Outcome of Pneumocystis jirovecii pneumonia (PcP) in post-CAR-T patients with hematological malignancies

Outcome of Pneumocystis jirovecii pneumonia (PcP) in post-CAR-T patients with hematological malignancies | 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 Outcome of Pneumocystis jirovecii pneumonia (PcP) in post-CAR-T patients with hematological malignancies Cheng Zu, Wenxiao Li, Mingming Zhang, Yetian Dong, Shan Fu, Jingjing Feng, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4613232/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Oct, 2024 Read the published version in BMC Infectious Diseases → Version 1 posted 4 You are reading this latest preprint version Abstract Background Pneumocystis jirovecii pneumonia (PcP) is an opportunistic infection associated with immunocompromised patients. The development of novel immunotherapies has promoted the incidence of PcP. This study describes the clinical course and outcome of PcP in chimeric antigen receptor (CAR) T cell recipients with hematological malignancies. Methods This is a retrospective case series of CAR-T recipients diagnosed with PcP in our center. The cases were all confirmed by metagenomic next-generation sequencing of clinical samples. The demographic, clinical, and outcome data were retrieved from the patients’ medical charts and electronic medical record system. Results In total, 8 cases of PcP were identified. The underlying malignancies included T-acute lymphoblastic leukemia (ALL) (n = 1), diffuse large B cell lymphoma (DLBCL) (n = 4), and B-ALL (n = 3). One patient received short-term sulfamethoxazole-trimethoprim (SMZ-TMP) while the others had no prophylaxis. Four patients had neutropenia/lymphopenia at the diagnosis of PcP, and two patients had immunosuppressants within one month before PcP manifestation. The median time from CAR-T infusion to PcP diagnosis was 98.5 days (range 52–251). Seven patients recovered from PcP after proper management while one died of septic shock. Conclusion PcP can occur after different CAR-T product, and the long-term depletion of immune cells seems to be related to PcP. SMZ-TMP is effective in this setting. More real-world experience of CAR-T therapy is required to assess the incidence and outcome of PcP in this population. Pneumocystis pneumonia Hematological malignancy Adoptive cell therapy Primary prophylaxis Figures Figure 1 Introduction Pneumocystis jirovecii is an opportunistic pathogen which causes Pneumocystis pneumonia (PcP), a life-threatening infection mostly seen in human immunodeficiency virus (HIV)-infected patients. As novel immunotherapies are now used in a wide spectrum of diseases, non-HIV, immunocompromised population at risk of PcP are increasing because of iatrogenic immunosuppression.[ 1 ] The incidence, course, and outcome of PcP in the setting of rituximab therapy have been widely reported,[ 2 ] while PcP cases in recipients of another immunotherapy with similar mechanism — chimeric antigen receptor (CAR)-T therapy — have been scarce. Despite the unprecedented efficacy in hematological malignancies, CAR-T cells induce profound immune cell depletion resulting in an immunocompromised state, to which the underlying malignancies and prior treatments also contribute.[ 3 ] Herein, we report 8 cases of PcP in leukemia and lymphoma patients who received CAR-T therapy. Methods CAR-T recipeints diagnosed with PcP within follow-up at the our center from November 2020 to September 2022 were included. A diagnosis of PcP was established when all three of the following criteria were met: 1) P. jirovecii DNA detected by metagenomic next-generation sequencing (mNGS); 2) characteristic radiological manifestations in chest computed tomography (CT); 3) clinical symptoms of pneumonia. Neutropenia was defined as a neutrophil count < 1000/mL, while lymphopenia was defined as a lymphocyte count < 500/mL. The clinical data were collected from the electronic medical record system. Results Cohort Characteristics In total, 8 patients were diagnosed with PcP during long-term follow-up. The median age was 60 years-old (range 50-70) at PcP diagnosis. One patient had a history of allogeneic hematopoietic stem cell transplantation. The underlying malignancies included T-acute lymphoblastic leukemia (ALL) (n = 1), diffuse large B cell lymphoma (DLBCL) (n = 4), and B-ALL (n = 3), and in accordance with it, CAR-T cells targeting CD7, CD19, and CD22 were infused, respectively. All patients with leukemia reached complete remission/response (CR), 1 with positive minimal residual disease (MRD) and 3 with negative MRD; while 3 patients with DLBCL achieved CR and 1 partial response (PR). (Table 1) Table 1. Baseline characteristics of patients. Patient No. Gender Age * Primary Disease Previous Cellular Therapy CAR-T Target Source of CAR-T Lymphodepletion Regimen # Best Response Consolidation Therapies between Response and PcP Immunosuppressive Agent(s) within 1 month before PcP Prophylaxis for PcP after CAR-T Infusion Last Neutropenia before PcP Manifestation (days) Last Lymphopenia before PcP Manifestation (days) 1 Male 65 T-ALL allo-HSCT CD7 HSC Donor FC BM: CR, MRD(-) EMD: SD None None None Never 34 2 Female 65 DLBCL None CD19 Autologous FACE CR PD-1 mAb Steroid None 5 72 3 Male 59 DLBCL None CD19 Autologous FACE CR PD-1 mAb None None 88 94 4 Male 70 DLBCL None CD19 Autologous FC CR None None None 0 0 5 Male 40 DLBCL None CD19 Autologous FACE PR PD-1 mAb None SMZ-TMP 3 107 6 Female 61 B-ALL CD19 CAR-T CD22 CAR-T CD19-22 Autologous FC CR, MRD(-) None None None 0 0 7 Female 50 B-ALL CD19 CAR-T CD22 CAR-T CD19+CD22 CAR-T CD19 Autologous FCE CR, MRD(-) None None None 24 0 8 Male 53 B-ALL CD19 CAR-T CD19 Autologous FC CR, MRD(+) Multiple Chemotherapy 1. Cytotoxic Chemotherapy 2. Steroid None 0 0 * Age at CAR-T infusion. # F stands for fludarabine, C stands for cyclophosphamide, A stands for anthracycline, E stands for etoposide. Abbreviations: ALL, acute lymphoid leukemia; DLBCL, diffuse large B cell lymphoma; allo, allogeneic; HSCT, hematopoietic stem cell transplantation; CAR-T, chimeric antigen receptor T cell; HSC, hematopoietic stem cell; BM, bone marrow; CR, complete remission/response; MRD, minimal residual disease; EMD, extramedullary disease; SD, stable disease; PR, partial response; PcP, Pneumocystis jirovecii pneumonia; PD-1, programmed death-1; mAb, monoclonal antibody; SMZ-TMP, sulfamethoxazole-trimethoprim Immunosuppression and Prophylaxis before PcP Two patients received immunosuppressive agents within 1 month before PcP manifestations, including corticosteroids (Patient 2, prednisone 30mg daily; and Patient 8, dexamethasone 10mg daily) and cytotoxic chemotherapies (Patient 8, because of the relapsed primary disease). Other treatments between CAR-T infusion and PcP manifestation which were assumed to be of no significant immunosuppression included sintilimab (Patients 2, 3, and 5 as consolidation for primary disease) and corticosteroids (Patient 4, methylprednisolone 4mg daily). (Figure 1) Figure 1. Brief timelines for each patients. Abbreviations: No., number; SMZ-TMP, sulfamethoxazole-trimethoprim; PD-1, programmed death-1; mAb, monoclonal antibody; PcP, Pneumocystis jirovecii pneumonia. * Patient 4 was not included because of the incompleteness of his follow-up data. Based on the protocols in our center, there has been no routine