Infectious complications in pediatric patients undergoing CD19+CD22+ chimeric antigen receptor T-cell therapy for relapsed/refractory B-lymphoblastic leukemia

Infectious complications in pediatric patients undergoing CD19+CD22+ chimeric antigen receptor T-cell therapy for relapsed/refractory B-lymphoblastic leukemia | 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 Infectious complications in pediatric patients undergoing CD19+CD22+ chimeric antigen receptor T-cell therapy for relapsed/refractory B-lymphoblastic leukemia Xiaochen Wu, Zhanmeng Cao, Zihan Chen, Yi Wang, Hailong He, Peifang Xiao, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3805105/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Apr, 2024 Read the published version in Clinical and Experimental Medicine → Version 1 posted 7 You are reading this latest preprint version Abstract Chimeric antigen receptor T cell (CAR-T) therapy is effective in the treatment of relapsed/refractory acute B-lymphoblastic leukemia (R/R B-ALL); however, patients who receive CAR-T therapy are predisposed to infections, with considerable detrimental effects on long-term survival rates and the quality of life of patients. This study retrospectively analyzed infectious complications in 79 pediatric patients with R/R B-ALL treated with CAR-T cells at our institution. Overall, 53 patients developed 97 infections. Ten patients experienced 11 infections during lymphodepletion chemotherapy, 34 experienced 46 infections during the early phase (days 0 to + 30 after infusion), and 29 experienced 40 infections during the late phase (day + 31 to + 90 after infusion). Pathogens were identified in 31 infections, including 23 bacteria, seven viruses, and one fungus. Four patients were admitted to the intensive care unit for infection and one died. The following factors were associated with infection: pre-infusion tumor load, intensity of lymphodepleting chemotherapy, lymphocyte count before infusion, duration of neutrophil deficiency and lymphocyte reduction after infusion, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome grades, use of interleukin-6 receptor antagonists and glucocorticoids, intensive care unit admission, and peak value of regulatory T cell proportion within one week after infusion (all P < 0.05). CRS ≥ grade 3 was identified as a risk factor for infection (hazard ratio = 2.41, 95% confidence interval: 1.08–5.36, P = 0.031). Therefore, actively reducing the CRS grade may decrease the risk of infection and improve the long-term quality of life of these patients. Infectious complications CAR-T Children Figures Figure 1 Figure 2 Introduction Adoptive immunotherapy with chimeric antigen receptor T-cells (CAR-Ts) targeting tumor-specific antigens is a novel treatment for relapsed/refractory acute B-lymphoblastic leukemia (R/R B-ALL). High clinical remission rates have been reported, highlighting its broad application prospects and offering new hope to patients with R/R hematological tumors. However, CAR-T therapy is also associated with life-threatening adverse events, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hemocytopenia, and infection [ 1 – 3 ]. With the wide application of CAR-Ts in clinics, the management of infections plays a significant role in improving the long-term quality of life of patients. According to research in adult patients, the incidence of infectious complications is 20–60% and many factors directly or indirectly increase the risk [ 4 – 6 ]. At present, few reports exist on CAR-T treatment-related infections in children. Therefore, addressing the gaps in the current understanding of CAR-T therapy-related complications in the pediatric population is an urgent need. In this study, we describe the infectious complications associated with CAR-T therapy in a cohort of pediatric patients and evaluate the potential risk factors for infection. Patients This retrospective study was conducted at Children's Hospital affiliated to Soochow University (Suzhou, China). Seventy-nine children with R/R B-ALL who underwent targeted CD19 + CD22 + CAR-T therapy for the first time between September 2018 and January 2022 were included. The patients all achieved remission after receiving treatment, and there was no recurrence within three months. Informed consent was obtained from all patients for being included in the study. The study was approved by the Ethics Committee of the Children's Hospital affiliated to Soochow University and was performed in accordance with the principles of the Declaration of Helsinki. Data collection The clinical data of the patients were collected in three periods (lymphodepletion [LD] chemotherapy, early, and late phases), including: (1) general information: sex, age, history of hematopoietic stem cell transplantation; (2) baseline data before infusion: LD chemotherapy, proportion of bone marrow primordial cells, bone marrow minimal residual disease (MRD), dose of CAR-Ts, absolute count of neutrophils and lymphocytes in peripheral blood; (3) post-infusion data: peak value of the regulatory T cell (Treg) proportion (within one week after infusion), duration of neutrophil deficiency and lymphopenia in peripheral blood, CRS grade, ICANS grade, use of interleukin (IL)-6 receptor antagonists and glucocorticoids, and admission to the intensive care unit (ICU); and (4) infection-related data: time, symptoms, prognosis, etiology, and medical imaging of the infection and part of the body infected. Manufacture of CAR-Ts and LD chemotherapy CAR-Ts were prepared by the Department of Hematology at the Shanghai Children's Medical Center(ChiCTR2000032211). The antibody sequence was murine and the costimulatory molecule was 4-1BB (CD137). The CAR-Ts were cultured for 7 days. The day of CAR-T infusion was defined as d0, and the children underwent LD chemotherapy with cyclophosphamide and fludarabine from d -4 to d -2. The LD chemotherapy regimen was divided into two groups. In Group A, the total dose of cyclophosphamide was > 1 g/m 2 and the total dose of fludarabine was > 0.12 g/m 2 . In Group B, the total dose of cyclophosphamide