Successful salvage therapy of Ruxolitinib on interstitial pneumonia after long COVID or post COVID-19 syndrome with follicular lymphoma: two-case report and literature review

Successful salvage therapy of Ruxolitinib on interstitial pneumonia after long COVID or post COVID-19 syndrome with follicular lymphoma: two-case report and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Successful salvage therapy of Ruxolitinib on interstitial pneumonia after long COVID or post COVID-19 syndrome with follicular lymphoma: two-case report and literature review Tingting Zhu, Xin Li, Shuquan Gao, Rui Cui, Jia Wang, Qi Deng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4425881/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Immunocompromised caused by B lymphocyte deficiency and hypogammaglobulinemia after anti-CD19 Chimeric antigen receptor (CAR) T cell therapy for patients with relapsed/refractory (R/R) follicular lymphoma (FL) are high risks of severe COVID-19 infection. In our study, two patients with refractory FL had persistence of COVID-19 infection after their anti-CD19-CAR T cell therapy. They were diagnosed with Post COVID-19 syndrome or Long COVID-19 with interstitial inflammation and persistent hypoxemia. They received Molnupiravir and/or Paxlovid, methylprednisolone therapy when their interleukin (IL)-6 was is at a high level. There was no response in interstitial inflammation, persistent hypoxemia and persistent positive expression of SARS-CoV-2 to the therapy above, but the level of IL-6 was decreased after these therapies. These two patients subsequently received low-dose of Ruxolitinib (5mg, twice a day) as a salvage therapy in combination with a gradually reduced dosage of methylprednisolone. One to two months of Ruxolitinib therapy, the persistent hypoxemia was relieved and the interstitial inflammation was significantly absorbed. At the same time, the SARS-CoV-2 detection was found to be negative. Even if SARS-CoV-2 was positive again, the interstitial pneumonia did not progress again and the symptoms such as dyspnea did not develop again. Ruxolitinib might be a safe and effective alternative salvage therapy for COVID-19 infection patients with interstitial inflammation and persistent hypoxemia who had no response to corticosteroid therapy. Ruxolitinib Post COVID-19 syndrome Long COVID-19 Follicular lymphoma Interstitial pneumonia Hypoxemia Figures Figure 1 Figure 2 Introduction There was a mortality rate ranging from 31–35% in non-hodgkin's lymphoma during the COVID-19 pandemic [ 1 , 2 ].Furthermore, persistent viral infection > 6 weeks was associated with high mortality [ 3 , 4 ]. Anti-CD19 chimeric antigen receptor (CAR) T cell therapy is performed after lymphodepleting conditioning, which produces long term B cell deficiency and hypogammaglobulinemia [ 5 , 6 ]. Data from the total number (17 out of 353) of patients received anti-CD19-CAR T cell therapy in European registry in 2020 for symptomatic COVID-19 infection showed that the prevalence of COVID-19 was 4.8% [ 7 ]. And the overall mortality was 50% in this report. In addition, about half of the patients developed COVID-19 within 6 months after their anti-CD19-CAR T cell therapy [ 7 ]. Radiographic changes in pulmonary fibrosis were found in 45%, 30–36%, and 28% of patients 1 month, 3 to 6 months, and 1 year after COVID-19 infection [ 8 ]. Pro-inflammatory cytokines are elevated in patients with severe COVID-19 infection, and several of these cytokines signal primarily through the Janus kinase (JAK)/ signal transduction and transcriptional activator (STAT) pathway [ 9 , 10 ]. Since these cytokines signal via JAK1 and/or JAK2, therapy with Ruxolitinib might yield very broad anti-inflammatory activity [ 11 ]. Here we show two patients with refractory Follicular lymphoma (FL) after anti-CD19-CAR T cell therapy who were successfully treated with Ruxolitinib as a salvage therapy for interstitial inflammation and persistent hypoxemia caused by COVID-19 infection, while they did not have high levels of cytokines and have no response to corticosteroid at this time. Case presentation Case 1 A 58-year-old male patient was enrolled in a clinical trial of anti-CD19 Chimeric antigen receptor (CAR) T cell therapy ( ChiCTR1800019622 ) as a refractory FL patient in our center in August 2020. He achieved complete remission (CR) in his anti-CD19 CAR T-cell therapy. Then he maintained his CR status without any maintenance therapy. He was first developed COVID-19 infection with fever in January 2023. This patient made a quick recovery after simple symptomatic therapy. Unfortunately, he developed COVID-19 infection for the second time in April 2023. He had symptoms of hyperpyrexia, dyspnea, coughing and shortness of breath this time. The oxygen saturation of the patient was about 88–92% without oxygen inhalation. He had a positive test for SARS-CoV-2 (Reverse transcription-polymerase chain reaction, RT-PCR). The C-reactive protein (CRP) was 36.2 mg/L and interleukin (IL)-6 was 658 pg/mL. He had B lymphocyte deficiency (expression of CD19 in B lymphocyte in peripheral blood was 3.42%) and hypogammaglobulinemia (12.3 g/L) at this time. Computed tomography (CT) on admission indicated interstitial pneumonia in his both lungs (Fig. 1 A). This patient received Paxlovid, Molnupiravir, methylprednisolone (80mg, daily for 14 days), tocilizumab (4mg/kg, daily for 3 days) and symptomatic treatment, but the symptoms of dyspnea and hypoxemia were not relieved and the SARS-CoV-2 remained positive. Then in the following four months he had persistent hypoxemia and persistent positive expression of SARS-CoV-2, although he received continuous oxygen therapy and methylprednisolone (40–60 mg, daily) therapy. He was admitted to our hospital again due to severe hypoxemia, dyspnea and shortness of breath in August 2023. He had an oxygen saturation at 82–88% without oxygen inhalation. The CRP was 60.5 mg/L, the IL-6 was 471 pg/mL, and SARS-CoV-2 was positive this time. His interstitial pneumonia was worse than before, with multiple spots and ground glass shadows in both lungs (Fig. 1 B). He was diagnosed with Post COVID-19 syndrome (over 12 weeks since infection) [ 12 , 13 ]. The bronchoscopy showed airway inflammation after he was hospitalized. No evidence of bacterial, fungal, or tuberculosis infection other than SARS-CoV-2 was detected in his alveolar lavage fluid. He received Molnupiravir, methylprednisolone (160mg, daily for 14 days) again. But his