Characteristics, predictive factors, and prognostic impact of effusion in multiple body cavities after allogeneic hematopoietic stem cell transplantation

Characteristics, predictive factors, and prognostic impact of effusion in multiple body cavities after allogeneic hematopoietic stem cell transplantation | 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 Article Characteristics, predictive factors, and prognostic impact of effusion in multiple body cavities after allogeneic hematopoietic stem cell transplantation Mineo Kurokawa, Yasutaka Masuda, Akira Honda, Takashi Oyama, Yosuke Masamoto This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4323328/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 Fluid retention presenting as effusions in body cavities in sometimes encountered following allogeneic stem cell transplantation (allo-HSCT), however, its spaciotemporal characteristics, predictive factors, and prognostic impact is poorly defined. Here, we comprehensively reviewed pleural (PL), peritoneal (PT), and pericardial (PC) effusions in 178 first allo-HSCT recipients retrospectively. A total of 123 (69.1%) patients developed effusions in either cavity: the PL, PT, and PC effusions were found in 106, 88, and 53 patients for the first time after allo-HSCT with a median of 38.0 (range, 2–2950), 22.5 (range, 2–1324), and 40 (range, 2–945) days. The cumulative incidence at day 100 was 41.0%, 40.4%, and 20.8%, respectively. Out of 92 patients presenting with effusions within day 100, 28 patients presented with effusion in a single cavity, 39 in two cavities, and 25 in all of three cavities. Higher disease risk index was identified as predictive factors for cavity effusion. The 2-year overall survival rate of patients with effusions at no, single, double, and triple cavities within day 100 were 86.1%, 60.0%, 59.6%, and 18.8%, respectively. Our results indicate that rigorous pre- and peri-transplantation management to avoid fluid retention is important to improve transplantation outcomes. Health sciences/Health care/Prognosis Biological sciences/Cancer/Haematological cancer Biological sciences/Stem cells/Haematopoietic stem cells Fluid retention cavity effusion allogeneic hematopoietic stem cell transplantation Figures Figure 1 Figure 2 Figure 3 Introduction The outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved over the last decades 1 – 3 , however, a unique array of complications still puts some patients at risk for potentially life-threatening situations. Thus, comprehensive assessment of the patient’s status and timely management are warranted to improve transplantation outcomes. Fluid retention presenting as effusions in body cavities is sometimes encountered post-allo-HSCT. Few studies have examined cavity effusions in adult patients undergoing allo-HSCT. While the causal link between effusions and prognosis is still obscure, previous studies have suggested that cavity effusions could be surrogates for poor survival 4 – 8 . These studies examined pleural (PL), peritoneal (PT), or pericardial (PC) effusions independently, and few studies have addressed when and where cavity effusions in different locations occur and how much those are related to prognosis. Under the hypothesis that cavity effusions at independent sites may serve as cumulative correlates of fluid overload and may be associated with a worse prognosis depending on the number of effusion sites, we conducted a comprehensive analysis of effusions in three body cavities simultaneously post-allo-HSCT to identify predictive factors for and prognostic impact of effusions. Methods Patients and data collection We conducted a retrospective study of adult patients (aged ≥ 16) who underwent their first allo-HSCT between January 2010 and December 2020 at the University of Tokyo Hospital. Patients who underwent computed tomography (CT) allowing cavity effusions at least once after transplantation were included for analysis. The clinical data were collected from electronic medical records. The study was approved by the Ethics Committee of the University of Tokyo Hospital. CT were conducted primarily to investigate the cause of clinical symptoms, such as fever and organ dysfunction. In these CT images, PL, PT, and PC effusions were evaluated by radiologists at the time of examination. The size of PL effusion was classified into small (≤ 20% of the hemithorax), moderate (20–40%), and large (> 40%) based on the estimation of the anteroposterior quartile 9 . The size of PT effusion was classified into small when confined to the rectovesical pouch and large in other cases 6 . Definitions For malignant hematological diseases, refined disease risk index (DRI) was defined as previously described 10 . For nonmalignant and non-hematological diseases, DRI was defined low. For solid tumors, DRI was not defined. Myeloablative conditioning was defined as regimens that included either total body irradiation > 8 Gy, busulfan > 9 mg/kg, or melphalan > 140 mg/m 2 , and all other regimens were considered reduced intensity conditioning 11 , 12 . The donor group was classified according to the number of mismatched alleles of human leucocyte antigen (HLA) loci (HLA-A, -B, -C, and -DR) for the graft-versus-host direction. The Hematopoietic Cell Transplantation-Comorbidity Index was evaluated based on the criteria by Sorror et al. 13 . Neutrophil engraftment was defined as the first day of three consecutive days with absolute neutrophil count exceeding 0.5 × 10 9 /L. Performance status was evaluated as per Eastern Cooperative Oncology Group Performance Status Scale 14 . Acute GVHD, thrombotic microangiopathy (TMA), and sinusoidal obstruction syndrome (SOS) were diagnosed according to the traditional criteria 15 – 20 . Cytomegalovirus (CMV) viremia was defined as three or more positive cells per two slides (CMV pp65 antigenemia C10/C11) 21 . During the first 100 days post-allo-HSCT (D100) and at the time of effusion recurrence, the number of concurrent cavities with effusion (zero to three) was counted. In a patient who underwent several CT examinations by D100, the maximum number of effusion-positive cavities was used for analysis. For the analysis of cumulative incidence of effusion according to the number of effusion-positive cavities and of the prognosis according to the attenuation of effusions, the date when the number of affected cavities reached the maximum was defined as the date of onset of effusion. Endpoints The primary endpoint was the 2-year overall survival (OS, time from transplantation until death from any cause) rate. Secondary endpoints included 100-day and 2-year cumulative incidence of cavity effusions, the 2-year cumulative incidence of relapse (CIR, the first documented relapse or progression of the disease) rate, the 2-year non-relapse mortality (NRM, death without evidence of relapse or progression of the disease) rate, and the relation between patient characteristics and the onset of cavity effusions. Patients who were alive at the last follow-up or who received a second transplantation were censored. Disease relapse was diagnosed with molecular, morphological, and/or imaging findings. When complete response was not achieved after transplantation in cases with a pre-transplantation disease status of not in remission in malignant disorders, the day of relapse was defined as day + 0.1 from the landmark point (described below). Statistical analysis