prophylaxis against P. jirovecii after infusion, while Patient 5 had been taking sulfamethoxazole-trimethoprim (SMZ-TMP) until 20 days after infusion because of suspected PcP during the myelosuppression resulted from previous chemotherapy. Clinical Course and Outcome Brief timelines for each patients are presented in Figure 1. Leukopenia was transient in Patients 1, 2, and 3, while Patients 5, 6, 7, and 8 developed PcP during recurrent or persistent neutropenia and/or lymphopenia. All the cases of pneumonia manifested at least 50 days from CAR-T infusion (52-251 days, median 98.5 days). The clinical presentations and outcome are summarized in Table 2. Most patients presented mild manifestations consisting of fever and nonproductive cough, and recovered rapidly after treatment based on SMZ-TMP. Three patients had comorbid viral and bacterial infections, including 2 with tuberculosis. Fortunately, 7 out of 8 patients recovered from PcP after treatment, while one (Patient 4) died of septic shock resulted from systemic infection. Given the emergency, he was treated at a lower local hospital rather than our center, and detailed disease course was not available. Table 2. PcP-related manifestations, treatments, and outcomes. Patient No. Time from CAR-T Infusion to PcP Manifestation (days) Initial Manifestations Primary Disease Status at PcP diagnosis Decisive Diagnosing Technique PcP Treatment PcP outcome Infectious Co-morbidity (Pathogen/Site) 1 60 1. Fever 2. Cough BM: CR, MRD(-) EMD: SD mNGS of BALF 1. SMZ-TMP 2. Caspofungin 3. Steroid Remission None 2 89 1. Fever 2. Cough CR mNGS of BALF 1. SMZ-TMP 2. Caspofungin 3. Steroid 4. IVIg Remission None 3 115 1. Fever 2. Cough CR mNGS of BALF 1. SMZ-TMP 2. Caspofungin 3. Steroid Remission None 4 251 1. Fever CR mNGS of PB 1. Caspofungin 2. Steroid Death None 5 108 1. Fever 2. Cough PR mNGS of BALF 1. SMZ-TMP 2. Caspofungin Remission 1. Mycobacterium tuberculosis /BALF 2. CMV/Blood & Aqueous humour 6 52 1. Fever 2. Fatigue 3. Dyspnea CR, MRD(-) mNGS of PB 1. SMZ-TMP 2. Caspofungin 3. Steroid Remission 1. CMV/Blood 2. BKV/Blood 7 159 1. Fever 2. Cough 3. Dyspnea CR, MRD(-) mNGS of BALF 1. SMZ-TMP 2. Steroid Remission 1. Stenotrophomonas maltophilia /BALF 2. Mycobacterium tuberculosis /BALF 3. Human Coronavirus NL63/BALF 4. CMV/Blood 5. CNS infection suspected without direct evidence. 8 89 1. Fever 2. Cough Relapsed mNGS of BALF 1. SMZ-TMP 2. Caspofungin 3. Steroid Remission None Abbreviations: CAR-T, chimeric antigen receptor T cell; PcP, Pneumocystis jirovecii pneumonia; BM, bone marrow; CR, complete remission/response; MRD, minimal residual disease; EMD, extramedullary disease; SD, stable disease; PR, partial response; mNGS, metagenomic next-generation sequencing; BALF, bronchoalveolar lavage fluid; PB, peripheral blood; SMZ-TMP, sulfamethoxazole-trimethoprim; IVIg, intravenous immunoglobulin; CMV, cytomegalovirus; BKV, BK polyomavirus; CNS, central nervous system. Representative Case Patient 7 had struggled through multiple infections ever since CAR-T infusion, in concordance with the prolonged and profound lymphopenia and neutropenia. Half a year after CAR-T infusion, she presented at our center with dyspnea, productive cough, and fever. A chest CT suggested severe pneumonia, thus, a bronchoscopy was warranted to get quick and accurate identification of possible pathogens. mNGS of BALF detected various pathogens including P. jiroveci, Stenotrophomonas maltophilia , Mycobacterium tuberculosis , and Human Coronavirus NL63. Meanwhile, cytomegalovirus reactivation was detected in peripheral blood. After the administration of combined drug treatment (meropenem for S. maltophilia , SMZ-TMP + caspofungin for P. jiroveci , ganciclovir for cytomegalovirus, isoniazid + ethambutol for tuberculosis, and linezolid to prevent potential additional infections), complex infection was mostly contained. Unfortunately, her impaired respiratory and immune systems were too vulnerable to resist another attack of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), and eventually died of consequent respiratory failure 1 month post the diagnosis of PcP. Discussion PcP has long been recognized as an acquired immunodeficiency syndrome (AIDS)-defining illness, and one of the most common opportunistic infection in human immunodeficiency virus (HIV)-infected patients.[4] However, different from decades ago, more cases of PcP are currently found in non-HIV patients than in patients with it.[5] Common risk factors of PcP development in patients without HIV include the use of immunosuppressive agents, hematopoietic stem cell or solid organ transplantation, and malignancies or inflammatory conditions (particularly when cytotoxic or immunologic treatments are involved).[5,6] Although the use of CAR-T cells for treating various tumors is increasing, data concerning the incidence, outcome, and disease course of PcP in post-CAR-T setting is scarce. A single-center retrospective cohort study including 280 CD19 CAR-T recipients with B cell lymphoma reported a cumulative incidence of 1.07% (3/280) with prophylaxis in a median follow-up of 259 days; other studies with smaller sample sizes identified cumulative incidences range from 1.67% to 7.32%.[7–9] In this study, we described 8 cases of PcP in differently targeted CAR-T recipients, which shows that this complication is not restricted to CD19 CAR-T. Nonetheless, there is no established guideline or consensus on the prophylaxis in CAR-T recipients, and data currently available are far from enough to conduct evident-based conclusion. Considering the prevalence of P. jirovecii exposure/colonization in vast population,[10,11] the disease should be taken seriously in the real-world application of CAR-T cells. The experiences in hematopoietic stem cell transplantation recipients and rituximab recipients might be helpful. Routine prophylaxis against P. jirovecii is now widely accepted in these two patient populations, while the duration varies greatly from center to center.[12,13] Even with prophylaxis, PcP cases have occasionally occurred right after the cessation, which shows that a defined period might not be optimal for every patient, personalized prophylactic regimen should be tailored. To our knowledge, this is the largest case series describing PcP in post-CAR-T patients, and the first report of PcP in patients receiving CD7 CAR-T. The benefit of bacterial and viral prophylaxis after CAR-T therapy has been recognized by different recommendations,[14,15] while routine PcP prophylaxis is still under debate because of the rarity of the disease and possible severe adverse events, e.g., myelosuppression, induced by prophylactic agents. Although our case series does not establish a conclusion that CAR-T recipients must be given PcP prophylaxis, it does highlight the importance of being vigilant for PcP in such patients. Long-term follow-up of CAR-T recipients in the real-world setting will aid our understanding of immune reconstitution of CAR-T therapy and allow for personalized anti-PcP prophylaxis. Abbreviations ALL acute lymphoid leukemia DLBCL diffuse large B cell lymphoma allo allogeneic HSCT hematopoietic stem cell transplantation CAR-T chimeric antigen receptor T cell HSC hematopoietic stem cell BM bone marrow CR complete remission/response MRD minimal residual disease EMD extramedullary