hypoxemia and interstitial pneumonia progressed. The oxygen saturation was at 85–88% without oxygen inhalation. The patient subsequently received Ruxolitinib (5mg, twice a day) as a salvage therap1y in combination with a gradually reduced dosage of methylprednisolone from September 2023. The CRP was 38.3 mg/L and IL-6 was 49 pg/mL at the beginning of salvage therapy. After two months of Ruxolitinib therapy, the oxygen saturation recovered to 92–96% without oxygen. And this patient has been discontinued methylprednisolone at this time. CT examination showed that his interstitial pneumonia was significantly better than that of before salvage therapy (Fig. 1 C). At this point, his SARS-CoV-2 expression turned negative. The CRP was 15.2 mg/L and IL-6 was 18.4 pg/mL at this time (Table 1 ). Throughout the course of Ruxolitinib therapy, he did not develop any degree of hemocytopenia. Two months later, the patient infected with COVID-19 again. But his interstitial pneumonia did not progress again, and the symptoms such as dyspnea did not develop again also (Fig. 1 D). Ruxolitinib was discontinued after six months of salvage therapy, during which the interstitial pneumonia did not progress again, and the SARS-CoV-2 detection was continued to be negative so far. Table 1. Changes of inflammatory indicators before and after salvage therapy CASE 1 CASE 2 CD19 in B lymphocyte (%) Hypogammaglobulinemia (g/L) Interval with CAR-T therapy (Mons) First severe COVID-19 infection CRP (mg/L) IL-6 (pg/mL) Pre-salvage therapy CRP (mg/L) IL-6 (pg/mL) Beginning of salvage therapy CRP (mg/L) IL-6 (pg/mL) After salvage therapy CRP (mg/L) IL-6 (pg/mL) 3.42 12.3 32 36.2 658 60.5 471 38.3 49 15.2 18.4 0.06 15.1 2 75.3 301 58.3 275 45.1 58 10.5 8.2 Case 2 A 70-year-old male patient was enrolled in a clinical trial of anti-CD19 CAR T-cell therapy ( ChiCTR1800019622 ) as a refractory FL patient in our center in November 2023. He developed COVID-19 infection when he was evaluated as CR in January 2024. He had symptoms of fever, cough, breathlessness and had an oxygen saturation at 90–93% without oxygen inhalation. The SARS-CoV-2 was found to be positive, while the CRP was 75.3 mg/L and the IL-6 was 301 pg/mL. The expression of CD19 in B lymphocyte in peripheral blood was 0.06% and hypogammaglobulinemia was 15.1 g/L at this time. CT examine indicated interstitial pneumonia in his both lungs (Fig. 2 A). He received Molnupiravir, methylprednisolone (60mg, daily for 14 days) and symptomatic treatment, but his symptoms were not relieved and the SARS-CoV-2 remained positive. Then in the following two months he received Paxlovid, methylprednisolone (40–60 mg, daily) and continuous oxygen therapy, but he had persistent hypoxemia, severe cough, and persistent positive expression of SARS-CoV-2. In March 2024, he was hospitalized again due to severe hypoxemia with cough, and had an oxygen saturation at 86–99% without oxygen inhalation. The CRP was 58.3 mg/L and IL-6 was 275 pg/mL this time, and the SARS-CoV-2 remained positive. His interstitial pneumonia was worse than before, with ground glass shadows in his left lung (Fig. 2 B). He was diagnosed with Long COVID: ongoing symptomatic COVID-19 (4–12 weeks since infection) [ 12 , 13 ].By bronchoscopy, evidence of SARS-CoV-2 infection was detected in his alveolar lavage fluid. He received Molnupiravir, methylprednisolone (160mg daily for 3 days, then 80mg daily for 7 days). But his symptoms of severe hypoxemia (the oxygen saturation at 86–99% without oxygen inhalation) and cough did not resolve. The patient subsequently received Ruxolitinib (5mg, twice a day) in combination with a gradually reduced dosage of methylprednisolone from March 2024. The CRP was 45.1 mg/L and IL-6 was 58 pg/mL at the beginning of salvage therapy. One month later, the oxygen saturation of the patient is about 91–93% without oxygen inhalation. After two months of salvage therapy of Ruxolitinib, the oxygen saturation was returned to 95–97% without methylprednisolone. CT examination showed that his interstitial pneumonia was significantly absorbed (Fig. 2 CD). His SARS-CoV-2 detection was found to be negative, while the CRP was 10.5 mg/L and IL-6 was 8.2 pg/mL at this time (Table 1 ). He did not develop any degree of hemocytopenia in the Ruxolitinib salvage therapy also. Discussion Anti-CD19-CAR T cell therapy has been an effective salvage therapy for R/R FL patients. The CR rates by the Lugano criteria were 88% and 46% for patients with FL and histologically transformed invasive lymphoma (tFL), respectively [ 14 , 15 ]. However, there are some complications after anti-CD19-CAR T cell therapy, such as B lymphocyte deficiency and hypogammaglobulinemia. It had been showed that 29% of patients had low level of IgG 63 days after anti-CD19-CAR T cell therapy[ 16 ]. Immunocompromised caused by B lymphocyte deficiency and hypogammaglobulinemia after anti-CD19-CAR T cell therapy are high risks of severe COVID-19 infection [ 17 ]. Even worse was the persistence of COVID-19 infection in patients who received anti-CD19-CAR T cell therapy, with 2 out of 3 patients persisting for more than 5 months [ 18 ]. In our report, these two patients with refractory FL had persistence of COVID-19 infection when they had B lymphocyte deficiency and hypogammaglobulinemia after their anti-CD19-CAR T cell therapy. An Italian study showed that 32% of 143 hospitalized patients continued to have at least one to two symptoms, and 55% had three or more symptoms within 60 days of COVID-19 infection [ 19 ]. The hyperinflammatory response in lungs triggered by COVID-19 viral infection potentially leads to dyspnea. Approximately 15% patients with COVID-19 infection progressed to severe pneumonia, 5% developed acute respiratory distress syndrome (ARDS) or multiple organ failure [ 20 ]. Cytokine storm is characteristic and common manifestation of these severe COVID-19 infection. Plasma levels of pro-inflammatory cytokines were high in patients with severe COVID-19 infection, such as IL-2, IL-6, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF), interferon gamma (IFN-γ) interferon gamma-induced protein 10 (IP-10/CXCL10), and tumor necrosis factor alpha (TNF-α) [ 21 , 22 ]These cytokines cause cytokine storm of COVID-19 mainly through the JAK/STAT signal pathway [ 23 ]Thus, inhibition of the JAK pathway might ameliorate the hyperinflammatory state associated with severe COVID-19 infection. Ruxolitinib was a selective inhibitor of JAK1 and JAK2, and has a