Mann–Whitney U test was used for continuous variables. The probability of OS was estimated according to the Kaplan-Meier method, and the groups were compared using the log-rank test; Holm-Bonferroni correction was applied for the comparisons among more than two groups. Probabilities of CIR, NRM, and cavity effusions were analyzed by cumulative incidence methods, and the groups were compared using the Gray test 22 . Relapse and NRM were considered competing risks with each other. The competing risk for cavity effusions was death before cavity effusions of interest. The Cox proportional hazard regression model was employed to identify the factors influencing OS, and the Fine-Gray competing risk regression model for CIR, NRM, and cavity effusions. Wald test was employed to assess overall P values for factors with > 2 levels (e.g., number of cavities of effusion). Univariate and multivariate analyses were performed to identify predictive factors for cavity effusions after allo-HSCT. Variables with a P value < 0.1 in the univariate analysis were subjected to the multivariate analysis. The effects of clinical events occurring post-transplantation on clinical outcomes were analyzed among patients who survived without undergoing second HSCT by D100 (landmark point). For the analysis on whether attenuation of effusions affected the prognosis, dynamic landmark method with three landmark points at two weeks, one month, and two months after the onset of cavity effusion(s) occurring by D100 was employed because CT-confirmed attenuation of effusions is a time-dependent variable 23 . Specifically, OS was analyzed among patients who survived and was performed CT at least once, allowing effusion follow-up, without undergoing second HSCT, by three landmark points after the onset of cavity effusion(s). All tests were two-sided, and P < 0.05 was considered statistically significant. Statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) 24 , which is a graphical user interface for R version 4.3-1 (R Foundation for Statistical Computing, Vienna, Austria). Figure presentation was performed either with EZR or with Python software program for Mac (version 3.8.18; https://www.python.org ). Results Patient characteristics During the study period, 191 patients underwent the first allo-HSCT at our institute. 178 patients who underwent CT examination at least once post-allo-HSCT were subjected to further analysis. Table 1 summarizes the baseline characteristics of the studied population. Timing of cavity effusions A total of 123 (69.1%) presented with effusions either in the PL, PT, or PC cavity post-allo-HSCT during the whole observation period. CT examinations were performed with the median of 9 (range, 1–50) times and 5 (range, 1–18) times in patients with and without effusion in at least one cavity, respectively ( P <0.001). To explore the temporal characteristics of cavity effusions post-allo-HSCT, the date of first or recurrent effusion was studied. The PL, PT, and PC effusions were found in 106, 88, and 53 patients for the first time post-allo-HSCT with a median of 38.0 (range, 2–2950), 22.5 (range, 2–1324), and 40 (range, 2–945) days. The cumulative incidence of PL, PT, and PC effusions were 41.0% (95% confidence interval (CI), 33.7–48.1%), 40.4% (95% CI, 33.2–47.6%), and 20.8% (95% CI, 15.2–27.1%) at D100, and 55.0% (95% CI, 47.3–62.1%), 48.1% (95% CI, 40.5–55.3%), and 30.1% (95% CI, 23.4–37.1%) at 2 years post-allo-HSCT, respectively ( Figure 1a-c ). We next focused on cavity effusions detected by D100. A total of 92 (51.7%) out of 178 patients presented with effusions in either cavity. The combinations of effusion-positive cavities are presented in Figure 1d . The PL, PT, and PC were found in 72, 72, and 37 patients, respectively. While 28 (30.4%) out of 92 patients with at least one effusion-positive cavity presented with an effusion in a single cavity, other patients presented with effusions in two or more studied cavities simultaneously or sequentially: 39 (42.4%) patients presented with effusions in two cavities, and 25 (27.2%) in all of three cavities. Out of 92 patients who presented with cavity effusions by D100, 42 (45.7%) patients developed recurrent cavity effusions at the same cavity beyond D100. The day of recurrence clustered around day 200, with a median of 213 (inter-quartile range, 154–379.3). Effusions in other cavities besides the recurrent cavities were observed in a subset of patients, with the number of affected cavities at recurrence totaling one in 18 patients, two in 17, and three in 7. Most of the effusion relapse occurred at PL: a total of 38, 24, and 11 patients presented with PL, PT, and PC effusions, respectively. Conditions associated with cavity effusions Primarily associated conditions at the time of effusions were next investigated. Cavity effusions were associated with varying conditions depending on the time of onset and whether they were recurrent or not ( Table 2 ). While volume overload/heart failure, SOS, and engraftment syndrome were predominantly associated with effusions within the first 100 days, pneumonia was associated with PL effusions both in the acute (14 cases) and chronic (8 cases) phases after allo-HSCT. Of note, no specific causes of effusions were identified in a substantial proportion of patients. As for 42 patients with recurrent effusions beyond D100, 37 were hospitalized for underlying conditions. Eighteen patients were receiving immunosuppressants for active chronic GVHD. A total of 18 cases with PL effusion were associated with pneumonia, although the causal microbes were not detected in all cases. Volume overload or heart failure was scarcely represented in this period. Predictive factors for cavity effusions To identify predictive factors for cavity effusions, various transplant-related variables were subjected to univariate and multivariate analysis. During the whole observation period, high/very high refined DRI was associated with effusions on univariate analysis, regardless of their location ( Supplementary Table 1 ). Except for PC effusion, high/very high refined DRI was associated with effusions also on multivariate analysis. Predictive factors for effusions depending on the number of effusion cavities during the acute phase (≤D100) following allo-HSCT were next investigated. Higher refined DRI was consistently associated both with single and with multiple cavities of effusions on multivariate analysis ( Table 3 ). Prognostic impact of cavity effusions We next examined the transplantation outcome and the prognostic impact of cavity effusions observed in the acute phase following allo-HSCT. The median observation period was 778 (range, 8–5088) days; 430 (range, 11–4839) days, and 1413 (range, 8–5088) days in patients with and without effusion in at least one cavity ( P <0.001). By D100, 5 patients underwent second allo-HSCT, and 18 died, with 155 remaining alive on D100 (landmark point). As a primary endpoint, the 2-year OS rate of the whole studied population was 63.7% (95% CI, 55.7–70.5%). The 2-year CIR and NRM rates were 30.1% (95% CI, 23.4–37.1%) and 19.7% (95% CI, 14.1–26.0%), respectively. On univariate and multivariate analysis to assess the impact of transplantation-related factors on OS, cavity effusions by D100 were associated with significant inferior OS regardless of its locations ( Table 4 ). The presence of effusions was associated with significantly worse OS on