-Based Consensus Treatment Guidelines for Idiopathic Multicentric Castleman Disease.” American Society of Hematology, American Society of Hematology, 15 Nov. 2018, https://ashpublications.org/blood/article/132/20/2115/39506/International-evidence-based-consensus-treatment. Reference #2: "Castleman Disease: Symptoms, Causes, Treatments and Tests.” Cleveland Clinic, https://my.clevelandclinic.org/health/diseases/17920-castleman-disease. Reference #3: "Castleman Disease.” NORD (National Organization for Rare Disorders), 10 July 2017, https://rarediseases.org/rare-diseases/castlemans-disease/. DISCLOSURES: No relevant relationships by Wajahat Khan No relevant relationships by Nashwa Yosry

CONSOLIDATION OF ERN-EUROBLOODNET: THE EUROPEAN REFERENCE NETWORK ON RARE HEMATOLOGICAL DISEASES FIRST 5 YEARS OF IMPLEMENTATION

Background: ERN-EuroBloodNet was established in 2017 as the European Reference Network on Rare Hematological Disorders (RHDs) bringing together nationally recognized centres of excellence with the goal of promoting EU best health care in RHDs. ERN-EuroBloodNet has been recently enlarged integrating 103 HCP from 24 EU-MS. Aims: ERN-EuroBloodNet was conceived to contribute to innovative, efficient and sustainable health systems and facilitate access to better and safer healthcare for EU citizens while decreasing the cross-border health barriers. Methods: Since 2017, ERN-EuroBloodNet established the state-of-the art of RHD allowing the implementation of transversal and disease-specific strategies, where actions on very rare RHD were prioritized. Results: Profile. 182 expert profiles were created freely accessible. Expert centers follow 65,000 RHD patients and treat 5,000 new patients per year, while 24 patients requested support for cross-border health assistance. Expertise. The need to improve access to next-generation sequencing for non-oncological RHD and bone marrow transplantation for sickle cell disease (SCD) was identified. Also, significant disparities in the clinical practice of primary vitreoretinal lymphoma were found and we demonstrated that less than 30% of children with SCD benefit from adequate annual stroke risk monitoring. Guidelines. A repository of 68 Clinical Practice Guidelines (CPG) classified on quality of evidence and consensus approach was created. Recommendations for diagnosis and treatment of methemoglobinemia was published in collaboration with EHA. A CPG on Adult Burkitt Lymphoma is under development. Next topics focus long-term complications in hemoglobinopathies and patients' pathways&summary. Education. ERN-EuroBloodNet Webinars were launched for professionals with 26 Thursdays Webinars and 3 EBAH accredited Topic on Focus on Cutaneous Lymphoma, Thrombotic Microangiopathies, and Bone Marrow Failures. A collaboration was established for EHA & ERN-EuroBloodNet Spotlight on Castleman Disease. For patients, 3 Topic on Focus were launched for Myelodysplastic syndromes, SCD, and Cutaneous lymphoma. Past webinars are available at EuroBloodNet EDU Youtube channel. Preceptorships on SCD will be launched soon. Telemedicine. 43 complex cases have been inter-professionally discussed in the Clinical Patient Management System with 21 outcome reports delivered. Registries. 184 Registries were identified through the European Rare Blood Diseases Platform (ENROL), endorsed by the EHA. The ENROL project, which includes rare anemias, dendritic cell leukemia and von Villebrand's disease pilots, aims to collect exhaustive and therefore epidemiological data for RHDs. The final objective is a possibility of EU health planningl and the promotion of research by identifying cohorts of patients. ERNEuroBloodNet launched the collaborative platform on patients with red blood cells and COVID-19 containing so far 373 patients. Collaborations. collaborative research projects were encouraged like EC-funded projects i.e., genomics and personalized medicine in hematological diseases (GenoMed4All) and the properties and viability of erythrocytes (EVIDENCE), or the International Hemoglobinopathy Research Network (INHERENT) for genomic and phenotypic correlations. Summary/Conclusion: The implementation of well-defined strategies but above all adapted to the specific and not yet covered needs of RHD has led to the realization of concrete projects. This has laid the foundations to strengthen health systems in the field of RHD and allow them to flourish under the new EU4Health programme.