disease SD stable disease PR partial response PcP Pneumocystis jirovecii pneumonia PD-1 programmed death-1 mAb monoclonal antibody SMZ-TMP sulfamethoxazole-trimethoprim Declarations Ethics approval, consent to participate, and consent for publication The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine. Informed consents were obtained from all subjects involved in the study. Availability of data and materials The data presented in this study are available on request from the corresponding authors. The data is not publicly available due to the privacy of the patients. Competing interests All of the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Fundings This work was supported by funding from the National Natural Science Foundation of China (grant No. 81730008, 81770201, He Huang), National Natural Science Foundation of China (grant No. 82270234, Yongxian Hu), and National Natural Science Foundation of China (No. 81800178, Mingming Zhang). Author’s Contributions Study concept and design: Y.H. and H.H.. Data collection: C.Z., W.L., M.Z., Y.D., S.F., J.F., and R.H.. Data interpretation: C.Z., W.L., M.Z., and Y.D.. First draft: C.Z., W.L., M.Z., and Y.D.. Critical revision for important intellectual content: S.F., J.F., and R.H., Y.H., H.H., J.S.. All authors have read and agreed with the submission of the manuscript for publication. Acknowledgements The authors acknowledge the support of Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. References Morris A, Norris KA. Colonization by Pneumocystis jirovecii and its role in disease. Clin Microbiol Rev. 2012;25:297–317. https://doi.org/10.1128/CMR.00013-12 . Alexandre K, Ingen-Housz-Oro S, Versini M, Sailler L, Benhamou Y. Pneumocystis jirovecii pneumonia in patients treated with rituximab for systemic diseases: Report of 11 cases and review of the literature. Eur J Intern Med. 2018;50:e23–4. https://doi.org/10.1016/j.ejim.2017.11.014 . Telli Dizman G, Aguado JM, Fernández-Ruiz M. Risk of infection in patients with hematological malignancies receiving CAR T-cell therapy: systematic review and meta-analysis. Expert Rev Anti Infect Ther. 2022;20:1455–76. https://doi.org/10.1080/14787210.2022.2128762 . Fishman JA. Pneumocystis jiroveci. Semin Respir Crit Care Med. 2020;41:141–57. https://doi.org/10.1055/s-0039-3399559 . Weyant RB, Kabbani D, Doucette K, Lau C, Cervera C. Pneumocystis jirovecii: a review with a focus on prevention and treatment. Expert Opin Pharmacother. 2021;22:1579–92. https://doi.org/10.1080/14656566.2021.1915989 . Kofteridis DP, Valachis A, Velegraki M, Antoniou M, Christofaki M, Vrentzos GE, et al. Predisposing factors, clinical characteristics and outcome of Pneumonocystis jirovecii pneumonia in HIV-negative patients. J Infect Chemother Off J Jpn Soc Chemother. 2014;20:412–6. https://doi.org/10.1016/j.jiac.2014.03.003 . Little JS, Aleissa MM, Beluch K, Gonzalez-Bocco IH, Marty FM, Manne-Goehler J, et al. Low incidence of invasive fungal disease following CD19 chimeric antigen receptor T-cell therapy for non-Hodgkin lymphoma. Blood Adv. 2022;6:4821–30. https://doi.org/10.1182/bloodadvances.2022007474 . Baird JH, Epstein DJ, Tamaresis JS, Ehlinger Z, Spiegel JY, Craig J, et al. Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma. Blood Adv. 2021;5:143–55. https://doi.org/10.1182/bloodadvances.2020002732 . Wudhikarn K, Palomba ML, Pennisi M, Garcia-Recio M, Flynn JR, Devlin SM, et al. Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma. Blood Cancer J. 2020;10:79. https://doi.org/10.1038/s41408-020-00346-7 . Jacobs JL, Libby DM, Winters RA, Gelmont DM, Fried ED, Hartman BJ, et al. A cluster of Pneumocystis carinii pneumonia in adults without predisposing illnesses. N Engl J Med. 1991;324:246–50. https://doi.org/10.1056/NEJM199101243240407 . Pifer LL, Hughes WT, Stagno S, Woods D. Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children. Pediatrics. 1978;61:35–41. Maertens J, Cesaro S, Maschmeyer G, Einsele H, Donnelly JP, Alanio A, et al. ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother. 2016;71:2397–404. https://doi.org/10.1093/jac/dkw157 . Park JW, Curtis JR, Choi SR, Kim MJ, Ha Y-J, Kang EH, et al. Risk-Benefit Analysis of Primary Prophylaxis Against Pneumocystis Jirovecii Pneumonia in Patients With Rheumatic Diseases Receiving Rituximab. Arthritis Rheumatol Hoboken NJ. 2023. https://doi.org/10.1002/art.42541 . Los-Arcos I, Iacoboni G, Aguilar-Guisado M, Alsina-Manrique L, Díaz de Heredia C, Fortuny-Guasch C, et al. Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: a position paper. Infection. 2021;49:215–31. https://doi.org/10.1007/s15010-020-01521-5 . Wudhikarn K, Perales M-A. Infectious complications, immune reconstitution, and infection prophylaxis after CD19 chimeric antigen receptor T-cell therapy. Bone Marrow Transpl. 2022;57:1477–88. https://doi.org/10.1038/s41409-022-01756-w . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 13 Oct, 2024 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 21 Jun, 2024 Editor assigned by journal 20 Jun, 2024 Submission checks completed at journal 20 Jun, 2024 First submitted to journal 20 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-4613232","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":317175335,"identity":"3c97f645-c95d-46ed-8ef3-3f0f9938ae53","order_by":0,"name":"Cheng Zu","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Cheng","middleName":"","lastName":"Zu","suffix":""},{"id":317175336,"identity":"016e8432-a34f-4e7e-9461-db2f9e05c1d6","order_by":1,"name":"Wenxiao Li","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Wenxiao","middleName":"","lastName":"Li","suffix":""},{"id":317175337,"identity":"1da80f82-3d14-4d8e-adcb-97590a0687e7","order_by":2,"name":"Mingming Zhang","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Mingming","middleName":"","lastName":"Zhang","suffix":""},{"id":317175338,"identity":"6fd2c9c0-6f4a-410f-8f1c-8481846407d0","order_by":3,"name":"Yetian Dong","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yetian","middleName":"","lastName":"Dong","suffix":""},{"id":317175339,"identity":"00e106b7-5dc4-4c49-9402-35d64cc9a1d1","order_by":4,"name":"Shan Fu","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shan","middleName":"","lastName":"Fu","suffix":""},{"id":317175340,"identity":"22a068f6-1775-4a0c-a405-1c67ff01be0a","order_by":5,"name":"Jingjing Feng","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jingjing","middleName":"","lastName":"Feng","suffix":""},{"id":317175341,"identity":"ca35feda-f8c8-4cd9-af9a-913c0db8d904","order_by":6,"name":"Ruimin Hong","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ruimin","middleName":"","lastName":"Hong","suffix":""},{"id":317175342,"identity":"3bb62d1f-485c-42cf-86ae-cace6ec9ffb5","order_by":7,"name":"He Huang","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"He","middleName":"","lastName":"Huang","suffix":""},{"id":317175343,"identity":"b4df3994-216e-4ae0-86d1-5ba7ffc501cc","order_by":8,"name":"Yongxian Hu","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yongxian","middleName":"","lastName":"Hu","suffix":""},{"id":317175344,"identity":"e7bd4241-3774-470c-812e-0a2784d915c9","order_by":9,"name":"Junwei Su","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYFCCA0DMA2IwNj6AMBKI19JsQKQWBGCTgNAEtMg3njH+zCNzOM/geHNb5Q+Zwwz87DkGDD934NbC2HDGTJqH53CxwZmDbTckeA4zSPa8MWDsPYNbCzPDGTNmoJbEbTcS224YALUY3MgxYGZsw+N+BpDDQFruP2wrSABqsSekhYfhjIE0xBagsgMgWyQIaJFgOFYmOYcnPXH/mcRmyQaedB6JM88KDvbi0SI/4/DmD297rBNnth9/+PFnj7Ucf3vyxgc/8WhhkDgADLYeKAfIAEfmATwaGBj4G4DEDxjvB26Fo2AUjIJRMHIBAOI/Umi0iLyUAAAAAElFTkSuQmCC","orcid":"","institution":"National Clinical Research Center for Infectious Diseases, Zhejiang University","correspondingAuthor":true,"prefix":"","firstName":"Junwei","middleName":"","lastName":"Su","suffix":""}],"badges":[],"createdAt":"2024-06-20 17:11:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4613232/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4613232/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-024-09893-x","type":"published","date":"2024-10-13T15:57:25+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60610247,"identity":"778731f8-ce62-4d19-8131-75f139672472","added_by":"auto","created_at":"2024-07-18 18:25:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1525245,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBrief timelines for each patients.