powerful JAK/STAT signal suppression effect[ 24 ]. In some studies, patients with progressive COVID-19 related ARDS who received Ruxolitinib therapy achieved clinical improvements compared to patients who received standard care[ 25 – 27 ]. Although Ruxolitinib therapy did not increase the rate of grade 3–4 cytopenias, but the rate of grade 1–2 anemia and thrombocytopenia was still relatively high [ 29 ][ 28 ]. In these two patients, interstitial inflammation and persistent hypoxemia relieved 1–2 months after salvage therapy of Ruxolitinib without any degree of hemocytopenia. This might be related to the relatively small dose of Ruxolitinib therapy. Although corticosteroid was the first method that showed a reduction of 36% mortality among patients with COVID-19 infection [ 30 ][ 29 ], several studies of patients with B lymphocyte deficiency, corticosteroid had no substantial impact on the outcomes, including survival [31,32][ 30 , 31 ]. Ruxolitinib might be a safe and effective alternative salvage therapy for such COVID-19 infection patients with interstitial inflammation and persistent hypoxemia who had no response to corticosteroid therapy. Declarations Acknowledgements We thank the Shanghai Genbase Biotechnology Co., Ltd. for providing us with anti-CD19-CAR-T-cells. We thank our patient for her participation in our clinical trials. Author Contribution Concept and design: DQ Drafted or revised the manuscript: ZTT Clinical work and acquisition of data: ZTT, CR and WJ Analysis and interpretation of data: LX and GSQ Writing, review and/or revision of manuscript: DQ Ethical Approval This study was approved by the Medical Ethics Committee of the Department of Hematology, Tianjin First Center Hospital (Tianjin, China). (Approved No. of ethic committee: 2018N105KY). This Clinical trial was registered at http://www.chictr.org.cn/index.aspx as ChiCTR1800019622 (We register our clinical trial at Chinese Clinical Trail Registry on November 21, 2018) . Funding This work was supported by the Sponsored by Tianjin Health Research Project (TJWJ2023ZD003). Chinese Society of Clinical Oncology Beijing Xisike Clinical Oncology Research Foundation (Y-SY2021QN-0184, Y-Young2022-0209, Y-NCJH202201-0027 and Y-2022YMJN/MS-0001). Statement of Informed Consent Written informed consent was obtained from a legally authorized representative for anonymized patient information to be published in this article. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Consent for publication: Not applicable. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/. ORCID ： Qi Deng https://orcid.org/0000-0002-3646-4953 Data availability The data that support the findings of this study are available on request from the authors. References Wang Q, Berger NA, Xu R (2021) When hematologic malignancies meet COVID-19 in the United States: Infections, death and disparities. Blood Rev 47:100775 Duléry R, Lamure S, Delord M et al (2021) Prolonged in-hospital stay and higher mortality after Covid-19 among patients with non-Hodgkin lymphoma treated with B-cell depleting immunotherapy. Am J Hematol 96:934–944 Regalado-Artamendi I, Jiménez-Ubieto A, Hernández-Rivas J et al (2021) Risk Factors and Mortality of COVID-19 in Patients With Lymphoma: A Multicenter Study. Hemasphere 5:e538 Hueso T, Pouderoux C, Péré H et al (2020) Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19. Blood 136:2290–2295 Fried S, Avigdor A, Bielorai B et al (2019) Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transpl 54:1643–1650 Nicolaus Kröger 1 JG (2022) Christian Chabannon 3, Ibrahim Yakoub-Agha 4, Hermann Einsele 5. The EBMT/EHA CAR-T Cell Handbook [Internet]. In: Kröger N, Gribben J, Chabannon C et al (eds) The EBMT/EHA CAR-T Cell Handbook. Cham (CH): Springer Copyright 2022, The Editor(s) (if applicable) and The Author(s). This book is an open access publication Busca A, Salmanton-García J, Corradini P et al (2022) COVID-19 and CAR T cells: a report on current challenges and future directions from the EPICOVIDEHA survey by EHA-IDWP. Blood Adv 6:2427–2433 Yang LL, Yang T (2020) Pulmonary rehabilitation for patients with coronavirus disease 2019 (COVID-19). Chronic Dis Transl Med 6:79–86 Morimoto A, Nakazawa Y, Ishii E (2016) Hemophagocytic lymphohistiocytosis: Pathogenesis, diagnosis, and management. Pediatr Int 58:817–825 Vainchenker W, Dusa A, Constantinescu SN (2008) JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol 19:385–393 Singer JW, Al-Fayoumi S, Taylor J et al (2019) Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures. PLoS ONE 14:e0222944 Soriano JB, Murthy S, Marshall JC et al (2022) A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis 22:e102–e107 CDC (2022) ; Post-COVID conditions: information for healthcare providers Nierengarten MB (2023) FDA grants accelerated approval of mosunetuzumab for relapsed, refractory follicular lymphoma. Cancer 129:1465–1466 Hirayama AV, Gauthier J, Hay KA et al (2019) High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy. Blood 134:636–640 Vora SB, Waghmare A, Englund JA et al (2020) Infectious Complications Following CD19 Chimeric Antigen Receptor T-cell Therapy for Children, Adolescents, and Young Adults. Open Forum Infect Dis 7:ofaa121 Jones JM, Faruqi AJ, Sullivan JK et al (2021) COVID-19 Outcomes in Patients Undergoing B Cell Depletion Therapy and Those with Humoral Immunodeficiency States: A Scoping Review. Pathog Immun 6:76–103 Mushtaq MU, Shahzad M, Chaudhary SG et al (2021) ; Impact of SARS-CoV-2 in Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Recipients. Transplant Cell Ther 27: 796.e791-796.e797 Carfì A, Bernabei R, Landi F (2020) Persistent Symptoms in Patients After Acute COVID-19. JAMA 324:603–605 Guan WJ, Ni ZY, Hu Y et al (2020) Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 382:1708–1720 Huang C, Wang Y, Li X et al (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395:497–506 Xu Z, Shi L, Wang Y et al (2020) Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 8:420–422 Pesu M, Laurence A, Kishore N et al (2008) Therapeutic targeting of Janus kinases. Immunol Rev 223:132–142 Quintás-Cardama A, Vaddi K, Liu P et al (2010) Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 115:3109–3117 Vannucchi AM, Sordi B, Morettini A et al (2021) Compassionate use of JAK1/2 inhibitor ruxolitinib for severe COVID-19: a prospective observational study. Leukemia 35:1121–1133 Capochiani E, Frediani B, Iervasi G et al (2020) Ruxolitinib Rapidly Reduces Acute Respiratory