AN UNUSUAL CASE OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH M.CHIMAERA OR LARGE CELL NEUROENDOCRINE CARCINOMA

CASE: 56-year-old Caucasian male presented to the hospital with worsening weakness, exertional dyspnea, dry and nonproductive cough, and a 5-pound weight loss in 2 weeks associated with loss of appetite. He has a significant medical history of mitral valve repair in July 2014, status post bioprosthetic mitral valve replacement in August 2019- culture-negative treated with ceftriaxone, vancomycin, and doxycycline for 6 weeks complicated with CVA, atrial flutter, tobacco abuse, alcohol abuse. His shortness of breath worsened quickly with O2 saturations dropping to 85% and had to be placed on BiPAP followed by high flow nasal cannula/ noninvasive ventilation and became febrile. He was then transferred to ICU for acute hypoxemic respiratory failure. Differentials could be very broad ranging from infections like visceral leishmaniasis, atypical/tuberculous mycobacteria, histoplasmosis, Ehrlichia, Bartonella, Brucella, adeno, disseminated HSV, hematological like Langerhans cell histiocytosis, multicentric Castleman disease. In this patient, differentials included hemophagocytic lymphohistiocytosis, COVID-19. Covid was negative x2. His lab abnormalities as well as diagnostic testing revealed hemophagocytic lymphohistiocytosis. He was empirically started on antibiotics and dexamethasone 20 mg to be continued for 2 weeks then taper if the patient has continued improvement. Dexamethasone was tapered over 8 weeks. On later admissions, Carious test was positive for M. chimaera, and core biopsy of the lung nodule showed large cell neuroendocrine carcinoma. IMPACT/DISCUSSION: Hemophagocytic lymphohistiocytosis (HLH) is a rare but very dangerous condition, characterized by abnormal activation of the immune system, causing hemophagocytosis, inflammation, and potentially widespread organ damage. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity, is most commonly seen in children. Secondary HLH is commonly associated with infections or malignancies. Most current information on diagnosis and treatment is based on pediatric populations. The HLH-2004 diagnostic criteria are the most commonly used diagnostic criteria and were developed for children;but used in adults as commonly as in children, although there is a gap in the knowledge. The HLH-2004 diagnosis criteria state that diagnosis of HLH can be established if either a molecular diagnosis is made consistent with HLH or diagnostic criteria for HLH is fulfilled, which includes meeting 5 of 8 criteria. These are lab and clinical findings including fever, splenomegaly, significant cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow/spleen or lymph nodes, low or no NK cell activity, ferritin >500 ug/L or sCD25 >2400 U/mL. CONCLUSION: HLH is a disease that needs to be diagnosed and treated promptly, it is fatal otherwise. Treatment is mostly tailored to the patient's root cause, treat the cause, and symptomatic treatment with dexamethasone and etoposide.

Adrenal Insufficiency: A Unique Presentation of Multicentric Castleman Disease with Human Herpes Virus 8 Positivity and Concomitant Kaposi Sarcoma