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: No., number; SMZ-TMP, sulfamethoxazole-trimethoprim; PD-1, programmed death-1; mAb, monoclonal antibody; PcP, \u003cem\u003ePneumocystis jirovecii \u003c/em\u003epneumonia.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003ePatient 4 was not included because of the incompleteness of his follow-up data.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4613232/v1/a8c141f6fbae3cadc8380310.jpg"},{"id":66597133,"identity":"02f7067f-73ae-4cd5-bb10-6fe75ac08854","added_by":"auto","created_at":"2024-10-14 16:07:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2001182,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4613232/v1/6623033b-a076-4f88-9d3f-775256cfc547.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Outcome of Pneumocystis jirovecii pneumonia (PcP) in post-CAR-T patients with hematological malignancies","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e is an opportunistic pathogen which causes \u003cem\u003ePneumocystis\u003c/em\u003e pneumonia (PcP), a life-threatening infection mostly seen in human immunodeficiency virus (HIV)-infected patients. As novel immunotherapies are now used in a wide spectrum of diseases, non-HIV, immunocompromised population at risk of PcP are increasing because of iatrogenic immunosuppression.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] The incidence, course, and outcome of PcP in the setting of rituximab therapy have been widely reported,[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] while PcP cases in recipients of another immunotherapy with similar mechanism \u0026mdash; chimeric antigen receptor (CAR)-T therapy \u0026mdash; have been scarce. Despite the unprecedented efficacy in hematological malignancies, CAR-T cells induce profound immune cell depletion resulting in an immunocompromised state, to which the underlying malignancies and prior treatments also contribute.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eHerein, we report 8 cases of PcP in leukemia and lymphoma patients who received CAR-T therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eCAR-T recipeints diagnosed with PcP within follow-up at the our center from November 2020 to September 2022 were included.\u003c/p\u003e \u003cp\u003eA diagnosis of PcP was established when all three of the following criteria were met: 1) \u003cem\u003eP. jirovecii\u003c/em\u003e DNA detected by metagenomic next-generation sequencing (mNGS); 2) characteristic radiological manifestations in chest computed tomography (CT); 3) clinical symptoms of pneumonia.\u003c/p\u003e \u003cp\u003eNeutropenia was defined as a neutrophil count\u0026thinsp;\u0026lt;\u0026thinsp;1000/mL, while lymphopenia was defined as a lymphocyte count\u0026thinsp;\u0026lt;\u0026thinsp;500/mL.\u003c/p\u003e \u003cp\u003eThe clinical data were collected from the electronic medical record system.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCohort Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn total, 8 patients were diagnosed with PcP during long-term follow-up. The median age was 60 years-old (range 50-70) at PcP diagnosis. One patient had a history of allogeneic hematopoietic stem cell transplantation. The underlying malignancies included T-acute lymphoblastic leukemia (ALL) (n = 1), diffuse large B cell lymphoma (DLBCL) (n = 4), and B-ALL (n = 3), and in accordance with it, CAR-T cells targeting CD7, CD19, and CD22 were infused, respectively. All patients with leukemia reached complete remission/response (CR), 1 with positive minimal residual disease (MRD) and 3 with negative MRD; while 3 patients with DLBCL achieved CR and 1 partial response (PR). (Table 1)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Baseline characteristics of patients.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"1188\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.812973883740522%\"\u003e\n \u003cp\u003ePatient No.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.7910699241786014%\"\u003e\n \u003cp\u003eAge\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003ePrimary Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.772535804549284%\"\u003e\n \u003cp\u003ePrevious\u003cbr\u003e\u0026nbsp;Cellular Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.655433866891323%\"\u003e\n \u003cp\u003eCAR-T\u003cbr\u003e\u0026nbsp;Target\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.981465880370682%\"\u003e\n \u003cp\u003eSource\u003cbr\u003e\u0026nbsp;of CAR-T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0766638584667225%\"\u003e\n \u003cp\u003eLymphodepletion Regimen\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eBest Response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.171861836562764%\"\u003e\n \u003cp\u003eConsolidation Therapies between Response and PcP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eImmunosuppressive Agent(s) within 1 month before PcP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.750631844987363%\"\u003e\n \u003cp\u003eProphylaxis for PcP after CAR-T Infusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.351305812973884%\"\u003e\n \u003cp\u003eLast Neutropenia before PcP\u003cbr\u003e\u0026nbsp;Manifestation (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.856781802864363%\"\u003e\n \u003cp\u003eLast Lymphopenia before PcP\u003cbr\u003e\u0026nbsp;Manifestation (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.812973883740522%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.7910699241786014%\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eT-ALL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.772535804549284%\"\u003e\n \u003cp\u003eallo-HSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.655433866891323%\"\u003e\n \u003cp\u003eCD7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.981465880370682%\"\u003e\n \u003cp\u003eHSC Donor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0766638584667225%\"\u003e\n \u003cp\u003eFC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eBM: CR, MRD(-)\u003cbr\u003e\u0026nbsp;EMD: SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.171861836562764%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.750631844987363%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.351305812973884%\"\u003e\n \u003cp\u003eNever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.856781802864363%\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.812973883740522%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.7910699241786014%\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eDLBCL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.772535804549284%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.655433866891323%\"\u003e\n \u003cp\u003eCD19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.981465880370682%\"\u003e\n \u003cp\u003eAutologous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0766638584667225%\"\u003e\n \u003cp\u003eFACE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.171861836562764%\"\u003e\n \u003cp\u003ePD-1 mAb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eSteroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.750631844987363%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.351305812973884%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.856781802864363%\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.812973883740522%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.7910699241786014%\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eDLBCL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.772535804549284%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.655433866891323%\"\u003e\n \u003cp\u003eCD19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.981465880370682%\"\u003e\n \u003cp\u003eAutologous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0766638584667225%\"\u003e\n \u003cp\u003eFACE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.171861836562764%\"\u003e\n \u003cp\u003ePD-1 mAb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.750631844987363%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.351305812973884%\"\u003e\n \u003cp\u003e88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.856781802864363%\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.812973883740522%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.7910699241786014%\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eDLBCL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.772535804549284%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.655433866891323%\"\u003e\n \u003cp\u003eCD19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.981465880370682%\"\u003e\n \u003cp\u003eAutologous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0766638584667225%\"\u003e\n \u003cp\u003eFC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.171861836562764%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.750631844987363%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.351305812973884%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.856781802864363%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.812973883740522%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.7910699241786014%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eDLBCL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.772535804549284%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.655433866891323%\"\u003e\n \u003cp\u003eCD19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.981465880370682%\"\u003e\n \u003cp\u003eAutologous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0766638584667225%\"\u003e\n \u003cp\u003eFACE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.171861836562764%\"\u003e\n \u003cp\u003ePD-1 mAb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.750631844987363%\"\u003e\n \u003cp\u003eSMZ-TMP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.351305812973884%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.856781802864363%\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.812973883740522%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.7910699241786014%\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eB-ALL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.772535804549284%\"\u003e\n \u003cp\u003eCD19 CAR-T\u003cbr\u003e\u0026nbsp;CD22 CAR-T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.655433866891323%\"\u003e\n \u003cp\u003eCD19-22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.981465880370682%\"\u003e\n \u003cp\u003eAutologous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0766638584667225%\"\u003e\n \u003cp\u003eFC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eCR, MRD(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.171861836562764%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.750631844987363%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.351305812973884%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.856781802864363%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.812973883740522%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.7910699241786014%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eB-ALL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.772535804549284%\"\u003e\n \u003cp\u003eCD19 CAR-T\u003cbr\u003e\u0026nbsp;CD22 CAR-T\u003cbr\u003e\u0026nbsp;CD19+CD22 CAR-T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.655433866891323%\"\u003e\n \u003cp\u003eCD19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.981465880370682%\"\u003e\n \u003cp\u003eAutologous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0766638584667225%\"\u003e\n \u003cp\u003eFCE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eCR, MRD(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.171861836562764%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.750631844987363%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.351305812973884%\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.856781802864363%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.812973883740522%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.7910699241786014%\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.043807919123841%\"\u003e\n \u003cp\u003eB-ALL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.772535804549284%\"\u003e\n \u003cp\u003eCD19 CAR-T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.655433866891323%\"\u003e\n \u003cp\u003eCD19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.981465880370682%\"\u003e\n \u003cp\u003eAutologous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.0766638584667225%\"\u003e\n \u003cp\u003eFC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003eCR, MRD(+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.171861836562764%\"\u003e\n \u003cp\u003eMultiple Chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.845829823083404%\"\u003e\n \u003cp\u003e1. Cytotoxic Chemotherapy\u003cbr\u003e\u0026nbsp;2. Steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.750631844987363%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.351305812973884%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.856781802864363%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003eAge at CAR-T infusion.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e#\u003c/sup\u003eF stands for fludarabine, C stands for cyclophosphamide, A stands for anthracycline, E stands for etoposide.