was ≤ 1 g/m 2 and the total dose of fludarabine was ≤ 0.12 g/m 2 . Definitions Evaluation standards for adverse reactions: CRS grading refers to Lee's grading standard [ 7 ], and ICANS classification refers to the American Society for Blood and Marrow Transplantation (ASBMT) Consensus Grading classification standard [ 8 ]. Definition of infection: a diagnosis of infection after CAR-T infusion was made according to the clinical symptoms, molecular biology, microbiology, and medical imaging. Infection can be divided into clinical diagnosis and etiological diagnosis. One or more infections may occur in the same patient. Infection in different parts of the body at the same time was considered an independent event and infection by different pathogens in the same part of the body was considered an independent event. Reinfection was defined as the first infection aggravated or reoccurring in the same part of the body during or after treatment. Bacteremia (including catheter-related): one or more bacterial or fungal pathogens from one or more blood samples; if the bacterial isolate is a common bacterium of the skin (such as diphtheria-like bacilli, non-pathogenic mycobacteria, or coagulase-negative staphylococci) and the patient has clinical symptoms, bacteremia is also regarded as an infection. Respiratory tract infection: symptoms (fever, cough, and expectoration) and/or angiography (chest radiography and chest computed tomography) and/or microbiology (sputum culture, alveolar lavage fluid, and viral nucleic acid). Urinary system infection: symptoms (frequent micturition, urgency, dysuria, and hematuria) and/or laboratory tests (bacteriuria and urine culture). Digestive tract infection: symptoms (diarrhea, abdominal pain, nausea, and vomiting) and/or laboratory tests (routine stool, stool culture, and viral nucleic acids). Infection density: the average number of infections per 100 patient days, calculated as the number of infections in different periods (first 30 days and the later 60 days) after transfusion/total number of people days ×100. Treatment of fever and infection Blood samples were obtained for routine blood tests, C-reactive protein levels, and blood cultures in all patients with fever. Broad-spectrum antibiotics were started empirically and the antibiotics were adjusted according to the pathogen identification results. Patients with fever after CAR-T infusion and clinical consideration of CRS should be re-evaluated 48 hours after fever onset. Antibiotic use should be discontinued in patients with no sign of active infection and negative results on pathogen testing. Antifungal drugs were administered within 90 days of CAR-T therapy to children with previous or current fungal infections. None of the patients received preventive antiviral treatments. Statistical analysis Statistical analysis was performed using SPSS version 24.0 (IBM SPSS Statistics for windows, Armonk, NY) software. Survival analysis was used to evaluate the clinical factors associated with infections. Independent variables included age, sex, history of hematopoietic stem cell transplantation, LD chemotherapy, CAR-T dose, and CRS grade. The Cox proportional hazard model was used to evaluate the independent risk factors of infection: first, the independent variables were screened by univariate analysis, and variables with P < 0.1 in univariate analysis were included in the multivariate model. The Kaplan-Meier curve was used to analyze the correlation between the CRS grade and infection. Results Clinical characteristics of patients A total of 79 children were diagnosed as R/R B-ALL and treated with CAR-Ts. The clinical features of the patient cohort, including 58 boys (73%) and 21 girls (27%) with a median age of 8 (5–11) years, are shown in Table 1. Before CAR-Ts therapy, the median number of bone marrow primordial cells was 6% (range, 3–49%), and the median bone marrow MRD was 9.34×10 -3 leukemia cells (range, 1.0×10 -4 –2.47×10 -1 leukemia cells). A total of 55.7% of the patients (n=44) were neutropenic (absolute neutrophil count [ANC] < 0.5×10 9 /L) and 55.7% (n=44) presented with lymphopenia (absolute lymphocyte count [ALC] <0.3×10 9 /L). Six (7.6%) children had a history of allogeneic hematopoietic stem cell transplantation. All the patients underwent treatment with fludarabine- and cyclophosphamide-based chemotherapy regimens (Group A, n=11; Group B, n=68). The median infusion of CAR-Ts was 6.8×10 6 /kg (range, 5–9.6 /kg). In the early phase after CAR-T infusion, the median duration of ANC < 0.5×10 9 /L and ALC < 0.3×10 9 /L was 13 days (range, 6–31 days) and 6 days (range, 2–11 days), respectively. Thirty-three (41.8%) patients presented with severe CRS (grade ≥3) after CAR-T infusion, while severe ICANS (grade ≥3) occurred in 9 (11.4%) patients. Fifty-one children (64.6%) were treated with IL-6 receptor antagonists, 33 (41.7%) with glucocorticoids, and 29 (36.7%) with steroids or tocilizumab to treat severe CRS and ICANS. Table 1 Clinical characteristics of the patients Total N=79 Age, years (range) 8 (range, 5–11) Sex, male n (%) 58 (73.4) CAR-T dose 6.8 (5–9.6) Bone marrow primordial cells 6 (3–49) Minimal Residual Disease 9.34×10 -3 (1 × 10 -4 –2.47 × 10 -1 ) Prior autologous and / or allogeneic HCT 6 (7.6%) Pre-infusion (range) ALC < 0.3 × 10 9 / L 44 (55.7%) ANC < 0.5 × 10 9 / L 44 (55.7%) Lymphodepleting preparative regimen, n (%) Group A 11 (13.9%) Group B 68 (86.1%) CRS, n (%) Grade < 3 46 (58.2%) Grade ≥ 3 33 (41.8%) ICANS, n (%) Grade < 3 70 (88.6%) Grade ≥ 3 9 (11.4%) Use of glucocorticoid Yes 33 (41.7%) No 46 (58.3%) Use of tocilizumab Yes 51 (64.6%) No 28 (35.4%) CAR-T chimeric antigen receptor T cell ; HCT Hematopoietic stem cell transplantation; ANC Absolute neutrophil count; ALC absolute lymphocyte count; CRS Cytokine release syndrome, ICANS Immune effector cell-associated neurotoxicity syndrome In Group A, the total dose of cyclophosphamide was > 1 g/m 2 , and the total dose of fludarabine was > 0.12 g/m 2 Group B: the total dose of cyclophosphamide ≤1 g/m 2 , the total dose of fludarabine ≤0.12 g/m 2 Infections