Distress Syndrome in COVID-19 Disease. Analysis of Data Collection From RESPIRE Protocol. Front Med (Lausanne) 7:466 La Rosée F, Bremer HC, Gehrke I et al (2020) The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation. Leukemia 34:1805–1815 Cao Y, Wei J, Zou L et al (2020) Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol 146:137–146e133 Horby P, Lim WS, Emberson JR et al (2021) Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med 384:693–704 Hueso T, Godron AS, Lanoy E et al (2022) Convalescent plasma improves overall survival in patients with B-cell lymphoid malignancy and COVID-19: a longitudinal cohort and propensity score analysis. Leukemia 36:1025–1034 Roeker LE, Eyre TA, Thompson MC et al (2021) COVID-19 in patients with CLL: improved survival outcomes and update on management strategies. Blood 138:1768–1773 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4425881","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":311988318,"identity":"664fd2d1-a845-4857-b71c-d93aed662e0a","order_by":0,"name":"Tingting Zhu","email":"","orcid":"","institution":"Tianjin First Central Hospital, Nankai University","correspondingAuthor":false,"prefix":"","firstName":"Tingting","middleName":"","lastName":"Zhu","suffix":""},{"id":311988319,"identity":"9711cb8e-6fcc-4450-8031-16eeb26710e4","order_by":1,"name":"Xin Li","email":"","orcid":"","institution":"Tianjin First Central Hospital, Nankai University","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Li","suffix":""},{"id":311988320,"identity":"5252eca1-048b-46da-845d-3158de6e5742","order_by":2,"name":"Shuquan Gao","email":"","orcid":"","institution":"Tianjin First Central Hospital, Nankai University","correspondingAuthor":false,"prefix":"","firstName":"Shuquan","middleName":"","lastName":"Gao","suffix":""},{"id":311988321,"identity":"65f1d7cf-34ed-409d-aab5-4930ae858235","order_by":3,"name":"Rui Cui","email":"","orcid":"","institution":"Tianjin First Central Hospital, Nankai University","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Cui","suffix":""},{"id":311988322,"identity":"f460810a-89b0-42ae-957d-4fcc405fc39d","order_by":4,"name":"Jia Wang","email":"","orcid":"","institution":"Tianjin First Central Hospital, Nankai University","correspondingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Wang","suffix":""},{"id":311988323,"identity":"fb1f98cf-4955-4a6b-95b5-cb440b27ec38","order_by":5,"name":"Qi Deng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYBACCQYGNjBiYG9sfPCBNC08h5sNZ5CmRSK9TZqDGC2S7YefPeYps8mTj3zYIM3AYCen20BAizRPmrkxz7m0YsPbiQ3GBQzJxmYHCGiRY8hhk+ZtO5y4cXZiQ/IMhgOJ2whq4X8D0vI/cePMgw2HeYjRIi0BtuVA4nwJxsZmorRIznhmJjnnXHLiBp7EZsYZBkT4ReJ88jOJN2V2ifPbjz//8aHCTo6gFhBg4gESBmCVBkQoBwHGH0BCvoFI1aNgFIyCUTDyAACUREJUsNz4IwAAAABJRU5ErkJggg==","orcid":"","institution":"Tianjin First Central Hospital, Nankai University","correspondingAuthor":true,"prefix":"","firstName":"Qi","middleName":"","lastName":"Deng","suffix":""}],"badges":[],"createdAt":"2024-05-15 14:39:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4425881/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4425881/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58246578,"identity":"079da503-f324-469a-8607-547087f64041","added_by":"auto","created_at":"2024-06-13 02:28:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":371335,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInterstitial pneumonia of case 1. A. \u003c/strong\u003eThe second time of COVID-19 infection withinterstitial inflammation.\u003cstrong\u003eB.\u003c/strong\u003e The third time of COVID-19 infection with severe interstitial pneumonia. \u003cstrong\u003eC.\u003c/strong\u003e After two months of Ruxolitinib therapy, the interstitial pneumonia was significantly relieved\u003cstrong\u003e. D. \u003c/strong\u003eThe fourth time of COVID-19 infectionwithout severe interstitial pneumonia.\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4425881/v1/3ab1e31d113081457f56217c.png"},{"id":58246579,"identity":"71293aac-a62a-40e2-8bff-78565da97c20","added_by":"auto","created_at":"2024-06-13 02:28:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5306378,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInterstitial pneumonia of case 2. A. \u003c/strong\u003eThe first time of COVID-19 infection after anti-CD19 CAR T-cell therapy.\u003cstrong\u003e B.\u003c/strong\u003e The second time of COVID-19 infection with severe interstitial pneumonia. \u003cstrong\u003eC\u0026amp;D.\u003c/strong\u003eAfter one and two months of Ruxolitinib therapy, the interstitial pneumonia was significantly relieved\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4425881/v1/03a0d983c29e8f2736179c92.png"},{"id":58595056,"identity":"2a3fb3f5-ab92-46cc-9a46-7c92d9d1cd6e","added_by":"auto","created_at":"2024-06-18 16:35:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8587248,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4425881/v1/00d5e989-b062-4242-aed8-4666347425a9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Successful salvage therapy of Ruxolitinib on interstitial pneumonia after long COVID or post COVID-19 syndrome with follicular lymphoma: two-case report and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThere was a mortality rate ranging from 31\u0026ndash;35% in non-hodgkin's lymphoma during the COVID-19 pandemic [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].Furthermore, persistent viral infection\u0026thinsp;\u0026gt;\u0026thinsp;6 weeks was associated with high mortality [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Anti-CD19 chimeric antigen receptor (CAR) T cell therapy is performed after lymphodepleting conditioning, which produces long term B cell deficiency and hypogammaglobulinemia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Data from the total number (17 out of 353) of patients received anti-CD19-CAR T cell therapy in European registry in 2020 for symptomatic COVID-19 infection showed that the prevalence of COVID-19 was 4.8% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. And the overall mortality was 50% in this report. In addition, about half of the patients developed COVID-19 within 6 months after their anti-CD19-CAR T cell therapy [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Radiographic changes in pulmonary fibrosis were found in 45%, 30\u0026ndash;36%, and 28% of patients 1 month, 3 to 6 months, and 1 year after COVID-19 infection [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Pro-inflammatory cytokines are elevated in patients with severe COVID-19 infection, and several of these cytokines signal primarily through the Janus kinase (JAK)/ signal transduction and transcriptional activator (STAT) pathway [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Since these cytokines signal via JAK1 and/or JAK2, therapy with Ruxolitinib might yield very broad anti-inflammatory activity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Here we show two patients with refractory Follicular lymphoma (FL) after anti-CD19-CAR T cell therapy who were successfully treated with Ruxolitinib as a salvage therapy for interstitial inflammation and persistent hypoxemia caused by COVID-19 infection, while they did not have high levels of cytokines and have no response to corticosteroid at this time.