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

MANIFESTAÇÕES DE TAFRO EM PACIENTE COM DOENÇA DE CASTLEMAN MULTICÊNTRICA POSITIVA PARA HERPES VIRUS HUMANO TIPO 8

Doença de Castleman ou hiperplasia linfoide angiofolicular é uma doença linfoproliferativa, não maligna e relativamente rara. Possui duas variantes: Unicêntrica (DCU) e Multicêntrica (DCM). A DCU manifesta-se em idade mais precoce (em média aos 33 anos), com predominância da variante hialino-vascular e localização preferencial na região da cabeça/pescoço e retroperitôneo. Cerca de 90% dos doentes são assintomáticos e o tratamento de primeira linha consiste na excisão curativa da lesão. Em contra-partida, sua forma multicêntrica envolve um grupo de entidades linfoproliferativas policlonais secundárias a um aumento na secreção de interleucinas, principalmente IL-6. Pode se apresentar de forma idiopática, estar relacionada ao Herpes virus humano (HHV-8) ou a Síndrome POEMS. Quando associada ao HHV-8, manifesta-se clinicamente com sintomas constitucionais (febre, sudorese noturna, perda ponderal), sintomas respiratórios, linfonodomegalias e esplenomegalia. Laboratorialmente pode ter anemia, trombocitopenia, hipoalbuminemia e hipergamaglobulinemia, com aumento de PCR. Apesar da extensa diversidade de manifestações tanto clínico como histopatológicas, há um consenso no “international working group”de que sua forma idiopática (sem HHV8) pode ainda ser subdividida conforme o fenótipo, com ou sem TAFRO - trombocitopenia (T), anasarca (A), febre (F), mielofibrose (R), organomegalia (O). No presente caso, porém, relata-se um paciente com DCM e HHV8 positivo com manifestações que mimetizaram TAFRO. Trata-se de paciente de 28 anos, branco, masculino, HIV positivo com carga viral indetectável e diagnóstico prévio de Sarcoma de Kaposi já tratado. Um ano antes do diagnóstico de DCM, iniciou quadro intermitente de febre, astenia, sintomas respiratórios, gastrointestinais e pancitopenia. Possuia esplenomegalia e linfonodopatias difusas e após biópsia recebeu diagnóstico de Doença de Castleman. O anatomopatológico mostrou-se compatível com variante intermediária entre espectros hialino vascular e plasmacítica. Teve pesquisa de HHV8 positiva na peça e no PCR sérico. Seis meses após este diagnóstico, doença entrou novamente em atividade e foi tratada com corticoterapia e etoposídeo, com resposta mínima. Trocada quimioterapia por esquema alternativo (contendo ciclofosfamida, talidomida e prednisona), cursou com remissões e recaídas, inclusive com recidiva do Sarcoma de Kaposi. Passados 3 anos do diagnóstico de Castleman, paciente manifestou anasarca, ascite, fibrose em biópsia da medula óssea, além de sintomas constitucionais, progressão de linfonodomegalia, esplenomegalia e excesso de IL-6. Assim paciente contemplou todos os cincos critérios maiores do diagnóstico de TAFRO. Na indisponibilidade de rituximabe e anticorpo monoclonal anti-IL-6, optou-se por pulsoterapia com corticoide e CHOP (ciclofosfamida, doxorrubicina, vincristina, prednisona). Após o primeiro ciclo complicou com hematotoxicidade, sepse urinária por KPC e infecção por SARS-CoV-2. Recebeu suporte clínico, com melhora lenta, discreta e momentânea, evoluindo com pancitopenia grave, icterícia. Agregou múltiplas disfunções e foi a óbito, exemplificando como realmente essa etidade rara, ainda pouco compreendida e de difícil diagnóstico se comporta de maneira extremamente agressiva.

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.

Virtual screening of the active ingredients of Shufeng Jiedu capsule for COVID-19 based on molecular docking and network pharmacology

Objective: To screen potential active ingredients of Shufeng Jiedu Capsule(SJC)for novel coronavirus pneumonia(COVID-19).

DIAGNOSING KAPOSI'S SARCOMA IN ABSENCE OF CUTANEOUS LESIONS IN THE HAART ERA

TYPE: Case Report TOPIC: Chest Infections INTRODUCTION: Kaposi sarcoma (KS) is very commonly associated with Human Immunodeficiency Virus (HIV) infection. The clinical course of HIV associated KS could be indolent with muco-cutaneous or aggressive with visceral organ system involvement. It is extremely uncommon for the visceral involvement to occur in the absence of mucocutaneous manifestations. CASE PRESENTATION: A 45-year male with HIV, presented with fatigue, exertional dyspnea, cough. Vital signs showed low grade fever and hypoxia. On physical exam the pertinent positive finding was diffuse inspiratory crackles. The CT chest showed multiple irregular nodular infiltrates in the lungs. Blood and sputum cultures were collected, and the patient was started on empiric antibiotics and fluconazole. The viral load and the absolute CD4 count were 64,360 and 17, respectively. The transesophageal echocardiogram was negative for vegetations. SARS-COVID19, blood culture and three sputum acid fast bacilli were negative. The patient continued to worsen. The bronchoscopy showed a friable mass in the left lower trachea. The immunohistochemistry analysis of the lesions was positive for CD34, CD31, HHV-8, FLI-1 which was diagnostic of KS. The patient was started on Highly Active Antiretroviral Therapy (HAART) and was discharged on HAART with a scheduled follow up. DISCUSSION: The introduction of HAART has decreased the incidence of KS to 0.03 per 1000 patient years in the HAART era. 15.5 % of patients have pulmonary KS in the absence of mucocutaneous lesions. These rates of pulmonary KS in autopsy findings were noted in the pre-HAART era. CONCLUSIONS: To establish a diagnosis of pulmonary KS in the absence of the characteristic cutaneous lesions is challenging. DISCLOSURE: Nothing to declare. KEYWORD: Kaposi Sarcoma

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.

Study on the potential mechanism of Fufang Yinhua Jiedu granules based on network pharmacology in the treatment of novel coronavirus

Objective To explore the potential effect and mechanism of Fufang Yinhua Jiedu Granules against the coronavirus disease 19 (COVID-19) by means of network pharmacology, and then to verify its anti-coronavirus effect through in vitro models.