\u003c/p\u003e\n\u003cp\u003eAbbreviations: ALL, acute lymphoid leukemia; DLBCL, diffuse large B cell lymphoma; allo, allogeneic; HSCT, hematopoietic stem cell transplantation; CAR-T, chimeric antigen receptor T cell; HSC, hematopoietic stem cell; BM, bone marrow; CR, complete remission/response; MRD, minimal residual disease; EMD, extramedullary disease; SD, stable disease; PR, partial response; PcP, \u003cem\u003ePneumocystis jirovecii\u0026nbsp;\u003c/em\u003epneumonia; PD-1, programmed death-1; mAb, monoclonal antibody; SMZ-TMP, sulfamethoxazole-trimethoprim\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImmunosuppression and Prophylaxis before PcP\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo patients received immunosuppressive agents within 1 month before PcP manifestations, including corticosteroids (Patient 2, prednisone 30mg daily; and Patient 8, dexamethasone 10mg daily) and cytotoxic chemotherapies (Patient 8, because of the relapsed primary disease). Other treatments between CAR-T infusion and PcP manifestation which were assumed to be of no significant immunosuppression included sintilimab (Patients 2, 3, and 5 as consolidation for primary disease) and corticosteroids (Patient 4, methylprednisolone 4mg daily). (Figure 1)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1. Brief timelines for each patients.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: No., number; SMZ-TMP, sulfamethoxazole-trimethoprim; PD-1, programmed death-1; mAb, monoclonal antibody; PcP, \u003cem\u003ePneumocystis jirovecii\u0026nbsp;\u003c/em\u003epneumonia.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003ePatient 4 was not included because of the incompleteness of his follow-up data.\u003c/p\u003e\n\u003cp\u003eBased on the protocols in our center, there has been no routine prophylaxis against \u003cem\u003eP. jirovecii\u0026nbsp;\u003c/em\u003eafter infusion, while Patient 5 had been taking sulfamethoxazole-trimethoprim (SMZ-TMP) until 20 days after infusion because of suspected PcP during the myelosuppression resulted from previous chemotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Course and Outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBrief timelines for each patients are presented in Figure 1. Leukopenia was transient in Patients 1, 2, and 3, while Patients 5, 6, 7, and 8 developed PcP during recurrent or persistent neutropenia and/or lymphopenia.\u003c/p\u003e\n\u003cp\u003eAll the cases of pneumonia manifested at least 50 days from CAR-T infusion (52-251 days, median 98.5 days). The clinical presentations and outcome are summarized in Table 2. Most patients presented mild manifestations consisting of fever and nonproductive cough, and recovered rapidly after treatment based on SMZ-TMP. Three patients had comorbid viral and bacterial infections, including 2 with tuberculosis. Fortunately, 7 out of 8 patients recovered from PcP after treatment, while one (Patient 4) died of septic shock resulted from systemic infection. Given the emergency, he was treated at a lower local hospital rather than our center, and detailed disease course was not available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. PcP-related manifestations, treatments, and outcomes.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"951\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.779179810725552%\"\u003e\n \u003cp\u003ePatient No.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.826498422712934%\"\u003e\n \u003cp\u003eTime from CAR-T Infusion\u0026nbsp;\u003cbr\u003e\u0026nbsp;to PcP Manifestation (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.56887486855941%\"\u003e\n \u003cp\u003eInitial Manifestations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.513144058885384%\"\u003e\n \u003cp\u003ePrimary Disease Status\u003cbr\u003e\u0026nbsp;at PcP diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.98527865404837%\"\u003e\n \u003cp\u003eDecisive Diagnosing Technique\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003ePcP Treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003ePcP outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.03049421661409%\"\u003e\n \u003cp\u003eInfectious Co-morbidity\u003cbr\u003e\u0026nbsp;(Pathogen/Site)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.779179810725552%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.826498422712934%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.56887486855941%\"\u003e\n \u003cp\u003e1. Fever\u003cbr\u003e\u0026nbsp;2. Cough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.513144058885384%\"\u003e\n \u003cp\u003eBM: CR, MRD(-)\u003cbr\u003e\u0026nbsp;EMD: SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.98527865404837%\"\u003e\n \u003cp\u003emNGS of BALF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003e1. SMZ-TMP\u003cbr\u003e\u0026nbsp;2. Caspofungin\u003cbr\u003e\u0026nbsp;3. Steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.03049421661409%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.779179810725552%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.826498422712934%\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.56887486855941%\"\u003e\n \u003cp\u003e1. Fever\u003cbr\u003e\u0026nbsp;2. Cough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.513144058885384%\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.98527865404837%\"\u003e\n \u003cp\u003emNGS of BALF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003e1. SMZ-TMP\u003cbr\u003e\u0026nbsp;2. Caspofungin\u003cbr\u003e\u0026nbsp;3. Steroid\u003cbr\u003e\u0026nbsp;4. IVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.03049421661409%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.779179810725552%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.826498422712934%\"\u003e\n \u003cp\u003e115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.56887486855941%\"\u003e\n \u003cp\u003e1. Fever\u003cbr\u003e\u0026nbsp;2. Cough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.513144058885384%\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.98527865404837%\"\u003e\n \u003cp\u003emNGS of BALF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003e1. SMZ-TMP\u003cbr\u003e\u0026nbsp;2. Caspofungin\u003cbr\u003e\u0026nbsp;3. Steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.03049421661409%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.779179810725552%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.826498422712934%\"\u003e\n \u003cp\u003e251\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.56887486855941%\"\u003e\n \u003cp\u003e1. Fever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.513144058885384%\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.98527865404837%\"\u003e\n \u003cp\u003emNGS of PB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003e1. Caspofungin\u003cbr\u003e\u0026nbsp;2. Steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.03049421661409%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.779179810725552%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.826498422712934%\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.56887486855941%\"\u003e\n \u003cp\u003e1. Fever\u003cbr\u003e\u0026nbsp;2. Cough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.513144058885384%\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.98527865404837%\"\u003e\n \u003cp\u003emNGS of BALF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003e1. SMZ-TMP\u003cbr\u003e\u0026nbsp;2. Caspofungin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.03049421661409%\"\u003e\n \u003cp\u003e1.