Introduction: Multicentric Castleman Disease (MCD) is a lymphoproliferative disorder involving multiple lymph nodes and can be associated with human herpes 8 virus (HHV-8). Hyaline vascular (HV) MCD is rare, occurring in < 10% of cases. MCD with concomitant HIV negative Kaposi Sarcoma (KS) is also uncommon and can peculiarly present with adrenal insufficiency. Case Description: 53-year-old male with biopsy proven diagnosis of HHV-8 positive KS was transferred to our institution with persistent hypotension requiring pressor support. He described a two-week history of night sweats, 20 Ib weight & appetite loss, fatigue, muscles aches, and subjective fevers. Vitals: BP: 99/50 mmHg, HR: 90 bpm, RR: 19 and T: 103oF. Physical exam revealed multiple violaceous, non-blanching plaques on his body, tender inguinal & axillary lymphadenopathy, and bilateral lower extremity edema. Initial labs: Na: 137 mmol/L, K: 3.6 mmol/L, WBC: 5.6 k/uL, Hg: 7.1 gm/dL, Hct: 21%, Plt: 91 k/uL, AM cortisol: 12.5 mcg/dL (5.3-22.5), ACTH < 1 pg/mL, TSH: 7.5 uIU/mL, FTF: 0.63 ng/dL, PRL: 7 ng/mL, Total testosterone: 20 ng/dL, FSH: 4.2 mIU/mL, LH: 8.3 mIU/mL, IGF-1: 77 ng/mL (64-218), ESR >85 mm/hr (< 20), and CRP: 76 mg/dL (< 3). HIV and COVID-19 tests were negative. He was started on oral Levothyroxine and IV Hydrocortisone with significant improvement in his BP leading to discontinuation of pressor support. CT chest/abdomen/pelvis showed diffuse lymphadenopathy consistent with KS with normal adrenal glands. Left axillary lymph node biopsy revealed HV MCD. Additional labs;IL-6: 11.5 pg/mL (< 2), IgG4: 45 mg/dL (1-123), normal CD4 count, renin and aldosterone levels. 21 alpha hydroxylase antibody, T-spot, extensive autoimmune and infectious work-up were negative. Pituitary MRI could not be obtained due to a metal object behind his right orbit. Head CT was negative for pituitary abnormality. He failed his ACTH stimulation test with cortisol level: 13 mcg/dL at 90 minutes (baseline ACTH was not obtained). Thus, he was discharged on physiological oral Hydrocortisone upon clinical improvement. He began chemotherapy 1 week post discharge, however he succumbed to his disseminated and aggressive disease 20 days later. Discussion: MCD with concomitant KS is a rare and rapidly progressive disease which can cause death within weeks. IL-6 overproduction is thought to be associated with its symptom progression. Worse clinical outcomes are correlated with HIV or HHV-8 positivity. It can uncommonly be associated with either primary or secondary adrenal insufficiency requiring prompt evaluation and treatment with systemic steroids to prevent development of adrenal crisis.

Association between Insufficient Interleukin-6 (IL-6) Inhibition and Worsening Outcomes in COVID-19 and Idiopathic Multicentric Castleman Disease (iMCD), and a Mathematical Model to Predict Optimal Dosing to Completely Block IL-6 Activity