post CAR-T Therapy The cumulative incidence of the first infection within 90 days of CAR-T infusion is shown in Figure 1. The cumulative incidence of the first infection was 32.9% (95% confidence interval [CI]: 19.5–55.8%) by day 7, 44.3% (95% CI: 32.1–55.8%) by day 30, and 67.1% (95% CI: 58.9–74.0%) by day 90 after CAR-T therapy. The median time to the first infection was 8 days (range, 4–55 days) after infusion, and most infections occurred in the early phase, with an infection density of 1.94. In contrast, infection density was 0.84 in the late phase. Bacterial infections mainly occurred in the early phase (n=20), whereas viral infections were more common in the late phase (n=7) (Table 2). In the LD chemotherapy phase, 10 patients experienced 11 infectious episodes, and no bacterial or viral infections were detected. In the early phase, 46 infections occurred in 35 children, and pathogens were identified in 20 infections, all of which were bacterial. Thirteen children had 14 episodes of bacteremia, of which six were gram-positive bacteria, eight were gram-negative bacteria, and all these children had neutropenia. Four children were admitted to the ICU for treatment because of infection, and one died because of grade 4 CRS complicated by Acinetobacter baumannii infection of the respiratory tract and Staphylococcus aureus bacteremia. In the late phase, 29 children had a total of 40 infectious episodes, and pathogens were detected in 11 cases, including seven viral (herpes virus and human parvovirus detected in plasma by PCR), three bacterial (one gram-positive bacterium and two gram-negative bacteria), and one fungal (urinary tract infection caused by Trichosporon asahii ) infection. Details of the pathogens are presented in Table 3. Table 2 Pathogens of infection * Type of Infection The phase of LD chemotherapy Days 0-30 Post CAR-T (the early phase) Days 31-90 Post CAR-T (the late phase) Total Episodes Patients Affected Total Episodes Patients Affected Total Episodes Patients Affected Bacterial Infections 0 0 20 16 3 3 Viral Infections 0 0 0 0 7 7 Fungal Infections 0 0 0 0 1 1 LD lymphodepletion; CAR-T Chimeric antigen receptor T cell * Pathogens were detected in 31 infections, including 23 bacterial, seven viral, and one fungal infection. Table 3 Microbiological description of infection events Number of patients Phase of LD chemotherapy Early phase Late phase 2 Pseudomonas aeruginosa （blood） Streptococcus pneumoniae （blood）+EBV（blood） 3 Stenotrophomonas maltophilia （urine） 7 Staphylococcus warneri （blood）+ Acinetobacter baumannii （sputum） 8 Staphylococcus （blood） 11 Haemophilus influenzae （blood）+ S. pneumoniae （blood）+ Stenotrophomonas maltophilia （Stool） CMV（blood） 12 Escherichia coli （blood） 13 Staphylococcus aureus （blood） 21 H. influenzae （blood） 30 Staphylococcus capitis （blood） VB19（blood） 35 E. coli （blood） 42 Klebsiella pneumoniae （sputum）+ Staphylococcus epidermidis （blood） CMV（blood） 49 S. pneumoniae （sputum） 56 S. pneumoniae （ blood） 58 E. coli （urine） 59 Staphylococcus hominis （blood） 62 Trichosporon asahii （ Urine） 63 CMV（blood） 64 Salmonella（stool） 76 K. pneumoniae （blood） 77 S. hominis （blood） VB19（blood） 79 VB19（blood） EBV Epstein–Barr Virus; CMV cytomegalovirus; VB19 parvovirus B19 Factors associated with the occurrence of infections Univariate and multivariate Cox regression analyses were performed on the clinical factors of the 79 patients, and the risk factors for CAR-T therapy-related infections were assessed (Table 4). Univariate analysis showed that the proportion of bone marrow primordial cells (pre-infusion), MRD of the bone marrow (pre-infusion), lymphopenia (pre-infusion), lymphocyte count before infusion, duration of neutrophil deficiency and lymphocyte reduction after infusion, CRS and ICANS grades, use of IL-6 receptor antagonists and glucocorticoids, ICU admission, and peak value of the Treg proportion (within one week after infusion) were associated with the presence of infection (P < 0.05). Multivariate analysis showed that CRS ≥3 was an independent risk factor for CAR-T therapy-related infection (hazard ratio = 2.41, 95% CI: 1.08–5.36, P = 0.031) and the infection risk of patients with CRS ≥ 3 after CAR-T infusion increased by 2.41-fold (Figure 2). Table 4 Association of chimeric antigen receptor T cell (CAR-T) therapy variables with time to first infection post CAR-T therapy Variables Univariate Hazard Ratio (95% CI) P-value Multivariate Hazard Ratio (95% CI) P-value General information Sex (F vs. M) 1.41 (0.79–2.51) 0.242 Age 1.06 (0.98–1.14) 0.114 Pre-CAR-T variables Dose of CAR-T cells 0.91 (0.83–1.00) 0.063 0.98 (0.87–1.09) 0.721 Bone marrow primordial cells 1.01 (1.00–1.02) 0.000 1.01 (0.99–1.02) 0.065 MRD 3.91 (1.38–11.07) 0.010 0.59 (0.10–3.25) 0.545 ANC < 0.5 (Yes vs. No） 1.51 (0.86–2.63) 0.147 ALC < 0.3 (Yes vs. No） 1.99 (1.13–3.52) 0.016 1.77 (0.90–3.47) 0.097 History of HCT (Yes vs. No） 1.66 (0.65–4.19) 0.281 LD chemotherapy (Group A vs. Group B） 2.10 (1.05–4.20) 0.035 2.01(0.92–4.38) 0.077 Post-CAR-T variables Duration of ANC < 0.5 1.03 (1.01–1.05) 0.005 0.99 (0.96–1.03) 0.841 Duration of ALC < 0.3 1.03 (1.00–1.06) 0.008 0.99 (0.95–1.02) 0.621 CRS grade （≥ 3 vs. < 3） 3.41 (1.95–5.94) 0.000 2.41 (1.08–5.36) 0.031 ICANS grade （≥ 3 vs. < 3） 2.62 (1.22–5.64) 0.013 1.64 (0.66–4.09) 0.285 Use of IL-6 receptor antagonists (yes vs. no) 1.87 (1.02–3.42) 0.040 1.06 (0.50–2.25) 0.874 Use of glucocorticoids (yes vs. no) 2.07 (1.20–3.57) 0.008 1.05 (0.55–2.00) 0.875 Admission to ICU (yes vs. no) 3.63 (2.07–6.37) 0.000 1.75 (0.77–3.98) 0.179 Peak value of Tregs proportion* 1.02 (1.00–1.05) 0.026 1.00 (0.98–1.03) 0.574 Cox proportional hazards model. M male; F female; CAR-T chimeric antigen receptor T cell; MRD Minimal residual disease; ANC Absolute neutrophil count; ALC Absolute lymphocyte count; CRS Cytokine release syndrome; ICANS Immune effector cell-associated neurotoxicity syndrome; HCT Hematopoietic stem cell transplantation; Tregs regulatory T-cells. * Peak value of regulatory T cell proportion within one week after CAR-T therapy.. Discussion CAR-T therapy can effectively