\u0026nbsp;\u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e/BALF\u003cbr\u003e\u0026nbsp;2. CMV/Blood \u0026amp; Aqueous humour\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.779179810725552%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.826498422712934%\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.56887486855941%\"\u003e\n \u003cp\u003e1. Fever\u003cbr\u003e\u0026nbsp;2. Fatigue\u003cbr\u003e\u0026nbsp;3. Dyspnea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.513144058885384%\"\u003e\n \u003cp\u003eCR, MRD(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.98527865404837%\"\u003e\n \u003cp\u003emNGS of PB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003e1. SMZ-TMP\u003cbr\u003e\u0026nbsp;2. Caspofungin\u003cbr\u003e\u0026nbsp;3. Steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.03049421661409%\"\u003e\n \u003cp\u003e1. CMV/Blood\u003cbr\u003e\u0026nbsp;2. BKV/Blood\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.779179810725552%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.826498422712934%\"\u003e\n \u003cp\u003e159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.56887486855941%\"\u003e\n \u003cp\u003e1. Fever\u003cbr\u003e\u0026nbsp;2. Cough\u003cbr\u003e\u0026nbsp;3. Dyspnea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.513144058885384%\"\u003e\n \u003cp\u003eCR, MRD(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.98527865404837%\"\u003e\n \u003cp\u003emNGS of BALF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003e1. SMZ-TMP\u003cbr\u003e\u0026nbsp;2. Steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.03049421661409%\"\u003e\n \u003cp\u003e1.\u0026nbsp;\u003cem\u003eStenotrophomonas maltophilia\u003c/em\u003e/BALF\u003cbr\u003e2.\u0026nbsp;\u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e/BALF\u003cbr\u003e\u0026nbsp;3. Human Coronavirus NL63/BALF\u003cbr\u003e\u0026nbsp;4. CMV/Blood\u003cbr\u003e\u0026nbsp;5. CNS infection suspected without direct evidence.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.779179810725552%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.826498422712934%\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.56887486855941%\"\u003e\n \u003cp\u003e1. Fever\u003cbr\u003e\u0026nbsp;2. Cough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.513144058885384%\"\u003e\n \u003cp\u003eRelapsed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.98527865404837%\"\u003e\n \u003cp\u003emNGS of BALF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003e1. SMZ-TMP\u003cbr\u003e\u0026nbsp;2. Caspofungin\u003cbr\u003e\u0026nbsp;3. Steroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.14826498422713%\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.03049421661409%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CAR-T, chimeric antigen receptor T cell; PcP, \u003cem\u003ePneumocystis jirovecii\u0026nbsp;\u003c/em\u003epneumonia; BM, bone marrow; CR, complete remission/response; MRD, minimal residual disease; EMD, extramedullary disease; SD, stable disease; PR, partial response; mNGS, metagenomic next-generation sequencing; BALF, bronchoalveolar lavage fluid; PB, peripheral blood; SMZ-TMP, sulfamethoxazole-trimethoprim; IVIg, intravenous immunoglobulin; CMV, cytomegalovirus; BKV, BK polyomavirus; CNS, central nervous system.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRepresentative Case\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient 7 had struggled through multiple infections ever since CAR-T infusion, in concordance with the prolonged and profound lymphopenia and neutropenia. Half a year after CAR-T infusion, she presented at our center with dyspnea, productive cough, and fever. A chest CT suggested severe pneumonia, thus, a bronchoscopy was warranted to get quick and accurate identification of possible pathogens. mNGS of BALF detected various pathogens including \u003cem\u003eP. jiroveci,\u003c/em\u003e \u003cem\u003eStenotrophomonas maltophilia\u003c/em\u003e, \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e, and Human Coronavirus NL63. Meanwhile, cytomegalovirus reactivation was detected in peripheral blood. After the administration of combined drug treatment (meropenem for \u003cem\u003eS. maltophilia\u003c/em\u003e, SMZ-TMP + caspofungin for \u003cem\u003eP. jiroveci\u003c/em\u003e, ganciclovir for cytomegalovirus, isoniazid + ethambutol for tuberculosis, and linezolid to prevent potential additional infections), complex infection was mostly contained. Unfortunately, her impaired respiratory and immune systems were too vulnerable to resist another attack of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), and eventually died of consequent respiratory failure 1 month post the diagnosis of PcP.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePcP has long been recognized as an acquired immunodeficiency syndrome (AIDS)-defining illness, and one of the most common opportunistic infection in human immunodeficiency virus (HIV)-infected patients.[4]\u0026nbsp;However, different from decades ago, more cases of PcP are currently found in non-HIV patients than in patients with it.[5]\u0026nbsp;Common risk factors of PcP development in patients without HIV include the use of immunosuppressive agents, hematopoietic stem cell or solid organ transplantation, and malignancies or inflammatory conditions (particularly when cytotoxic or immunologic treatments are involved).[5,6]\u0026nbsp;Although the use of CAR-T cells for treating various tumors is increasing, data concerning the incidence, outcome, and disease course of PcP in post-CAR-T setting is scarce. A single-center retrospective cohort study including 280 CD19 CAR-T recipients with B cell lymphoma reported a cumulative incidence of 1.07% (3/280) with prophylaxis in a median follow-up of 259 days; other studies with smaller sample sizes identified cumulative incidences range from 1.67% to 7.32%.[7\u0026ndash;9]\u003c/p\u003e\n\u003cp\u003eIn this study, we described 8 cases of PcP in differently targeted CAR-T recipients, which shows that this complication is not restricted to CD19 CAR-T. Nonetheless, there is no established guideline or consensus on the prophylaxis in CAR-T recipients, and data currently available are far from enough to conduct evident-based conclusion. Considering the prevalence of \u003cem\u003eP. jirovecii\u0026nbsp;\u003c/em\u003eexposure/colonization in vast population,[10,11]\u0026nbsp;the disease should be taken seriously in the real-world application of CAR-T cells. The experiences in hematopoietic stem cell transplantation recipients and rituximab recipients might be helpful. Routine prophylaxis against \u003cem\u003eP. jirovecii\u0026nbsp;\u003c/em\u003eis now widely accepted in these two patient populations, while the duration varies greatly from center to center.[12,13]\u0026nbsp;Even with prophylaxis, PcP cases have occasionally occurred right after the cessation, which shows that a defined period might not be optimal for every patient, personalized prophylactic regimen should be tailored.\u003c/p\u003e\n\u003cp\u003eTo our knowledge,\u0026nbsp;this is the largest case series describing PcP in post-CAR-T patients, and the first report of PcP in patients receiving CD7 CAR-T.