Dysregulated inflammatory responses are characterized by inappropriate levels of inflammatory markers, speed of generation, degree, and major site of production, such as a vital organ. COVID-19 severity and mortality are strongly associated with interleukin (IL)-6 levels. High IL-6 levels are also observed in idiopathic Multicentric Castleman Disease (iMCD). Previously, we developed the first anti-IL-6 monoclonal antibody (mAb) treatments and showed that C-reactive protein (CRP) production could be fully controlled by IL-6 in humans. Using mathematical modeling, with CRP as an IL-6 surrogate marker, we predicted the ability of an anti-IL-6 mAb to block plasma IL-6 activity and showed IL-6 inhibition was dependent on the extent of whole-body IL-6 production. We postulate that in patients (pts) in whom IL-6 concentration at the site of inflammation is higher than in the plasma, full blockade of plasma IL-6 activity, shown by complete CRP inhibition, is the minimum requirement to achieve clinical efficacy. CRP inhibition with tocilizumab (TCZ) in pts with COVID-19. We identified 35 published studies evaluating the efficacy or potential role of anti-IL-6 therapy in pts with severe COVID-19. Surprisingly, only one (Luo et al. J Med Virol 2020;92:814) reported dynamics of CRP reduction for individual patients throughout treatment. We fitted a hypothetical curve of CRP reduction required to completely block IL-6, based on the half-life of CRP, and added data points of CRP serum levels from pts treated with anti-IL-6 receptor (IL-6R) therapy, TCZ, in this study. Complete reduction of CRP was not achieved in all patients: 3 pts who died had CRP levels ≥12.8 mg/l. Of 2 pts whose disease worsened, CRP levels were 93.5 mg/l and 6.3 mg/l. However, pts whose condition stabilized (n=9), or whose symptoms improved (n=1), had CRP levels close to the theoretical curve that is likely required to fully block IL-6 (CRP levels ≤5.0 mg/l). Half of these pts had been given repeated doses of TCZ. Siltuximab (SIL) treatment (NCT01024036 trial) for pts with iMCD. To assess the impact of baseline CRP levels on response to anti-IL-6 therapy, SIL, patients were divided into low and high CRP groups based on a baseline CRP level threshold of 40 mg/l (corresponding to ~40 pg/ml of IL-6;Fig 1). In patients with low baseline CRP levels (<40 mg/l;n=35), CRP levels were significantly reduced with SIL treatment on day 8 (n=26;P=0.0003) and day 15 (n=22;P=0.0043) post-dosing. In patients with high baseline CRP levels (>40 mg/l;n=17), CRP levels were significantly reduced on day 8 (n=17;P<0.0001) and day 15 (n=15;P<0.0001) post-dosing (Fig 1). A significant increase in CRP levels from day 8 to day 15 was observed in these patients (P=0.0120);this increase was not observed in patients with low baseline CRP levels (P=0.243;Fig 1). There was a negative correlation between maximum CRP and hemoglobin change (P<0.001). Inhibition of IL-6 activity by anti-IL-6 (SIL 700 mg) and anti-IL-6R (TCZ 800 mg) as monotherapy, intensified, or combined therapy. To evaluate the effect of therapy on IL-6 activity, our algorithm modeled inhibition of IL-6-(IL-6R/soluble IL-6R)-gp130 transducer complexes. This serves as a proxy for IL-6 bioactivity and accounts for the buffering capacity of gp130, which can be overwhelmed in inflammatory situations with high IL-6 concentrations. Due to uncertainty over the concentration of mAbs in alveoli relative to plasma, we modeled the effects of SIL and TCZ at local concentrations of 100%, 10%, and 1% (Fig 2) of those in plasma. Our model demonstrated that anti-IL-6 was associated with stronger inhibition of CRP than anti-IL-6R. However, only the association of both anti-IL-6 and anti-IL-6R mAbs was associated with a total blockade of CRP, which is probably necessary when IL-6 levels are associated with high risk to the patient. Different administration schedules to intensify anti-IL-6 therapy were modeled, including the repeated or combined use of anti-IL-6 and anti-IL-6R mAbs. The results form a basis to optimize treatment trategies to avoid the cytokine storm in several diseases, including cancer, iMCD, and autoimmune disorders. The feasibility of the theoretically defined approaches needs to be evaluated, particularly the potential side-effect profile for a combined treatment approach. In conclusion, in clinical practice, IL-6 inhibition should be individualized based on pathophysiology and regular CRP monitoring. [Formula presented] Disclosures: Rossi: E-SANA Inc: Other: Co-founder of E-SANA Inc;EUSA Pharma: Consultancy;LEO Pharma: Consultancy;NPO Petrovax Pharm: Consultancy. Levon: E-SANA Inc: Other: Co-founder of E-SANA Inc. Kanhai: EUSA Pharma: Current Employment. Fajgenbaum: EUSA Pharma: Research Funding;N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’;Pfizer: Other: Study drug for clinical trial of sirolimus. OffLabel Disclosure: Siltuximab is approved for the treatment of iMCD. Tocilizumab is approved for the treatment of Rheumatoid arthritis, Giant cell arteritis, Cytokine release syndrome, Systemic juvenile idiopathic arthritis and Polyarticular juvenile idiopathic arthritis. Combination therapy using Siltuximab and Tocilizumab has not yet been approved.