improve the remission and survival rates of patients with R/R B-ALL. However, adverse events, including CRS, ICANS, infections, and hematological toxicity are associated with CAR-T therapy. In recent years, CAR-T therapy-related infections have attracted increasing attention. In some prospective clinical trials and retrospective studies, the incidence of infection was approximately 18–60% [ 9 – 14 ]. Our research suggests that the cumulative infection rate within 90 days after CAR-T transfusion was 67.1%, the early infection density was 1.94, and the late infection density was 0.8, which were similar to recent reports [ 3 , 15 – 17 ]. Neutropenia is an important risk factor for bacterial infection, and early bacterial infection with CAR-T therapy may be related to multiple neutropenic episodes during this period. Neutropenia is more common after CAR-T therapy, which can be caused by many factors (including CRS and LD chemotherapy) [ 14 , 18 – 20 ]. In a clinical study of CAR-T therapy in patients with relapsed/refractory lymphoma, the incidence of neutropenia was 71%, and most of these cases (98%) occurred in the early phase after CAR-T therapy [ 21 ]. Fried et al. [ 19 ] reported that 72% patients (n = 38) with R/R B-ALL had severe neutropenia (grade ≥ 3) and the median occurrence time of neutropenia was by day 17 after the initiation of CAR-T therapy. Our data suggest that 16 children developed infections following CAR-T therapy, with a total of 20 bacterial infections in the early phase. All 16 children developed neutropenia, and seven of these patients had persistent neutropenia (lasting > 20 days). Therefore, antibiotics may be used preventively to reduce the risk of bacterial infections in children with neutropenia. In addition, patients could receive granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) treatment to decrease the duration of neutropenia and thus decrease the risk of bacterial infection, although this approach remains controversial [ 22 – 24 ]. Studies have shown that GM-CSF is associated with the occurrence of CRS and ICANS. The incidence and severity of CRS and ICANS can be reduced by inhibition of GM-CSF after CAR-T treatment; meanwhile, it does not affect the proliferation or antitumor activity of CAR-Ts in vivo [ 23 ]. Conversely, another single-center study on R/R diffuse large B-cell lymphoma (DLBCL) showed that the use of G-CSF in the early phase of reinfusion did not increase the risk of severe CRS and ICANS or interfere with the expansion of CAR-Ts [ 22 ]. None of the children in our center were treated with GM-CSF or G-CSF; the incidence of CRS and ICANS was 90% and 30%, respectively, and the cumulative incidence of infection in the early phase was 47.4%. Some studies including patients treated with G-CSF or GM-CSF have reported a CRS incidence of 72.7–97% and ICANS incidence of 27–65%, with an incidence of infection of 33.3–45% [ 14 , 17 , 24 , 25 ]. The infection rate in patients treated with G-CSF or GM-CSF was significantly reduced. Therefore, the use of G-CSF or GM-CSF at the proper time may help reduce the incidence of infection. However, further research is needed to determine the optimal time and duration of this treatment. Viral infections mostly occur in the late phase after CAR-T infusion, which may be related to B cell aplasia and hypogammaglobulinemia [ 26 ]. The “off-target” effect of CAR-Ts (CAR-Ts not only kill malignant B cells, but also target normal B cells) leads to the failure of B cell regeneration, inducing hypogammaglobulinemia. The incidence of hypogammaglobulinemia varies across treatment centers, with reports indicating an incidence of 20–90% due to differences in research objects, definitions of hypogammaglobulinemia, and methods of immunoglobulin determination [ 10 , 27 – 29 ]. In our study, 53 children had complete humoral immunity data including 27 (50.9%) with late-phase hypogammaglobulinemia. Among the 27 children with hypogammaglobulinemia, 11 developed infections, and the pathogens were identified in four children, of which three were viral infections. The infection density in the late phase was lower than that in the early phase, which may be related to the routine monthly infusion of gamma globulin for patients in our center after CAR-T therapy (until 6 months after treatment), which reduces the incidence of hypogammaglobulinemia. Moreover, lymphocyte and neutrophil counts recovered over time in most cases. In our study, lymphocyte and neutrophil counts recovered in 54 (54/60, 90%) and 48 (48/71, 67.6%) children, respectively, in the late phase. At present, most reports show that respiratory viruses (including influenza virus, parainfluenza virus, metapneumovirus, and respiratory syncytial virus [ 30 ]) are the most common pathogens in the late phase of reinfusion, and only a small number of herpes viruses are observed. The reported incidence of cytomegalovirus (CMV) infection is 1–2%, with viremia constituting most cases, whereas organ damage is rare. However, an increasing number of fatal cases of viral infections have been reported in recent years [ 31 , 32 ]. Respiratory tract infection was the most common in our study; however, the etiological examination of respiratory tract infection has not been checked routinely; CMV and human parvovirus B19 were commonly detected in our data, although patients without clinical symptoms were not treated with antiviral therapy. Fungal infections after CAR-T therapy are rare, with an incidence between 1% and 5% [ 17 , 33 ], which may be related to persistent neutropenia or the long-term use of glucocorticoids. Our center usually administers antifungal treatment to children with fungal infections during CAR-T treatment. Only one case of urinary tract fungal infection ( T. asahii ) was detected and the infection was successfully treated with voriconazole. The child had long-term cytopenia, neutropenia lasting up to 30 days, a history of glucocorticoid use, and persistent application of broad-spectrum antibiotics. These factors increase the risk of fungal infection in children. Therefore, antifungal