univariate analysis. Concomitantly, the 2-year OS rate of patients with PL, PT, and PC effusions were 51.1% (95% CI, 36.0–64.3%), 54.4% (95% CI, 39.2–67.3%), and 23.9% (95% CI, 8.8–43.0%), respectively ( Figure 2a-c ). The impact of the number of effusion-positive cavities on OS showed additive effect; effusions in single, double, and triple cavities were associated with OS with the HR of 2.96 (95% CI, 1.30–6.67; P =0.01), 2.77 (95% CI, 1.30–5.90; P =0.008), and 6.69 (95% CI, 2.77–16.1; P <0.001), respectively on multivariate analysis (overall P <0.001; Table 4 ). The 2-year OS rate of patients with effusions at no, single, double, and triple cavities were 86.1% (95% CI, 76.3–92.1), 60.0% (95% CI, 38.3–76.2), 59.6% (95% CI, 39.0–75.3), and 18.8% (95% CI, 3.1–44.7), respectively (overall P <0.001; Figure 2d ). To investigate the causal relationship between cavity effusions and OS, regression analysis of CIR and NRM was performed, and the causes of death in patients with or without cavity effusions were examined. Neither PL, PT, nor PC effusions were associated with CIR ( Table 4 ). Concomitantly, the number of effusion cavities was not associated with CIR (overall P =0.43; Figure 2E ). In contrast, PL, PT, and PC effusions were significantly associated with NRM on univariate analysis. Although number of effusion cavities were not significantly associated with NRM overall ( P =0.08), effusion in triple cavities was significantly associated with NRM on multivariate analysis ( Figure 2F and Table 4 ). Regarding the causes of death, patients with multiple effusion cavities were more likely to die due to infection than those with none or single effusion cavities (16 out of 41 deaths vs. 3 out of 32 deaths: Table 5 ). Lastly, we examined whether attenuation of cavity effusions affected the prognosis. Patients with cavity effusion(s) occurring by D100 were stratified according to whether the attenuation of effusion was confirmed in all affected cavities by three landmark points: two weeks, one month, or two months after the onset of effusion(s) ( Figure 3 ). The respective number of patients used for analysis were 48, 50, and 46 patients. Regardless of the landmark point, the effect of attenuation on OS was not significant. With landmark of two months, the 2-year OS rate was 46.7% (95% CI, 27.8–63.6%) in 30 patients with attenuation and 36.7% (95% CI, 13.6–60.4%) in 16 patients without attenuation ( P =0.73). Discussion In this study, we comprehensively analyzed CT-detected effusions in body cavities following allo-HSCT. We revealed the predominant occurrence of cavity effusions in the acute phase post-allo-HSCT, presenting with irreversible adverse effects on the transplantation outcome in a manner dependent on the number of effusion cavities. In our retrospective analysis, most effusions occurred in the acute phase following allo-HSCT, with the median cumulative incidence of PL, PT, and PC effusions reaching 41.0%, 40.4%, and 20.8% at D100, respectively. The cumulative incidence of PL effusion was much higher than in the previous study, reporting 9.9% (95% CI, 7.7–12.5%) at one year 4 . The discrepancy would be explained by the definition of PL effusion; in that study, PL effusions were included in the analysis only when symptomatic, while in our study, all PL effusions detected on CT were included. Assessing whether PL effusion is symptomatic or not could be arbitrary, especially in a retrospective study. Therefore, we adopted CT-based judgment on the existence of effusions, in line with several other studies 5 , 6 , 8 , 25 , showing the incidence of PT and PC effusions 27% 6 and 20–26% 5, 8 in adult patients. The unique aspect of our study was that effusions in three cavities were examined in the same cohort simultaneously, enabling the comparative and combinatory assessment of the incidence and outcome of effusions in each cavity. First, the incidence of PL and PT effusions was higher than PC effusion. Second, higher disease risk was associated with the development of PL and PT, but not of PC, in multivariate analysis. Third, although not mutually exclusive and thus denied direct comparison, PC effusions tended to be associated with a worse prognosis than PL or PT effusions, which showed similar prognostic impact. These findings suggest that PL and PT cavities might be more sensitive to fluid and disease burden than PC cavities. This might reflect the distinct pathophysiological basis among different body cavities or simply hat PL and PT effusions could be more easily detected on CT than PC effusion. Another interesting observation is that the number of effusion cavities showed an additive adverse effect on the transplantation outcome. This finding is an important confirmation that fluid retention is associated with worse survival. Rondón et al. reported that fluid overload, defined by weight gain immediately following allo-HSCT, was associated with higher NRM and worse OS 26 . However, the immunological disturbance post-allo-HSCT adds complexity to a mere fluid overload in traditional intensive care unit settings 27 . In the allo-HSCT setting, the complex combinations of fluid overload, endothelial damage, and inflammatory conditions may all contribute to cavity effusions in a single patient. Our findings extend the current knowledge to propose that cavity effusion serves as a qualitative surrogate for these multifactorial conditions and as a quantitative proxy for survival. Notably, attenuation of effusions was not significantly associated with improved OS in our cohort. To overcome wide temporal variations of follow-up CT, we employed dynamic landmark method to show that even temporal presence of effusions was associated with worse prognosis. Similar to our result, a previous study showed no significant difference in OS between patients with or without attenuation of ascites following allo-HSCT 6 . These suggest that effusion-guided post-transplantation management might be a dilatory approach; instead, proactive management to avoid the occurrence of effusion would be necessary. We acknowledge that our study harbors limitations inherent to a retrospective study confined to a single institution. CT was conducted only upon some clinical suspicion of the patient’s status. Therefore, the true incidence and timing of effusions might have been underestimated. Indeed, CT examinations were more often performed in patients with effusion than in those without effusion in shorter period of observation period. Precise documentation of the emergence of cavity effusions with standardized timepoints of assessment would guide the fluid and immunosuppressant management post-allo-HSCT. In conclusion, we showed that fluid retention observed as effusions in body cavities is a frequent complication associated with inferior survival after allo-HSCT. The number of effusion cavities showed an additive adverse effect on the transplantation outcome. A common predictive factor for effusions was identified as a higher disease risk. Given that even the temporal presence of effusions was associated with a worse prognosis, proactive and aggressive management in terms of in-out fluid balance, infection, and immunity to avoid fluid retention is warranted to improve transplantation outcomes. Declarations Competing interest statement: The authors declare no competing financial interests. Acknowledgments: This work was supported by grants from the Japan Society for the Promotion of Science (21H04805) (M.K.). The authors would like to thank the patients and the physicians, nurses, pharmacists, and other co-medical staff for caring for the patients involved in the study. Author Contributions: Y.Masuda. designed the study, collected, analyzed, interpreted data, and drafted the manuscript; A.H. supervised research and wrote the manuscript; T.O. contributed to the data analysis and data interpretation. Y.Masamoto and M.K. critically revised the draft and commented on the manuscript. All authors approved the final paper. Competing interests: The authors declare no competing financial interests. Data Availability Statement: Relevant data is available upon reasonable request to the corresponding author. References Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363(22): 2091–2101. e-pub ahead of print 2010/11/26; doi: 10.1056/NEJMoa1004383 McDonald GB, Sandmaier BM, Mielcarek M, Sorror M, Pergam SA, Cheng GS et al. 