Safety and Tolerability of Sars-Cov-2 Vaccination and Natural History of Infection Among Patients with Castleman Disease

Castleman Disease (CD) represents a group of rare and heterogeneous hematologic disorders that have common lymph node histopathology. Patients with CD are often immunosuppressed as a consequence of immunemodulating therapy or possibly due to an underlying immunologic dysfunction attributable to B-cell dysfunction. The most severe CD cases experience a cytokine storm disorder, a life-threatening exacerbation of circulating cytokines and immune-cell hyperactivation. Infection with SARS-CoV-2 progresses to a severe cytokine storm in the most severe cases of COVID-19. Interleukin-6 (IL-6) is central to the pathogenesis of CD, and increased IL-6 often accompanies severe COVID-19 cases;inhibition of IL-6 with monoclonal antibodies has been shown to be effective therapy for both CD and severe COVID-19. We therefore sought to understand the impact of COVID-19 infection on the natural history of CD and also examined the safety and tolerability of COVID-19 vaccines in this vulnerable patient population. Patients enrolled in a longitudinal natural history study of CD (N=298) were invited to participate in a survey designed to characterize their experience with COVID-19 disease and vaccination. Surveys were emailed to all eligible patients, and reminders were sent up to 3 times. All data is self-reported;descriptive analyses are reported herein. Of the 298 patients who received a survey, 101 (33.9%) completed it. Sixty-nine (68%) had been tested for SARS-CoV-2 at least once, and 10 (14.5%) reported testing positive - including 6 UCD, 3 iMCD, and 1 HHV8+ MCD patients. The reported prevalence of SARS-CoV-2 infection in the US compares at 10.5%. Two of the 10 patients reported asymptomatic disease (both UCD), 7 reported mild disease (4 UCD, 1 iMCD, 1 HHV8+MCD), and 1 reported moderate disease requiring hospitalization but not a ventilator or intensive care (iMCD). This severity distribution suggests that these potentially immunocompromised patients experience a range of disease severity consistent with SARS-CoV-2 infection in the broader US population. The most commonly-reported symptoms included fevers/chills, headaches, and loss of taste or smell (N=7 each), as well as shortness of breath/difficulty breathing, muscle and body aches, and cough (N=5 each). Rarer symptoms were also noted among the iMCD patients, including discoloration of skin, lips, or nailbeds (N=1) and newfound confusion (N=2). Two of the 10 patients reported stopping siltuximab treatment during their COVID-19 diagnosis;both subsequently resumed treatment. No other treatment changes were reported. Of the 101 respondents, 87 (86%) had received at least 1 vaccine dose. Treatments, such as immunosuppressants and immunomodulators, were paused for 7 of these patients including, during the vaccination period;this was presumably done to increase the likelihood of a robust response to the vaccine. Fifty-one patients (59%) reported side effects to either dose 1 or 2. Side effects were generally mild, and none required hospitalization. Side effects were more commonly reported after dose 2, with the most common being arm pain (N=34), fatigue (N=30), and headache (N=26). Of those who reported not receiving the vaccine, 2 intend to receive it in the future, 5 reported being unsure about receiving it, and 7 do not intend to receive the vaccine. Common concerns include potential interaction with CD (N=9) and limited safety data (N=8). This study represents the first investigation into the experience of CD patients with SARS-CoV-2 testing, diagnosis, and vaccination. We did not observe a markedly increased inflammatory response to SARS-CoV-2 infection, and vaccination was well-tolerated. A limitation is self-selection survey bias;it is possible that those who chose to participate represent those who had a milder reaction in general. However, it is noteworthy that there were no reports of severe disease in this sample. The prevalence of confirmed SARS-CoV-2 infection in this cohort (14.5%) is marginally higher than reported in the US population (10.5%) but statistical comp risons were not performed given that this study does not provide a general epidemiological estimate. However, the distribution of symptoms and vaccine adverse effects in this sample were comparable to the general population. Though additional follow-up is planned for the future, these data are an important basis for understanding the interaction of SARS-CoV-2 and CD. Disclosures: Casper: EUSA Pharma: Consultancy. Fajgenbaum: Pfizer: Other: Study drug for clinical trial of sirolimus;N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’;EUSA Pharma: Research Funding. OffLabel Disclosure: Our makes reference to the following: “Interleukin-6 (IL-6) is central to the pathogenesis of CD, and increased IL-6 often accompanies severe COVID-19 cases;inhibition of IL-6 with monoclonal antibodies has been shown to be effective therapy for both CD and severe COVID-19.” Inhibition of IL-6 with monoclonal antibodies for use in COVID-19 is off-label.