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCase 1\u003c/h2\u003e \u003cp\u003eA 58-year-old male patient was enrolled in a clinical trial of anti-CD19 Chimeric antigen receptor (CAR) T cell therapy (\u003cem\u003eChiCTR1800019622\u003c/em\u003e) as a refractory FL patient in our center in August 2020. He achieved complete remission (CR) in his anti-CD19 CAR T-cell therapy. Then he maintained his CR status without any maintenance therapy. He was first developed COVID-19 infection with fever in January 2023. This patient made a quick recovery after simple symptomatic therapy. Unfortunately, he developed COVID-19 infection for the second time in April 2023. He had symptoms of hyperpyrexia, dyspnea, coughing and shortness of breath this time. The oxygen saturation of the patient was about 88\u0026ndash;92% without oxygen inhalation. He had a positive test for SARS-CoV-2 (Reverse transcription-polymerase chain reaction, RT-PCR). The C-reactive protein (CRP) was 36.2 mg/L and interleukin (IL)-6 was 658 pg/mL. He had B lymphocyte deficiency (expression of CD19 in B lymphocyte in peripheral blood was 3.42%) and hypogammaglobulinemia (12.3 g/L) at this time. Computed tomography (CT) on admission indicated interstitial pneumonia in his both lungs (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). This patient received Paxlovid, Molnupiravir, methylprednisolone (80mg, daily for 14 days), tocilizumab (4mg/kg, daily for 3 days) and symptomatic treatment, but the symptoms of dyspnea and hypoxemia were not relieved and the SARS-CoV-2 remained positive. Then in the following four months he had persistent hypoxemia and persistent positive expression of SARS-CoV-2, although he received continuous oxygen therapy and methylprednisolone (40\u0026ndash;60 mg, daily) therapy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHe was admitted to our hospital again due to severe hypoxemia, dyspnea and shortness of breath in August 2023. He had an oxygen saturation at 82\u0026ndash;88% without oxygen inhalation. The CRP was 60.5 mg/L, the IL-6 was 471 pg/mL, and SARS-CoV-2 was positive this time. His interstitial pneumonia was worse than before, with multiple spots and ground glass shadows in both lungs (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). He was diagnosed with Post COVID-19 syndrome (over 12 weeks since infection) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The bronchoscopy showed airway inflammation after he was hospitalized. No evidence of bacterial, fungal, or tuberculosis infection other than SARS-CoV-2 was detected in his alveolar lavage fluid. He received Molnupiravir, methylprednisolone (160mg, daily for 14 days) again. But his hypoxemia and interstitial pneumonia progressed. The oxygen saturation was at 85\u0026ndash;88% without oxygen inhalation. The patient subsequently received Ruxolitinib (5mg, twice a day) as a salvage therap1y in combination with a gradually reduced dosage of methylprednisolone from September 2023. The CRP was 38.3 mg/L and IL-6 was 49 pg/mL at the beginning of salvage therapy. After two months of Ruxolitinib therapy, the oxygen saturation recovered to 92\u0026ndash;96% without oxygen. And this patient has been discontinued methylprednisolone at this time. CT examination showed that his interstitial pneumonia was significantly better than that of before salvage therapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). At this point, his SARS-CoV-2 expression turned negative. The CRP was 15.2 mg/L and IL-6 was 18.4 pg/mL at this time (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Throughout the course of Ruxolitinib therapy, he did not develop any degree of hemocytopenia. Two months later, the patient infected with COVID-19 again. But his interstitial pneumonia did not progress again, and the symptoms such as dyspnea did not develop again also (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). Ruxolitinib was discontinued after six months of salvage therapy, during which the interstitial pneumonia did not progress again, and the SARS-CoV-2 detection was continued to be negative so far.\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eChanges of inflammatory indicators before and after salvage therapy\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.293072824156305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.596802841918294%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCASE 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.1101243339254%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCASE 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.293072824156305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD19 in B lymphocyte (%)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHypogammaglobulinemia (g/L)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eInterval with CAR-T therapy (Mons)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFirst severe COVID-19 infection\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp;\u003c/strong\u003eCRP (mg/L)\u003c/p\u003e\n \u003cp\u003eIL-6 (pg/mL)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePre-salvage therapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u0026nbsp;\u003c/strong\u003eCRP (mg/L)\u003c/p\u003e\n \u003cp\u003eIL-6 (pg/mL)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eBeginning of salvage therapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp;\u003c/strong\u003eCRP (mg/L)\u003c/p\u003e\n \u003cp\u003eIL-6 (pg/mL)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAfter salvage therapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp;\u003c/strong\u003eCRP (mg/L)\u003c/p\u003e\n \u003cp\u003eIL-6 (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.596802841918294%\" valign=\"top\"\u003e\n \u003cp\u003e3.42\u003c/p\u003e\n \u003cp\u003e12.3\u003c/p\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e36.2\u003c/p\u003e\n \u003cp\u003e658\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e60.5\u003c/p\u003e\n \u003cp\u003e471\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e38.3\u003c/p\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15.2\u003c/p\u003e\n \u003cp\u003e18.