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Impact of Fluid Overload as New Toxicity Category on Hematopoietic Stem Cell Transplantation Outcomes. Biol Blood Marrow Transplant 2017; 23(12): 2166–2171. e-pub ahead of print 2017/08/29; doi: 10.1016/j.bbmt.2017.08.021 Claure-Del Granado R, Mehta RL. Fluid overload in the ICU: evaluation and management. BMC Nephrol 2016; 17(1): 109. e-pub ahead of print 2016/08/04; doi: 10.1186/s12882-016-0323-6 Tables Tables 1 to 5 are available in the Supplementary Files section Additional Declarations The authors have declared there is NO conflict of interest to disclose. Supplementary Files SupplementaryTable1.docx Supplementary Table 1. Transplantation variables associated with cavity effusions according to cavity cavities. AML, acute myeloid leukemia; BMT, bone marrow transplantation; CB, cord blood; CBT, cord blood transplantation; CNI, calcineurin inhibitor; DRI, disease risk index; ECOG PS, Eastern Cooperative Oncology Group Performance Status Scale; HCT-CI, Hematopoietic Cell Transplantation-Comorbidity Index; MAC, Myeloablative conditioning; MMRD, HLA-mismatched related donor; MMUD, HLA-mismatched unrelated donor; MRD, HLA-matched related donor; MTX, methotrexate; MUD, HLA-matched unrelated donor; PBSCT, peripheral blood stem cell transplantation; and RIC, reduced intensity conditioning. Table1.docx Table2.docx Table3.docx Table4.docx Table5.docx Cite Share Download PDF Status: Posted Version 1 posted 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. 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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-4323328","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":295836690,"identity":"0d24cc5a-38fc-4095-b321-2eed678dc00a","order_by":0,"name":"Mineo Kurokawa","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYBACCSBmbAAz2RgYPjAw8EDEeYjRwsbGwDiDZC3MeBQigOSM3IcPZ9QclmeQb0uTtm3bJmPOwPzwA4PMHZxapCXSjQ03HDts2MDGdkw6t+02j2UDm7EEA88znFrkJNLYJB+w3Wbcf4y9DazF4ACDGdAvhwlo+XfbvoENqMUSrIX9G14t0iAtG9tuJ4IdxgjWwoPfFsmeZ8yGM/v+JzewpSVb9pwDajnMUyyRgMcvEsfTGB/2fEuzbWA+ZnjjR9lte4Pj7Rs/fOzBHWLIgEUCTDEDcWLPAaK0MH9AsH8Qp2UUjIJRMApGBAAAMU9Otka5oYEAAAAASUVORK5CYII=","orcid":"","institution":"The University of Tokyo","correspondingAuthor":true,"prefix":"","firstName":"Mineo","middleName":"","lastName":"Kurokawa","suffix":""},{"id":295836691,"identity":"e8a4c4cf-5208-4c23-b5dd-bfaf4909d31e","order_by":1,"name":"Yasutaka Masuda","email":"","orcid":"","institution":"The University of Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Yasutaka","middleName":"","lastName":"Masuda","suffix":""},{"id":295836692,"identity":"3d28808d-dbc0-4ec0-9208-08f13e233fc5","order_by":2,"name":"Akira Honda","email":"","orcid":"","institution":"1.\tDepartment of Haematology and Oncology, Graduate School of Medicine, The University of Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Akira","middleName":"","lastName":"Honda","suffix":""},{"id":295836693,"identity":"eba238f9-cc30-49f1-a53c-fd1db5d56226","order_by":3,"name":"Takashi Oyama","email":"","orcid":"https://orcid.org/0000-0002-8553-2975","institution":"The University of Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Oyama","suffix":""},{"id":295836694,"identity":"d5e49b2e-acf6-4948-97d1-b4d57c8370b5","order_by":4,"name":"Yosuke Masamoto","email":"","orcid":"","institution":"The University of Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Yosuke","middleName":"","lastName":"Masamoto","suffix":""}],"badges":[],"createdAt":"2024-04-25 10:05:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4323328/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4323328/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55807780,"identity":"f2eeb96e-e457-436e-9e8a-6b0cd3ba0021","added_by":"auto","created_at":"2024-05-03 15:33:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":20470,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIncidence and locations of cavity effusions following allo-HSCT. \u003c/strong\u003e(a-c) Cumulative incidence of pleural (a), peritoneal (b), and pericardial (c) effusions after allo-HSCT. (d) Combinations of effusion locations that presented within 100 days following allo-HSCT.\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-4323328/v1/2f2f881dfa11a5f6f0b8d692.png"},{"id":55809428,"identity":"7c599321-1639-4f5e-92e5-7c27fcb937b8","added_by":"auto","created_at":"2024-05-03 15:41:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24712,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrognostic impact of cavity effusions following allo-HSCT. \u003c/strong\u003eOverall survival of patients with pleural (a), peritoneal (b), and pericardial (c) effusions within the first 100 days following allo-HSCT. Overall survival (d), cumulative incidence (e), and non-relapse mortality (f) stratified according to the number of effusion cavities within the first 100 days following allo-HSCT.\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-4323328/v1/feca259957c14deb31db0936.png"},{"id":55807785,"identity":"9e89f89f-f2b3-421b-b426-3f23c5381ac0","added_by":"auto","created_at":"2024-05-03 15:33:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":11591,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClinical outcomes according to the attenuation of effusions.\u003c/strong\u003e Overall survival of patients using multiple landmark time points; at two weeks (a), one month (b), and two months (c) from the onset of effusions occurring within the first 100 days.\u003c/p\u003e","description":"","filename":"Slide3.png","url":"https://assets-eu.researchsquare.com/files/rs-4323328/v1/505a48c3cc412179839a65e2.png"},{"id":58047042,"identity":"a510ca6d-deb6-43a6-8a9d-694f3b37a0c5","added_by":"auto","created_at":"2024-06-10 11:48:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":557615,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4323328/v1/60d93d98-4ede-4264-b063-cce647d9dbe3.pdf"},{"id":55807781,"identity":"41d4e963-13b3-4209-9b05-33c66c178f57","added_by":"auto","created_at":"2024-05-03 15:33:09","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34234,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Table 1. Transplantation variables associated with cavity effusions according to cavity cavities. \u003c/strong\u003eAML, acute myeloid leukemia; BMT, bone marrow transplantation\u003cstrong\u003e; \u003c/strong\u003eCB, cord blood; CBT, cord blood transplantation; CNI, calcineurin inhibitor; DRI, disease risk index; ECOG PS, Eastern Cooperative Oncology Group Performance Status Scale; HCT-CI, Hematopoietic Cell Transplantation-Comorbidity Index; MAC, Myeloablative conditioning; MMRD, HLA-mismatched related donor; MMUD, HLA-mismatched unrelated donor; MRD, HLA-matched related donor; MTX, methotrexate; MUD, HLA-matched unrelated donor; PBSCT, peripheral blood stem cell transplantation; and RIC, reduced intensity conditioning.