drugs should be used preventively in children with high-risk factors. Although infections following CAR-T therapy are common, life-threatening infections are rare. Hill et al. performed a retrospective analysis of 133 patients who underwent CD19 CAR-T therapy, and found that 30 children had 43 infectious episodes, but only two led to death [ 33 ]. A report on CAR-T treatment in children and adolescents showed that two of 39 patients died of colibacillosis [ 3 ]. In this study, only one child died of Grade 4 CRS complicated by infection, which was caused by A. baumannii infection in the respiratory tract and Staphylococcus wallichii bacteremia. Following treatment with imipenem, amikacin, and voriconazole, the oxygen saturation and blood pressure could not be maintained at stable levels and the patient died of multiple organ dysfunction syndrome and septic shock. The low mortality rate of CAR-T therapy-related infections is associated with early identification of infection and active anti-infection treatment. Therefore, when children have symptoms of infection, we should promptly identify the infection site, conduct pathogen identification, actively and empirically use broad-spectrum antibiotics, regularly evaluate the severity of infection, and adjust antibiotics according to the pathogen test results. We also analyzed the clinical factors related to infection and found that they were related to pre-infusion tumor load, intensity of LD chemotherapy, lymphocyte count before infusion, duration of neutrophil deficiency and lymphocyte reduction after infusion, CRS and ICANS grades, use of IL-6 receptor antagonists and glucocorticoids, admission to the ICU, and peak value of the Treg proportion (within one week after infusion). High tumor load and intensive lymphocyte clearance usually lead to an increased incidence of severe CRS and ICANS [ 34 , 35 ], and patients with severe CRS have a higher risk of infection [ 3 , 33 ]. CRS is one of the most common adverse reactions after CAR-T therapy and typically occurs 1–14 days after CAR-T infusion for a duration of approximately 1–10 days, with an incidence of 30–100% while the incidence of CRS grade ≥ 3 being approximately 10–30% [ 9 ]. CRS is mainly characterized by fever, hypotension, decreased pulse oxygen, and toxicity of various organs [ 30 ]. CRS is a systemic inflammatory response syndrome caused by excessive activation of immune cells and the production of a large amount of cytokines, which leads to microvascular endothelial damage, increased vascular permeability, capillary leakage syndrome, and disseminated intravascular hemolysis. These manifestations are often difficult to distinguish from sepsis caused by bacterial infection. Some studies have attempted to distinguish between CRS and infection by analyzing cytokines. Park et al. identified the cytokines related to CRS, notably interferon γ (IFN-γ), tumor necrosis factor α, IL-6, IL-10, and IL-15; however, no difference was found between these cytokines and those of patients with infection [ 16 ]. Luo et al. [ 36 ] noted that subtle differences exist between CRS and infection inflammatory indicators; for example, both ferritin and IL-6 levels increase in CRS, whereas only IL-6 levels increase during infection, with ferritin remaining normal. The authors built a prediction model including three cytokines (IL-8, IL-1β, and IFN-γ) to predict severe infection. However, further data are required to corroborate this model and verify its applicability in the clinic. Patients with severe CRS often require admission to the ICU. Indwelling catheters (central venous catheters, urinary catheters, and tracheal catheters) in the ICU increase the risk of infection, and patients often require glucocorticoid and/or IL-6 receptor antagonist treatment, which may inhibit the ability of the patient’s immune system to respond effectively to pathogens [ 26 ]. A single-center study on rheumatoid arthritis showed that the use of IL-6 receptor antagonists was associated with an increase in infection [ 37 ]. However, Frigault et al. noted that IL-6 receptor antagonist use in patients after CAR-T treatment was not associated with the occurrence of infection [ 38 ]. Regarding the association between glucocorticoid use and infection risk, current findings have yielded conflicting results with some studies showing no increased infection risk [ 15 ] and others demonstrating an increased infection risk [ 39 ]. These contradictory results may be due to the selection bias of different studies as different research centers have different standards for the selection of research participants, definition of infection, and use of antibacterial drugs. In summary, owing to the comprehensive effects of many factors, severe CRS increases the risk of infection in patients. Interestingly, we also found that Tregs were related to infections after CAR-T therapy, and the risk of infection increased with an increase in the peak value of the Treg proportion. Tregs are a subset of T cells with strong negative immunoregulatory functions that actively inhibit the activation, amplification, and function of other immune cells, thus regulating the intensity and duration of the immune response and maintaining immune homeostasis in vivo [ 40 – 42 ]. Sustained high expression of Tregs inhibit the activation and expansion of tumor antigen-specific effector T cells, affecting the curative effect of CAR-Ts, further aggravating the immune deficiency of patients, and increasing the risk of infection. Therefore, inhibiting the activation of Tregs, when necessary, may promote the tumor-killing effect of CAR-Ts and reduce the risk of infection. We intend to explore this intriguing aspect in our future clinical work. After the remission of CAR-T therapy in our center, most children underwent hematopoietic stem cell transplantation within approximately 90 days, and long-term infection after CAR-T transfusion could not be tracked. Further research is required to generate robust data on etiology and immunology to address this limitation. The incidence, pathogens, and severity of