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.1101243339254%\" valign=\"top\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003cp\u003e15.1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e75.3\u003c/p\u003e\n \u003cp\u003e301\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e58.3\u003c/p\u003e\n \u003cp\u003e275\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e45.1\u003c/p\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10.5\u003c/p\u003e\n \u003cp\u003e8.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e \u003c/div\u003e\u003cbr\u003e\n\u003ch3\u003eCase 2\u003c/h3\u003e\n\u003cp\u003eA 70-year-old male patient was enrolled in a clinical trial of anti-CD19 CAR T-cell therapy (\u003cem\u003eChiCTR1800019622\u003c/em\u003e) as a refractory FL patient in our center in November 2023. He developed COVID-19 infection when he was evaluated as CR in January 2024. He had symptoms of fever, cough, breathlessness and had an oxygen saturation at 90\u0026ndash;93% without oxygen inhalation. The SARS-CoV-2 was found to be positive, while the CRP was 75.3 mg/L and the IL-6 was 301 pg/mL. The expression of CD19 in B lymphocyte in peripheral blood was 0.06% and hypogammaglobulinemia was 15.1 g/L at this time. CT examine indicated interstitial pneumonia in his both lungs (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). He received Molnupiravir, methylprednisolone (60mg, daily for 14 days) and symptomatic treatment, but his symptoms were not relieved and the SARS-CoV-2 remained positive. Then in the following two months he received Paxlovid, methylprednisolone (40\u0026ndash;60 mg, daily) and continuous oxygen therapy, but he had persistent hypoxemia, severe cough, and persistent positive expression of SARS-CoV-2.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn March 2024, he was hospitalized again due to severe hypoxemia with cough, and had an oxygen saturation at 86\u0026ndash;99% without oxygen inhalation. The CRP was 58.3 mg/L and IL-6 was 275 pg/mL this time, and the SARS-CoV-2 remained positive. His interstitial pneumonia was worse than before, with ground glass shadows in his left lung (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). He was diagnosed with Long COVID: ongoing symptomatic COVID-19 (4\u0026ndash;12 weeks since infection) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].By bronchoscopy, evidence of SARS-CoV-2 infection was detected in his alveolar lavage fluid. He received Molnupiravir, methylprednisolone (160mg daily for 3 days, then 80mg daily for 7 days). But his symptoms of severe hypoxemia (the oxygen saturation at 86\u0026ndash;99% without oxygen inhalation) and cough did not resolve. The patient subsequently received Ruxolitinib (5mg, twice a day) in combination with a gradually reduced dosage of methylprednisolone from March 2024. The CRP was 45.1 mg/L and IL-6 was 58 pg/mL at the beginning of salvage therapy. One month later, the oxygen saturation of the patient is about 91\u0026ndash;93% without oxygen inhalation. After two months of salvage therapy of Ruxolitinib, the oxygen saturation was returned to 95\u0026ndash;97% without methylprednisolone. CT examination showed that his interstitial pneumonia was significantly absorbed (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e CD). His SARS-CoV-2 detection was found to be negative, while the CRP was 10.5 mg/L and IL-6 was 8.2 pg/mL at this time (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). He did not develop any degree of hemocytopenia in the Ruxolitinib salvage therapy also.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAnti-CD19-CAR T cell therapy has been an effective salvage therapy for R/R FL patients. The CR rates by the Lugano criteria were 88% and 46% for patients with FL and histologically transformed invasive lymphoma (tFL), respectively [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, there are some complications after anti-CD19-CAR T cell therapy, such as B lymphocyte deficiency and hypogammaglobulinemia. It had been showed that 29% of patients had low level of IgG 63 days after anti-CD19-CAR T cell therapy[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Immunocompromised caused by B lymphocyte deficiency and hypogammaglobulinemia after anti-CD19-CAR T cell therapy are high risks of severe COVID-19 infection [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Even worse was the persistence of COVID-19 infection in patients who received anti-CD19-CAR T cell therapy, with 2 out of 3 patients persisting for more than 5 months [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In our report, these two patients with refractory FL had persistence of COVID-19 infection when they had B lymphocyte deficiency and hypogammaglobulinemia after their anti-CD19-CAR T cell therapy.\u003c/p\u003e \u003cp\u003eAn Italian study showed that 32% of 143 hospitalized patients continued to have at least one to two symptoms, and 55% had three or more symptoms within 60 days of COVID-19 infection [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The hyperinflammatory response in lungs triggered by COVID-19 viral infection potentially leads to dyspnea. Approximately 15% patients with COVID-19 infection progressed to severe pneumonia, 5% developed acute respiratory distress syndrome (ARDS) or multiple organ failure [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Cytokine storm is characteristic and common manifestation of these severe COVID-19 infection. Plasma levels of pro-inflammatory cytokines were high in patients with severe COVID-19 infection, such as IL-2, IL-6, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF), interferon gamma (IFN-γ) interferon gamma-induced protein 10 (IP-10/CXCL10), and tumor necrosis factor alpha (TNF-α) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]These cytokines cause cytokine storm of COVID-19 mainly through the JAK/STAT signal pathway [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]Thus, inhibition of the JAK