\u003c/p\u003e","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4323328/v1/a1e5ab117c9ab53c8421d451.docx"},{"id":55809430,"identity":"2fe8b441-be13-405b-8cff-bc6c74381938","added_by":"auto","created_at":"2024-05-03 15:41:10","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20419,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4323328/v1/7b0cf9c68a1b9e471699fef2.docx"},{"id":55807783,"identity":"eb9bbada-5fe7-40b8-b581-19336b79b5d2","added_by":"auto","created_at":"2024-05-03 15:33:09","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":18681,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4323328/v1/3387e4e502339b3a62a47921.docx"},{"id":55807788,"identity":"4e2e1e59-cd8c-4aff-9844-c71e05a6bdea","added_by":"auto","created_at":"2024-05-03 15:33:10","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":34001,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4323328/v1/30be05c762ea6fa369ad38ef.docx"},{"id":55807787,"identity":"63dc9e73-acb4-44ee-830c-584f46db8026","added_by":"auto","created_at":"2024-05-03 15:33:10","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":42417,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-4323328/v1/ac79837abecbaccfdb089cfe.docx"},{"id":55807789,"identity":"e7cf6795-74e9-4a22-a0f4-be87b2cbeddb","added_by":"auto","created_at":"2024-05-03 15:33:10","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":16856,"visible":true,"origin":"","legend":"","description":"","filename":"Table5.docx","url":"https://assets-eu.researchsquare.com/files/rs-4323328/v1/c817fe589f8caa90ebf53376.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Characteristics, predictive factors, and prognostic impact of effusion in multiple body cavities after allogeneic hematopoietic stem cell transplantation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved over the last decades \u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, however, a unique array of complications still puts some patients at risk for potentially life-threatening situations. Thus, comprehensive assessment of the patient\u0026rsquo;s status and timely management are warranted to improve transplantation outcomes. Fluid retention presenting as effusions in body cavities is sometimes encountered post-allo-HSCT. Few studies have examined cavity effusions in adult patients undergoing allo-HSCT. While the causal link between effusions and prognosis is still obscure, previous studies have suggested that cavity effusions could be surrogates for poor survival \u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. These studies examined pleural (PL), peritoneal (PT), or pericardial (PC) effusions independently, and few studies have addressed when and where cavity effusions in different locations occur and how much those are related to prognosis. Under the hypothesis that cavity effusions at independent sites may serve as cumulative correlates of fluid overload and may be associated with a worse prognosis depending on the number of effusion sites, we conducted a comprehensive analysis of effusions in three body cavities simultaneously post-allo-HSCT to identify predictive factors for and prognostic impact of effusions.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and data collection\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective study of adult patients (aged\u0026thinsp;\u0026ge;\u0026thinsp;16) who underwent their first allo-HSCT between January 2010 and December 2020 at the University of Tokyo Hospital. Patients who underwent computed tomography (CT) allowing cavity effusions at least once after transplantation were included for analysis. The clinical data were collected from electronic medical records. The study was approved by the Ethics Committee of the University of Tokyo Hospital.\u003c/p\u003e \u003cp\u003eCT were conducted primarily to investigate the cause of clinical symptoms, such as fever and organ dysfunction. In these CT images, PL, PT, and PC effusions were evaluated by radiologists at the time of examination. The size of PL effusion was classified into small (\u0026le;\u0026thinsp;20% of the hemithorax), moderate (20\u0026ndash;40%), and large (\u0026gt;\u0026thinsp;40%) based on the estimation of the anteroposterior quartile \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The size of PT effusion was classified into small when confined to the rectovesical pouch and large in other cases \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions\u003c/h2\u003e \u003cp\u003eFor malignant hematological diseases, refined disease risk index (DRI) was defined as previously described \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. For nonmalignant and non-hematological diseases, DRI was defined low. For solid tumors, DRI was not defined. Myeloablative conditioning was defined as regimens that included either total body irradiation\u0026thinsp;\u0026gt;\u0026thinsp;8 Gy, busulfan\u0026thinsp;\u0026gt;\u0026thinsp;9 mg/kg, or melphalan\u0026thinsp;\u0026gt;\u0026thinsp;140 mg/m\u003csup\u003e2\u003c/sup\u003e, and all other regimens were considered reduced intensity conditioning \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. The donor group was classified according to the number of mismatched alleles of human leucocyte antigen (HLA) loci (HLA-A, -B, -C, and -DR) for the graft-versus-host direction. The Hematopoietic Cell Transplantation-Comorbidity Index was evaluated based on the criteria by Sorror et al. \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Neutrophil engraftment was defined as the first day of three consecutive days with absolute neutrophil count exceeding 0.5 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L. Performance status was evaluated as per Eastern Cooperative Oncology Group Performance Status Scale \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Acute GVHD, thrombotic microangiopathy (TMA), and sinusoidal obstruction syndrome (SOS) were diagnosed according to the traditional criteria \u003csup\u003e\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Cytomegalovirus (CMV) viremia was defined as three or more positive cells per two slides (CMV pp65 antigenemia C10/C11) \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDuring the first 100 days post-allo-HSCT (D100) and at the time of effusion recurrence, the number of concurrent cavities with effusion (zero to three) was counted. In a patient who underwent several CT examinations by D100, the maximum number of effusion-positive cavities was used for analysis. For the analysis of cumulative incidence of effusion according to the number of effusion-positive cavities and of the prognosis according to the attenuation of effusions, the date when the number of affected cavities reached the maximum was defined as the date of onset of effusion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEndpoints\u003c/h2\u003e \u003cp\u003eThe primary endpoint was the 2-year overall survival (OS, time from transplantation until death from any cause) rate. Secondary endpoints included 100-day and 2-year cumulative incidence of cavity effusions, the 2-year cumulative incidence of relapse (CIR, the first documented relapse or progression of the disease) rate, the 2-year non-relapse mortality (NRM, death without evidence of relapse or progression of the disease) rate, and the relation between patient characteristics and the onset of cavity effusions.