\u0026nbsp;The benefit of bacterial and viral prophylaxis after CAR-T therapy has been recognized by different recommendations,[14,15]\u0026nbsp;while routine PcP prophylaxis is still under debate because of the rarity of the disease and possible severe adverse events, e.g., myelosuppression, induced by prophylactic agents. Although our case series does not establish a conclusion that CAR-T recipients must be given PcP prophylaxis, it does highlight the importance of being vigilant for PcP in such patients.\u0026nbsp;Long-term follow-up of CAR-T recipients in the real-world setting will\u0026nbsp;aid our understanding of immune reconstitution of CAR-T therapy and allow for personalized anti-PcP prophylaxis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eacute lymphoid leukemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDLBCL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ediffuse large B cell lymphoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eallo\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eallogeneic\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHSCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehematopoietic stem cell transplantation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCAR-T\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003echimeric antigen receptor T cell\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHSC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehematopoietic stem cell\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebone marrow\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomplete remission/response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eminimal residual disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEMD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eextramedullary disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estable disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epartial response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePcP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e pneumonia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogrammed death-1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emAb\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emonoclonal antibody\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSMZ-TMP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esulfamethoxazole-trimethoprim\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval, consent to participate, and consent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine. Informed consents were obtained from all subjects involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data presented in this study are available on request from the corresponding authors. The data is not publicly available due to the privacy of the patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll of the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFundings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by funding from the\u0026nbsp;National Natural Science Foundation\u0026nbsp;of China\u0026nbsp;(grant No. 81730008, 81770201, He Huang), National Natural Science Foundation of China (grant No. 82270234, Yongxian Hu), and National Natural Science Foundation of China (No. 81800178, Mingming Zhang).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy concept and design: Y.H. and H.H.. Data collection:\u0026nbsp;C.Z., W.L., M.Z.,\u0026nbsp;Y.D., S.F., J.F., and R.H.. Data interpretation: C.Z., W.L., M.Z., and Y.D.. First draft: C.Z., W.L., M.Z., and Y.D.. Critical revision for important intellectual content: S.F., J.F., and R.H., Y.H., H.H., J.S..\u003c/p\u003e\n\u003cp\u003eAll authors have read and agreed with the submission of the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the support of Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMorris A, Norris KA. Colonization by Pneumocystis jirovecii and its role in disease. 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Bone Marrow Transpl. 2022;57:1477\u0026ndash;88. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41409-022-01756-w\u003c/span\u003e\u003cspan address=\"10.1038/s41409-022-01756-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pneumocystis pneumonia, Hematological malignancy, Adoptive cell therapy, Primary prophylaxis","lastPublishedDoi":"10.21203/rs.3.rs-4613232/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4613232/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e pneumonia (PcP) is an opportunistic infection associated with immunocompromised patients. The development of novel immunotherapies has promoted the incidence of PcP. This study describes the clinical course and outcome of PcP in chimeric antigen receptor (CAR) T cell recipients with hematological malignancies.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis is a retrospective case series of CAR-T recipients diagnosed with PcP in our center. The cases were all confirmed by metagenomic next-generation sequencing of clinical samples. The demographic, clinical, and outcome data were retrieved from the patients\u0026rsquo; medical charts and electronic medical record system.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn total, 8 cases of PcP were identified. The underlying malignancies included T-acute lymphoblastic leukemia (ALL) (n\u0026thinsp;=\u0026thinsp;1), diffuse large B cell lymphoma (DLBCL) (n\u0026thinsp;=\u0026thinsp;4), and B-ALL (n\u0026thinsp;=\u0026thinsp;3). One patient received short-term sulfamethoxazole-trimethoprim (SMZ-TMP) while the others had no prophylaxis. Four patients had neutropenia/lymphopenia at the diagnosis of PcP, and two patients had immunosuppressants within one month before PcP manifestation. The median time from CAR-T infusion to PcP diagnosis was 98.5 days (range 52\u0026ndash;251). Seven patients recovered from PcP after proper management while one died of septic shock.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePcP can occur after different CAR-T product, and the long-term depletion of immune cells seems to be related to PcP. SMZ-TMP is effective in this setting. More real-world experience of CAR-T therapy is required to assess the incidence and outcome of PcP in this population.\u003c/p\u003e","manuscriptTitle":"Outcome of Pneumocystis jirovecii pneumonia (PcP) in post-CAR-T patients with hematological malignancies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 18:25:37","doi":"10.21203/rs.3.rs-4613232/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-21T06:53:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-21T01:15:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-21T01:13:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2024-06-20T17:09:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f048a963-bebf-4657-89c2-3fae0d93721c","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-14T16:00:52+00:00","versionOfRecord":{"articleIdentity":"rs-4613232","link":"https://doi.org/10.1186/s12879-024-09893-x","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2024-10-13 15:57:25","publishedOnDateReadable":"October 13th, 2024"},"versionCreatedAt":"2024-07-18 18:25:37","video":"","vorDoi":"10.1186/s12879-024-09893-x","vorDoiUrl":"https://doi.org/10.1186/s12879-024-09893-x","workflowStages":[]},"version":"v1","identity":"rs-4613232","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4613232","identity":"rs-4613232","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}