pathway might ameliorate the hyperinflammatory state associated with severe COVID-19 infection. Ruxolitinib was a selective inhibitor of JAK1 and JAK2, and has a powerful JAK/STAT signal suppression effect[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In some studies, patients with progressive COVID-19 related ARDS who received Ruxolitinib therapy achieved clinical improvements compared to patients who received standard care[\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Although Ruxolitinib therapy did not increase the rate of grade 3\u0026ndash;4 cytopenias, but the rate of grade 1\u0026ndash;2 anemia and thrombocytopenia was still relatively high [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e][\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In these two patients, interstitial inflammation and persistent hypoxemia relieved 1\u0026ndash;2 months after salvage therapy of Ruxolitinib without any degree of hemocytopenia. This might be related to the relatively small dose of Ruxolitinib therapy.\u003c/p\u003e \u003cp\u003eAlthough corticosteroid was the first method that showed a reduction of 36% mortality among patients with COVID-19 infection [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e][\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], several studies of patients with B lymphocyte deficiency, corticosteroid had no substantial impact on the outcomes, including survival [31,32][\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Ruxolitinib might be a safe and effective alternative salvage therapy for such COVID-19 infection patients with interstitial inflammation and persistent hypoxemia who had no response to corticosteroid therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the Shanghai Genbase Biotechnology Co., Ltd. for providing us with anti-CD19-CAR-T-cells. We thank our patient for her participation in our clinical trials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConcept and design: DQ\u003c/p\u003e\n\u003cp\u003eDrafted or revised the manuscript: ZTT\u003c/p\u003e\n\u003cp\u003eClinical work and acquisition of data: ZTT, CR and WJ\u003c/p\u003e\n\u003cp\u003eAnalysis and interpretation of data: LX and GSQ\u003c/p\u003e\n\u003cp\u003eWriting, review and/or revision of manuscript: DQ\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Medical Ethics Committee of the Department of Hematology, Tianjin First Center Hospital (Tianjin, China). (Approved No. of ethic committee: 2018N105KY).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis Clinical trial was registered at http://www.chictr.org.cn/index.aspx as \u003cem\u003eChiCTR1800019622\u003c/em\u003e\u003cem\u003e(We register our clinical trial at Chinese Clinical Trail Registry on November 21, 2018)\u003c/em\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Sponsored by Tianjin Health Research Project (TJWJ2023ZD003). Chinese Society of Clinical Oncology Beijing Xisike Clinical Oncology Research Foundation (Y-SY2021QN-0184, Y-Young2022-0209, Y-NCJH202201-0027 and Y-2022YMJN/MS-0001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of Informed Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from a legally authorized representative for anonymized patient information to be published in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Conflicting Interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOpen Access:\u0026nbsp;\u003c/strong\u003eThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article\u0026rsquo;s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article\u0026rsquo;s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORCID\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eQi Deng\u0026nbsp;\u003c/em\u003e\u003c/strong\u003ehttps://orcid.org/0000-0002-3646-4953\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWang Q, Berger NA, Xu R (2021) When hematologic malignancies meet COVID-19 in the United States: Infections, death and disparities. Blood Rev 47:100775\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDul\u0026eacute;ry R, Lamure S, Delord M et al (2021) Prolonged in-hospital stay and higher mortality after Covid-19 among patients with non-Hodgkin lymphoma treated with B-cell depleting immunotherapy. Am J Hematol 96:934\u0026ndash;944\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRegalado-Artamendi I, Jim\u0026eacute;nez-Ubieto A, Hern\u0026aacute;ndez-Rivas J et al (2021) Risk Factors and Mortality of COVID-19 in Patients With Lymphoma: A Multicenter Study. Hemasphere 5:e538\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHueso T, Pouderoux C, P\u0026eacute;r\u0026eacute; H et al (2020) Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19. Blood 136:2290\u0026ndash;2295\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFried S, Avigdor A, Bielorai B et al (2019) Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transpl 54:1643\u0026ndash;1650\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNicolaus Kr\u0026ouml;ger 1 JG (2022) Christian Chabannon 3, Ibrahim Yakoub-Agha 4, Hermann Einsele 5. The EBMT/EHA CAR-T Cell Handbook [Internet]. In: Kr\u0026ouml;ger N, Gribben J, Chabannon C et al (eds) The EBMT/EHA CAR-T Cell Handbook. Cham (CH): Springer Copyright 2022, The Editor(s) (if applicable) and The Author(s). This book is an open access publication\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBusca A, Salmanton-Garc\u0026iacute;a J, Corradini P et al (2022) COVID-19 and CAR T cells: a report on current challenges and future directions from the EPICOVIDEHA survey by EHA-IDWP. Blood Adv 6:2427\u0026ndash;2433\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang LL, Yang T (2020) Pulmonary rehabilitation for patients with coronavirus disease 2019 (COVID-19). Chronic Dis Transl Med 6:79\u0026ndash;86\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorimoto A, Nakazawa Y, Ishii E (2016) Hemophagocytic lymphohistiocytosis: Pathogenesis, diagnosis, and management. Pediatr Int 58:817\u0026ndash;825\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVainchenker W, Dusa A, Constantinescu SN (2008) JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol 19:385\u0026ndash;393\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSinger JW, Al-Fayoumi S, Taylor J et al (2019) Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures. PLoS ONE 14:e0222944\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoriano JB, Murthy S, Marshall JC et al (2022) A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis 22:e102\u0026ndash;e107\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCDC (2022) ; Post-COVID conditions: information for healthcare providers\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNierengarten MB (2023) FDA grants accelerated approval of mosunetuzumab for relapsed, refractory follicular lymphoma. Cancer 129:1465\u0026ndash;1466\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirayama AV, Gauthier J, Hay KA et al (2019) High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy. Blood 134:636\u0026ndash;640\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVora SB, Waghmare A, Englund JA et al (2020) Infectious Complications Following CD19 Chimeric Antigen Receptor T-cell Therapy for Children, Adolescents, and Young Adults. Open Forum Infect Dis 7:ofaa121\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJones JM, Faruqi AJ, Sullivan JK et al (2021) COVID-19 Outcomes in Patients Undergoing B Cell Depletion Therapy and Those with Humoral Immunodeficiency States: A Scoping Review. Pathog Immun 6:76\u0026ndash;103\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMushtaq MU, Shahzad M, Chaudhary SG et al (2021) ; Impact of SARS-CoV-2 in Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Recipients. Transplant Cell Ther 27: 796.e791-796.e797\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarf\u0026igrave; A, Bernabei R, Landi F (2020) Persistent Symptoms in Patients After Acute COVID-19. JAMA 324:603\u0026ndash;605\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuan WJ, Ni ZY, Hu Y et al (2020) Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 382:1708\u0026ndash;1720\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang C, Wang Y, Li X et al (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395:497\u0026ndash;506\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu Z, Shi L, Wang Y et al (2020) Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 8:420\u0026ndash;422\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePesu M, Laurence A, Kishore N et al (2008) Therapeutic targeting of Janus kinases. Immunol Rev 223:132\u0026ndash;142\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuint\u0026aacute;s-Cardama A, Vaddi K, Liu P et al (2010) Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 115:3109\u0026ndash;3117\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVannucchi AM, Sordi B, Morettini A et al (2021) Compassionate use of JAK1/2 inhibitor ruxolitinib for severe COVID-19: a prospective observational study. Leukemia 35:1121\u0026ndash;1133\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCapochiani E, Frediani B, Iervasi G et al (2020) Ruxolitinib Rapidly Reduces Acute Respiratory Distress Syndrome in COVID-19 Disease. Analysis of Data Collection From RESPIRE Protocol. Front Med (Lausanne) 7:466\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLa Ros\u0026eacute;e F, Bremer HC, Gehrke I et al (2020) The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation. Leukemia 34:1805\u0026ndash;1815\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCao Y, Wei J, Zou L et al (2020) Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol 146:137\u0026ndash;146e133\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHorby P, Lim WS, Emberson JR et al (2021) Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med 384:693\u0026ndash;704\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHueso T, Godron AS, Lanoy E et al (2022) Convalescent plasma improves overall survival in patients with B-cell lymphoid malignancy and COVID-19: a longitudinal cohort and propensity score analysis. Leukemia 36:1025\u0026ndash;1034\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoeker LE, Eyre TA, Thompson MC et al (2021) COVID-19 in patients with CLL: improved survival outcomes and update on management strategies. Blood 138:1768\u0026ndash;1773\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Ruxolitinib, Post COVID-19 syndrome, Long COVID-19, Follicular lymphoma, Interstitial pneumonia, Hypoxemia","lastPublishedDoi":"10.21203/rs.3.rs-4425881/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4425881/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eImmunocompromised caused by B lymphocyte deficiency and hypogammaglobulinemia after anti-CD19 Chimeric antigen receptor (CAR) T cell therapy for patients with relapsed/refractory (R/R) follicular lymphoma (FL) are high risks of severe COVID-19 infection. In our study, two patients with refractory FL had persistence of COVID-19 infection after their anti-CD19-CAR T cell therapy. They were diagnosed with Post COVID-19 syndrome or Long COVID-19 with interstitial inflammation and persistent hypoxemia. They received Molnupiravir and/or Paxlovid, methylprednisolone therapy when their interleukin (IL)-6 was is at a high level. There was no response in interstitial inflammation, persistent hypoxemia and persistent positive expression of SARS-CoV-2 to the therapy above, but the level of IL-6 was decreased after these therapies. These two patients subsequently received low-dose of Ruxolitinib (5mg, twice a day) as a salvage therapy in combination with a gradually reduced dosage of methylprednisolone. One to two months of Ruxolitinib therapy, the persistent hypoxemia was relieved and the interstitial inflammation was significantly absorbed. At the same time, the SARS-CoV-2 detection was found to be negative. Even if SARS-CoV-2 was positive again, the interstitial pneumonia did not progress again and the symptoms such as dyspnea did not develop again. Ruxolitinib might be a safe and effective alternative salvage therapy for COVID-19 infection patients with interstitial inflammation and persistent hypoxemia who had no response to corticosteroid therapy.\u003c/p\u003e","manuscriptTitle":"Successful salvage therapy of Ruxolitinib on interstitial pneumonia after long COVID or post COVID-19 syndrome with follicular lymphoma: two-case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-13 02:28:00","doi":"10.21203/rs.3.rs-4425881/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"512a3cd0-9646-4501-be57-1be3b3326b19","owner":[],"postedDate":"June 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-18T16:27:40+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-13 02:28:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4425881","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4425881","identity":"rs-4425881","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}