\u003c/p\u003e \u003cp\u003ePatients who were alive at the last follow-up or who received a second transplantation were censored. Disease relapse was diagnosed with molecular, morphological, and/or imaging findings. When complete response was not achieved after transplantation in cases with a pre-transplantation disease status of not in remission in malignant disorders, the day of relapse was defined as day\u0026thinsp;+\u0026thinsp;0.1 from the landmark point (described below).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eMann\u0026ndash;Whitney U test was used for continuous variables. The probability of OS was estimated according to the Kaplan-Meier method, and the groups were compared using the log-rank test; Holm-Bonferroni correction was applied for the comparisons among more than two groups. Probabilities of CIR, NRM, and cavity effusions were analyzed by cumulative incidence methods, and the groups were compared using the Gray test \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Relapse and NRM were considered competing risks with each other. The competing risk for cavity effusions was death before cavity effusions of interest. The Cox proportional hazard regression model was employed to identify the factors influencing OS, and the Fine-Gray competing risk regression model for CIR, NRM, and cavity effusions. Wald test was employed to assess overall \u003cem\u003eP\u003c/em\u003e values for factors with \u0026gt;\u0026thinsp;2 levels (e.g., number of cavities of effusion). Univariate and multivariate analyses were performed to identify predictive factors for cavity effusions after allo-HSCT. Variables with a \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.1 in the univariate analysis were subjected to the multivariate analysis.\u003c/p\u003e \u003cp\u003eThe effects of clinical events occurring post-transplantation on clinical outcomes were analyzed among patients who survived without undergoing second HSCT by D100 (landmark point). For the analysis on whether attenuation of effusions affected the prognosis, dynamic landmark method with three landmark points at two weeks, one month, and two months after the onset of cavity effusion(s) occurring by D100 was employed because CT-confirmed attenuation of effusions is a time-dependent variable \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Specifically, OS was analyzed among patients who survived and was performed CT at least once, allowing effusion follow-up, without undergoing second HSCT, by three landmark points after the onset of cavity effusion(s).\u003c/p\u003e \u003cp\u003eAll tests were two-sided, and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, which is a graphical user interface for R version 4.3-1 (R Foundation for Statistical Computing, Vienna, Austria). Figure presentation was performed either with EZR or with Python software program for Mac (version 3.8.18; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.python.org\u003c/span\u003e\u003cspan address=\"https://www.python.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the study period, 191 patients underwent the first allo-HSCT at our institute. 178 patients who underwent CT examination at least once post-allo-HSCT were subjected to further analysis. \u003cstrong\u003eTable 1\u003c/strong\u003e summarizes the baseline characteristics of the studied population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTiming of cavity effusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 123 (69.1%) presented with effusions either in the PL, PT, or PC cavity post-allo-HSCT during the whole observation period. CT examinations were performed with the median of 9 (range, 1–50) times and 5 (range, 1–18) times in patients with and without effusion in at least one cavity, respectively (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003eTo explore the temporal characteristics of cavity effusions post-allo-HSCT, the date of first or recurrent effusion was studied. The PL, PT, and PC effusions were found in 106, 88, and 53 patients for the first time post-allo-HSCT with a median of 38.0 (range, 2–2950), 22.5 (range, 2–1324), and 40 (range, 2–945) days. The cumulative incidence of PL, PT, and PC effusions were 41.0% (95% confidence interval (CI), 33.7–48.1%), 40.4% (95% CI, 33.2–47.6%), and 20.8% (95% CI, 15.2–27.1%) at D100, and 55.0% (95% CI, 47.3–62.1%), 48.1% (95% CI, 40.5–55.3%), and 30.1% (95% CI, 23.4–37.1%) at 2 years post-allo-HSCT, respectively (\u003cstrong\u003eFigure 1a-c\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe next focused on cavity effusions detected by D100. A total of 92 (51.7%) out of 178 patients presented with effusions in either cavity. The combinations of effusion-positive cavities are presented in \u003cstrong\u003eFigure 1d\u003c/strong\u003e. The PL, PT, and PC were found in 72, 72, and 37 patients, respectively. While 28 (30.4%) out of 92 patients with at least one effusion-positive cavity presented with an effusion in a single cavity, other patients presented with effusions in two or more studied cavities simultaneously or sequentially: 39 (42.4%) patients presented with effusions in two cavities, and 25 (27.2%) in all of three cavities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOut of 92 patients who presented with cavity effusions by D100, 42 (45.7%) patients developed recurrent cavity effusions at the same cavity beyond D100. The day of recurrence clustered around day 200, with a median of 213 (inter-quartile range, 154–379.3). Effusions in other cavities besides the recurrent cavities were observed in a subset of patients, with the number of affected cavities at recurrence totaling one in 18 patients, two in 17, and three in 7. Most of the effusion relapse occurred at PL: a total of 38, 24, and 11 patients presented with PL, PT, and PC effusions, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConditions associated with cavity effusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimarily associated conditions at the time of effusions were next investigated. Cavity effusions were associated with varying conditions depending on the time of onset and whether they were recurrent or not (\u003cstrong\u003eTable 2\u003c/strong\u003e). While volume overload/heart failure, SOS, and engraftment syndrome were predominantly associated with effusions within the first 100 days, pneumonia was associated with PL effusions both in the acute (14 cases) and chronic (8 cases) phases after allo-HSCT. Of note, no specific causes of effusions were identified in a substantial proportion of patients.