infection after CAR-T therapy are affected by many factors. Therefore, integrating the experience of CAR-T therapy for various hematological diseases is important to better understand related infectious complications and formulate the optimal infection management strategy to improve the safety and effectiveness of CAR-T therapy for children with R/R B-ALL. Declarations Acknowledgements XCW thanks the staff and faculty of the department of hematology at Children's Hospital of Soochow University for tireless work caring for the patients involved in this study, especially appreciating Jinran Li and Qi Ji for their assistance during this study. Funding Design of the study and collection, analysis and interpretation of data by fund from Medical Research Project of Jiangsu Provincial Health and Family Planning Commission (Key Project ZD2021006), National Natural Science Foundation of China (Nos. 81770193, 82100229, and 81970163), Jiangsu Project (No. BE2021654), Suzhou Enterprise Technology Innovation's project, Suzhou Key Laboratory of Childhood Leukemia (SZS201615). Author contributions XCW, ZMC and ZHC analyzed data and wrote the manuscript. YW, HLH and PFX reviewed that data and edited the manuscript. SYH, BSL and JL guided the study, proposed the study protocol, supervised its implementation, and provided funding. All authors approved the final manuscript prior to submission. Ethical approval All procedures performed in studies involving human participants were approved by the Ethics Committee of Children's Hospital affiliated to Suzhou University, which is in line with the guidelines of Helsinki Declaration. Informed consent Informed consent was obtained from all individual participants included in the study. Conflict of interest The authors declare no conflicts of interest. References Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. Apr 6 2021;11(4):69. doi: 10.1038/s41408-021-00459-7 Holstein SA, Lunning MA. CAR T-Cell Therapy in Hematologic Malignancies: A Voyage in Progress. Clin Pharmacol Ther. Jan 2020;107(1):112–122. doi: 10.1002/cpt.1674 Maron GM, Hijano DR, Epperly R, et al. Infectious Complications in Pediatric, Adolescent and Young Adult Patients Undergoing CD19-CAR T Cell Therapy. Front Oncol. 2022;12:845540. doi: 10.3389/fonc.2022.845540 Bupha-Intr O, Haeusler G, Chee L, Thursky K, Slavin M, Teh B. CAR-T cell therapy and infection: a review. Expert Rev Anti Infect Ther. Jun 2021;19(6):749–758. doi: 10.1080/14787210.2021.1855143 Telli Dizman G, Aguado JM, Fernández-Ruiz M. 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Effect of early granulocyte-colony-stimulating factor administration in the prevention of febrile neutropenia and impact on toxicity and efficacy of anti-CD19 CAR-T in patients with relapsed/refractory B-cell lymphoma. Bone Marrow Transplant. Mar 2022;57(3):431–439. doi: 10.1038/s41409-021-01526-0 Strati P, Varma A, Adkins S, et al. Hematopoietic recovery and immune reconstitution after axicabtagene ciloleucel in patients with large B-cell lymphoma. Haematologica. Oct 1 2021;106(10):2667–2672. doi: 10.3324/haematol.2020.254045 Wudhikarn K, Perales MA. Infectious complications, immune reconstitution, and infection prophylaxis after CD19 chimeric antigen receptor T-cell therapy. Bone Marrow Transplant. Oct 2022;57(10):1477–1488. doi: 10.1038/s41409-022-01756-w Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. Feb 1 2018;378(5):439–448. doi: 10.1056/NEJMoa1709866 Kampouri E, Walti CS, Gauthier J, Hill JA. Managing hypogammaglobulinemia in patients treated with CAR-T-cell therapy: key points for clinicians. Expert Rev Hematol. Apr 2022;15(4):305–320. doi: 10.1080/17474086.2022.2063833 Doan A, Pulsipher MA. Hypogammaglobulinemia due to CAR T-cell therapy. Pediatr Blood Cancer. Apr 2018;65(4)doi: 10.1002/pbc.26914 Los-Arcos I, Iacoboni G, Aguilar-Guisado M, 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. Apr 2021;49(2):215–231. doi: 10.1007/s15010-020-01521-5 Korell F, Schubert ML, Sauer T, et al. Infection Complications after Lymphodepletion and Dosing of Chimeric Antigen Receptor T (CAR-T) Cell Therapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia or B Cell Non-Hodgkin Lymphoma. Cancers (Basel). Apr 2 2021;13(7)doi: 10.3390/cancers13071684 Wang D, Mao X, Que Y, et al. Viral infection/reactivation during long-term follow-up in multiple myeloma patients with anti-BCMA CAR therapy. Blood Cancer J. Oct 18 2021;11(10):168. doi: 10.1038/s41408-021-00563-8 Hill JA, Li D, Hay KA, et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. Jan 4 2018;131(1):121–130. doi: 10.1182/blood-2017-07-793760 Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management. Blood Rev. Mar 2019;34:45–55. doi: 10.1016/j.blre.2018.11.002 Wang Y, Wang T, Yang J. Research progress on pretreatment scheme of chimeric antigen receptor T cell immunotherapy(in Chinese). International journal of blood transfusion and hematology.2020;43(1):77–81. doi: 10.3760/cma.j.issn.1673-419X.2020.01.014 Luo H, Wang N, Huang L, et al. Inflammatory signatures for quick diagnosis of life-threatening infection during the CAR T-cell therapy. J Immunother Cancer. Oct 22 2019;7(1):271. doi: 10.1186/s40425-019-0767-x Schiff MH, Kremer JM, Jahreis A, Vernon E, Isaacs JD, van Vollenhoven RF. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011;13(5):R141. doi: 10.1186/ar3455 Frigault MJ, Nikiforow S, Mansour MK, et al. Tocilizumab not associated with increased infection risk after CAR T-cell therapy: implications for COVID-19? Blood. Jul 2 2020;136(1):137–139. doi: 10.1182/blood.2020006216 Strati P, Ahmed S, Furqan F, et al. Prognostic impact of corticosteroids on efficacy of chimeric antigen receptor T-cell therapy in large B-cell lymphoma. Blood. Jun 10 2021;137(23):3272–3276. doi: 10.1182/blood.2020008865 Rana J, Biswas M. Regulatory T cell therapy: Current and future design perspectives. Cell Immunol. Oct 2020;356:104193. doi: 10.1016/j.cellimm.2020.104193 Perry JA, Shallberg L, Clark JT, et al. PD-L1-PD-1 interactions limit effector regulatory T cell populations at homeostasis and during infection. Nat Immunol. May 2022;23(5):743–756. doi: 10.1038/s41590-022-01170-w Qu G, Chen J, Li Y, Yuan Y, Liang R, Li B. Current status and perspectives of regulatory T cell-based therapy. J Genet Genomics. Jul 2022;49(7):599–611. doi: 10.1016/j.jgg.2022.05.005 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 25 Apr, 2024 Read the published version in Clinical and Experimental Medicine → Version 1 posted Editorial decision: Revision requested 21 Feb, 2024 Reviews received at journal 22 Jan, 2024 Reviewers agreed at journal 22 Jan, 2024 Reviewers invited by journal 18 Jan, 2024 Editor assigned by journal 26 Dec, 2023 Submission checks completed at journal 26 Dec, 2023 First submitted to journal 25 Dec, 2023 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. We do this by developing innovative software and high quality services for the global research community. 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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-3805105","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":263465421,"identity":"d736d963-242c-4a58-83a6-5f76298968ff","order_by":0,"name":"Xiaochen Wu","email":"","orcid":"","institution":"Children's Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Xiaochen","middleName":"","lastName":"Wu","suffix":""},{"id":263465423,"identity":"0c7b14fb-6a81-4a47-84ea-65cd4574f723","order_by":1,"name":"Zhanmeng Cao","email":"","orcid":"","institution":"Children's Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Zhanmeng","middleName":"","lastName":"Cao","suffix":""},{"id":263465425,"identity":"af98ebed-1214-4f4c-b6fd-a343434b6404","order_by":2,"name":"Zihan Chen","email":"","orcid":"","institution":"Children's Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Zihan","middleName":"","lastName":"Chen","suffix":""},{"id":263465427,"identity":"1696a92f-e2dd-42f8-b7af-bff6e0a4e7d0","order_by":3,"name":"Yi Wang","email":"","orcid":"","institution":"Children's Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Wang","suffix":""},{"id":263465428,"identity":"4e35548d-766c-4417-82db-1ad0302ef7ec","order_by":4,"name":"Hailong He","email":"","orcid":"","institution":"Children's Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Hailong","middleName":"","lastName":"He","suffix":""},{"id":263465430,"identity":"08fae1eb-c2d0-4573-b479-6b90797acbdf","order_by":5,"name":"Peifang Xiao","email":"","orcid":"","institution":"Children's Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Peifang","middleName":"","lastName":"Xiao","suffix":""},{"id":263465432,"identity":"fe691fa3-b82e-4a6d-9c7b-e9915c9f5280","order_by":6,"name":"Shaoyan Hu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYBACAwYGNgiLvYGBgQfEOEC0Fp4DJGuRSCBSi7lE+rMHPyoOy5tLPn8m8aaGQY7vRgLj5wI8Wixn5Jgb9pw5bLhzdo6Z5JxjDMaSNxKYpWfgc9iNHDYJ3rbDjBtu57BJ87AxJG64kcDGzINXS/ozyb9th+033Dz+TJrnH0M9EVoSzKSBtgANZwAxGBIMCGo588ZMWuZMevKGMznGlnP7JAxnnnnYLI1Xy3Ggw95UWNtuOH784Y0332zk+Y4nH/yMTwsUNMMYEkDM2EBYAwNDHTGKRsEoGAWjYKQCAN/NTjd4JfIFAAAAAElFTkSuQmCC","orcid":"","institution":"Children's Hospital of Soochow University","correspondingAuthor":true,"prefix":"","firstName":"Shaoyan","middleName":"","lastName":"Hu","suffix":""},{"id":263465433,"identity":"0ff31318-36da-4b60-834f-2d973bfc94e5","order_by":7,"name":"Benshang Li","email":"","orcid":"","institution":"Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Benshang","middleName":"","lastName":"Li","suffix":""},{"id":263465435,"identity":"fc0bc8a3-1920-4a62-a540-96e3edc7ab9a","order_by":8,"name":"Jun Lu","email":"","orcid":"","institution":"Children's Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Lu","suffix":""}],"badges":[],"createdAt":"2023-12-25 15:59:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3805105/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3805105/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10238-024-01339-7","type":"published","date":"2024-04-25T22:00:31+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49072597,"identity":"e6e158ec-2ad7-4586-8bd6-89ad5c0fe478","added_by":"auto","created_at":"2024-01-02 17:18:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":131487,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of infections post chimeric antigen receptor T cell (CAR-T) therapy in pediatric patients.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3805105/v1/da71a044a44081266973ac94.png"},{"id":49072596,"identity":"9ef8a2ca-5558-43a4-ae44-757a405976e2","added_by":"auto","created_at":"2024-01-02 17:18:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37918,"visible":true,"origin":"","legend":"\u003cp\u003eThe Kaplan-Meier curve was used to analyze the correlation between cytokine release syndrome (CRS) grades and infection. The infection risk of patients with CRS ≥ 3 after CAR-T infusion increased by 2.41-fold.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3805105/v1/c7d6de0992d25852ca8c6ef9.png"},{"id":55689427,"identity":"1df330d0-9c1c-46f5-8cad-1bd1d1bd5bab","added_by":"auto","created_at":"2024-05-01 22:00:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":850098,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3805105/v1/8c7dee0e-7e68-4a6b-a7b8-e2244acf08eb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Infectious complications in pediatric patients undergoing CD19+CD22+ chimeric antigen receptor T-cell therapy for relapsed/refractory B-lymphoblastic leukemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAdoptive immunotherapy with chimeric antigen receptor T-cells (CAR-Ts) targeting tumor-specific antigens is a novel treatment for relapsed/refractory acute B-lymphoblastic leukemia (R/R B-ALL). High clinical remission rates have been reported, highlighting its broad application prospects and offering new hope to patients with R/R hematological tumors. However, CAR-T therapy is also associated with life-threatening adverse events, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hemocytopenia, and infection [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. With the wide application of CAR-Ts in clinics, the management of infections plays a significant role in improving the long-term quality of life of patients. According to research in adult patients, the incidence of infectious complications is 20\u0026ndash;60% and many factors directly or indirectly increase the risk [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. At present, few reports exist on CAR-T treatment-related infections in children. Therefore, addressing the gaps in the current understanding of CAR-T therapy-related complications in the pediatric population is an urgent need. In this study, we describe the infectious complications associated with CAR-T therapy in a cohort of pediatric patients and evaluate the potential risk factors for infection.