\u003c/p\u003e\n\u003cp\u003eAs for 42 patients with recurrent effusions beyond D100, 37 were hospitalized for underlying conditions. Eighteen patients were receiving immunosuppressants for active chronic GVHD. A total of 18 cases with PL effusion were associated with pneumonia, although the causal microbes were not detected in all cases. Volume overload or heart failure was scarcely represented in this period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePredictive factors for cavity effusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo identify predictive factors for cavity effusions, various transplant-related variables were subjected to univariate and multivariate analysis. During the whole observation period, high/very high refined DRI was associated with effusions on univariate analysis, regardless of their location (\u003cstrong\u003eSupplementary\u003c/strong\u003e \u003cstrong\u003eTable 1\u003c/strong\u003e). Except for PC effusion, high/very high refined DRI was associated with effusions also on multivariate analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePredictive factors for effusions depending on the number of effusion cavities during the acute phase (≤D100) following allo-HSCT were next investigated. Higher refined DRI was consistently associated both with single and with multiple cavities of effusions on multivariate analysis (\u003cstrong\u003eTable 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrognostic impact of cavity effusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe next examined the transplantation outcome and the prognostic impact of cavity effusions observed in the acute phase following allo-HSCT. The median observation period was 778 (range, 8–5088) days; 430 (range, 11–4839) days, and 1413 (range, 8–5088) days in patients with and without effusion in at least one cavity (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). By D100, 5 patients underwent second allo-HSCT, and 18 died, with 155 remaining alive on D100 (landmark point). As a primary endpoint, the 2-year OS rate of the whole studied population was 63.7% (95% CI, 55.7–70.5%). The 2-year CIR and NRM rates were 30.1% (95% CI, 23.4–37.1%) and 19.7% (95% CI, 14.1–26.0%), respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn univariate and multivariate analysis to assess the impact of transplantation-related factors on OS, cavity effusions by D100 were associated with significant inferior OS regardless of its locations (\u003cstrong\u003eTable 4\u003c/strong\u003e). The presence of effusions was associated with significantly worse OS on univariate analysis. Concomitantly, the 2-year OS rate of patients with PL, PT, and PC effusions were 51.1% (95% CI, 36.0–64.3%), 54.4% (95% CI, 39.2–67.3%), and 23.9% (95% CI, 8.8–43.0%), respectively (\u003cstrong\u003eFigure 2a-c\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe impact of the number of effusion-positive cavities on OS showed additive effect; effusions in single, double, and triple cavities were associated with OS with the HR of 2.96 (95% CI, 1.30–6.67; \u003cem\u003eP\u003c/em\u003e=0.01), 2.77 (95% CI, 1.30–5.90; \u003cem\u003eP\u003c/em\u003e=0.008), and 6.69 (95% CI, 2.77–16.1; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), respectively on multivariate analysis (overall \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001; \u003cstrong\u003eTable 4\u003c/strong\u003e). The 2-year OS rate of patients with effusions at no, single, double, and triple cavities were 86.1% (95% CI, 76.3–92.1), 60.0% (95% CI, 38.3–76.2), 59.6% (95% CI, 39.0–75.3), and 18.8% (95% CI, 3.1–44.7), respectively (overall \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001; \u003cstrong\u003eFigure 2d\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eTo investigate the causal relationship between cavity effusions and OS, regression analysis of CIR and NRM was performed, and the causes of death in patients with or without cavity effusions were examined. Neither PL, PT, nor PC effusions were associated with CIR (\u003cstrong\u003eTable 4\u003c/strong\u003e). Concomitantly, the number of effusion cavities was not associated with CIR (overall \u003cem\u003eP\u003c/em\u003e=0.43; \u003cstrong\u003eFigure 2E\u003c/strong\u003e). In contrast, PL, PT, and PC effusions were significantly associated with NRM on univariate analysis. Although number of effusion cavities were not significantly associated with NRM overall (\u003cem\u003eP\u003c/em\u003e=0.08), effusion in triple cavities was significantly associated with NRM on multivariate analysis (\u003cstrong\u003eFigure 2F\u003c/strong\u003e and \u003cstrong\u003eTable 4\u003c/strong\u003e). Regarding the causes of death, patients with multiple effusion cavities were more likely to die due to infection than those with none or single effusion cavities (16 out of 41 deaths vs. 3 out of 32 deaths: \u003cstrong\u003eTable 5\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eLastly, we examined whether attenuation of cavity effusions affected the prognosis. Patients with cavity effusion(s) occurring by D100 were stratified according to whether the attenuation of effusion was confirmed in all affected cavities by three landmark points: two weeks, one month, or two months after the onset of effusion(s) (\u003cstrong\u003eFigure 3\u003c/strong\u003e). The respective number of patients used for analysis were 48, 50, and 46 patients. Regardless of the landmark point, the effect of attenuation on OS was not significant. With landmark of two months, the 2-year OS rate was 46.7% (95% CI, 27.8–63.6%) in 30 patients with attenuation and 36.7% (95% CI, 13.6–60.4%) in 16 patients without attenuation (\u003cem\u003eP\u003c/em\u003e=0.73).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we comprehensively analyzed CT-detected effusions in body cavities following allo-HSCT. We revealed the predominant occurrence of cavity effusions in the acute phase post-allo-HSCT, presenting with irreversible adverse effects on the transplantation outcome in a manner dependent on the number of effusion cavities.\u003c/p\u003e \u003cp\u003eIn our retrospective analysis, most effusions occurred in the acute phase following allo-HSCT, with the median cumulative incidence of PL, PT, and PC effusions reaching 41.0%, 40.4%, and 20.8% at D100, respectively. The cumulative incidence of PL effusion was much higher than in the previous study, reporting 9.9% (95% CI, 7.7\u0026ndash;12.5%) at one year \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The discrepancy would be explained by the definition of PL effusion; in that study, PL effusions were included in the analysis only when symptomatic, while in our study, all PL effusions detected on CT were included. Assessing whether PL effusion is symptomatic or not could be arbitrary, especially in a retrospective study. Therefore, we adopted CT-based judgment on the existence of effusions, in line with several other studies \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e, showing the incidence of PT and PC effusions 27% \u003csup\u003e6\u003c/sup\u003e and 20\u0026ndash;26% \u003csup\u003e5, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e in adult patients.\u003c/p\u003e \u003cp\u003eThe unique aspect of our study was that effusions in three cavities were examined in the same cohort simultaneously, enabling the comparative and combinatory assessment of the incidence and outcome of effusions in each cavity. First, the incidence of PL and PT effusions was higher than PC effusion. Second, higher disease risk was associated with the development of PL and PT, but not of PC, in multivariate analysis. Third, although not mutually exclusive and thus denied direct comparison, PC effusions tended to be associated with a worse prognosis than PL or PT effusions, which showed similar prognostic impact. These findings suggest that PL and PT cavities might be more sensitive to fluid and disease burden than PC cavities. This might reflect the distinct pathophysiological basis among different body cavities or simply hat PL and PT effusions could be more easily detected on CT than PC effusion. Another interesting observation is that the number of effusion cavities showed an additive adverse effect on the transplantation outcome. This finding is an important confirmation that fluid retention is associated with worse survival. Rond\u0026oacute;n et al. reported that fluid overload, defined by weight gain immediately following allo-HSCT, was associated with higher NRM and worse OS \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. However, the immunological disturbance post-allo-HSCT adds complexity to a mere fluid overload in traditional intensive care unit settings \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. In the allo-HSCT setting, the complex combinations of fluid overload, endothelial damage, and inflammatory conditions may all contribute to cavity effusions in a single patient. Our findings extend the current knowledge to propose that cavity effusion serves as a qualitative surrogate for these multifactorial conditions and as a quantitative proxy for survival.\u003c/p\u003e \u003cp\u003eNotably, attenuation of effusions was not significantly associated with improved OS in our cohort. To overcome wide temporal variations of follow-up CT, we employed dynamic landmark method to show that even temporal presence of effusions was associated with worse prognosis. Similar to our result, a previous study showed no significant difference in OS between patients with or without attenuation of ascites following allo-HSCT \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. These suggest that effusion-guided post-transplantation management might be a dilatory approach; instead, proactive management to avoid the occurrence of effusion would be necessary.\u003c/p\u003e \u003cp\u003eWe acknowledge that our study harbors limitations inherent to a retrospective study confined to a single institution. CT was conducted only upon some clinical suspicion of the patient\u0026rsquo;s status. Therefore, the true incidence and timing of effusions might have been underestimated. Indeed, CT examinations were more often performed in patients with effusion than in those without effusion in shorter period of observation period. Precise documentation of the emergence of cavity effusions with standardized timepoints of assessment would guide the fluid and immunosuppressant management post-allo-HSCT.\u003c/p\u003e \u003cp\u003eIn conclusion, we showed that fluid retention observed as effusions in body cavities is a frequent complication associated with inferior survival after allo-HSCT. The number of effusion cavities showed an additive adverse effect on the transplantation outcome. A common predictive factor for effusions was identified as a higher disease risk. Given that even the temporal presence of effusions was associated with a worse prognosis, proactive and aggressive management in terms of in-out fluid balance, infection, and immunity to avoid fluid retention is warranted to improve transplantation outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting interest statement:\u0026nbsp;\u003c/strong\u003eThe authors declare no competing financial interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThis work was supported by grants from the Japan Society for the Promotion of Science (21H04805) (M.K.). The authors would like to thank the patients and the physicians, nurses, pharmacists, and other co-medical staff for caring for the patients involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eY.Masuda. designed the study, collected, analyzed, interpreted data, and drafted the manuscript; A.H. supervised research and wrote the manuscript; T.O. contributed to the data analysis and data interpretation. Y.Masamoto and M.K. critically revised the draft and commented on the manuscript. All authors approved the final paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare no competing financial interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eRelevant data is available upon reasonable request to the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M \u003cem\u003eet al.\u003c/em\u003e Reduced mortality after allogeneic hematopoietic-cell transplantation. 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Fluid overload in the ICU: evaluation and management. \u003cem\u003eBMC Nephrol\u003c/em\u003e 2016; 17(1): 109. e-pub ahead of print 2016/08/04; doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12882-016-0323-6\u003c/span\u003e\u003cspan address=\"10.1186/s12882-016-0323-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the Supplementary Files section\u003c/p\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":"Fluid retention, cavity effusion, allogeneic hematopoietic stem cell transplantation","lastPublishedDoi":"10.21203/rs.3.rs-4323328/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4323328/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eFluid retention presenting as effusions in body cavities in sometimes encountered following allogeneic stem cell transplantation (allo-HSCT), however, its spaciotemporal characteristics, predictive factors, and prognostic impact is poorly defined. Here, we comprehensively reviewed pleural (PL), peritoneal (PT), and pericardial (PC) effusions in 178 first allo-HSCT recipients retrospectively. A total of 123 (69.1%) patients developed effusions in either cavity: the PL, PT, and PC effusions were found in 106, 88, and 53 patients for the first time after allo-HSCT with a median of 38.0 (range, 2\u0026ndash;2950), 22.5 (range, 2\u0026ndash;1324), and 40 (range, 2\u0026ndash;945) days. The cumulative incidence at day 100 was 41.0%, 40.4%, and 20.8%, respectively. Out of 92 patients presenting with effusions within day 100, 28 patients presented with effusion in a single cavity, 39 in two cavities, and 25 in all of three cavities. Higher disease risk index was identified as predictive factors for cavity effusion. The 2-year overall survival rate of patients with effusions at no, single, double, and triple cavities within day 100 were 86.1%, 60.0%, 59.6%, and 18.8%, respectively. Our results indicate that rigorous pre- and peri-transplantation management to avoid fluid retention is important to improve transplantation outcomes.\u003c/p\u003e","manuscriptTitle":"Characteristics, predictive factors, and prognostic impact of effusion in multiple body cavities after allogeneic hematopoietic stem cell transplantation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-03 15:33:04","doi":"10.21203/rs.3.rs-4323328/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":"feb8772d-d04e-44d1-a1b7-b7f20f0eddff","owner":[],"postedDate":"May 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":31199964,"name":"Health sciences/Health care/Prognosis"},{"id":31199965,"name":"Biological sciences/Cancer/Haematological cancer"},{"id":31199966,"name":"Biological sciences/Stem cells/Haematopoietic stem cells"}],"tags":[],"updatedAt":"2024-06-10T11:40:29+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-03 15:33:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4323328","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4323328","identity":"rs-4323328","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}