\u003c/p\u003e"},{"header":"Patients","content":"\u003cp\u003eThis retrospective study was conducted at Children's Hospital affiliated to Soochow University (Suzhou, China). Seventy-nine children with R/R B-ALL who underwent targeted CD19\u0026thinsp;+\u0026thinsp;CD22\u0026thinsp;+\u0026thinsp;CAR-T therapy for the first time between September 2018 and January 2022 were included. The patients all achieved remission after receiving treatment, and there was no recurrence within three months. Informed consent was obtained from all patients for being included in the study. The study was approved by the Ethics Committee of the Children's Hospital affiliated to Soochow University and was performed in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eThe clinical data of the patients were collected in three periods (lymphodepletion [LD] chemotherapy, early, and late phases), including: (1) general information: sex, age, history of hematopoietic stem cell transplantation; (2) baseline data before infusion: LD chemotherapy, proportion of bone marrow primordial cells, bone marrow minimal residual disease (MRD), dose of CAR-Ts, absolute count of neutrophils and lymphocytes in peripheral blood; (3) post-infusion data: peak value of the regulatory T cell (Treg) proportion (within one week after infusion), duration of neutrophil deficiency and lymphopenia in peripheral blood, CRS grade, ICANS grade, use of interleukin (IL)-6 receptor antagonists and glucocorticoids, and admission to the intensive care unit (ICU); and (4) infection-related data: time, symptoms, prognosis, etiology, and medical imaging of the infection and part of the body infected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eManufacture of CAR-Ts and LD chemotherapy\u003c/h2\u003e \u003cp\u003eCAR-Ts were prepared by the Department of Hematology at the Shanghai Children's Medical Center(ChiCTR2000032211). The antibody sequence was murine and the costimulatory molecule was 4-1BB (CD137). The CAR-Ts were cultured for 7 days. The day of CAR-T infusion was defined as d0, and the children underwent LD chemotherapy with cyclophosphamide and fludarabine from d -4 to d -2. The LD chemotherapy regimen was divided into two groups. In Group A, the total dose of cyclophosphamide was \u0026gt;\u0026thinsp;1 g/m\u003csup\u003e2\u003c/sup\u003e and the total dose of fludarabine was \u0026gt;\u0026thinsp;0.12 g/m\u003csup\u003e2\u003c/sup\u003e. In Group B, the total dose of cyclophosphamide was \u0026le;\u0026thinsp;1 g/m\u003csup\u003e2\u003c/sup\u003e and the total dose of fludarabine was \u0026le;\u0026thinsp;0.12 g/m\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions\u003c/h2\u003e \u003cp\u003eEvaluation standards for adverse reactions: CRS grading refers to Lee's grading standard [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and ICANS classification refers to the American Society for Blood and Marrow Transplantation (ASBMT) Consensus Grading classification standard [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDefinition of infection: a diagnosis of infection after CAR-T infusion was made according to the clinical symptoms, molecular biology, microbiology, and medical imaging. Infection can be divided into clinical diagnosis and etiological diagnosis.\u003c/p\u003e \u003cp\u003eOne or more infections may occur in the same patient. Infection in different parts of the body at the same time was considered an independent event and infection by different pathogens in the same part of the body was considered an independent event. Reinfection was defined as the first infection aggravated or reoccurring in the same part of the body during or after treatment.\u003c/p\u003e \u003cp\u003eBacteremia (including catheter-related): one or more bacterial or fungal pathogens from one or more blood samples; if the bacterial isolate is a common bacterium of the skin (such as diphtheria-like bacilli, non-pathogenic mycobacteria, or coagulase-negative staphylococci) and the patient has clinical symptoms, bacteremia is also regarded as an infection.\u003c/p\u003e \u003cp\u003eRespiratory tract infection: symptoms (fever, cough, and expectoration) and/or angiography (chest radiography and chest computed tomography) and/or microbiology (sputum culture, alveolar lavage fluid, and viral nucleic acid).\u003c/p\u003e \u003cp\u003eUrinary system infection: symptoms (frequent micturition, urgency, dysuria, and hematuria) and/or laboratory tests (bacteriuria and urine culture).\u003c/p\u003e \u003cp\u003eDigestive tract infection: symptoms (diarrhea, abdominal pain, nausea, and vomiting) and/or laboratory tests (routine stool, stool culture, and viral nucleic acids).\u003c/p\u003e \u003cp\u003eInfection density: the average number of infections per 100 patient days, calculated as the number of infections in different periods (first 30 days and the later 60 days) after transfusion/total number of people days \u0026times;100.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eTreatment of fever and infection\u003c/h2\u003e \u003cp\u003eBlood samples were obtained for routine blood tests, C-reactive protein levels, and blood cultures in all patients with fever. Broad-spectrum antibiotics were started empirically and the antibiotics were adjusted according to the pathogen identification results. Patients with fever after CAR-T infusion and clinical consideration of CRS should be re-evaluated 48 hours after fever onset. Antibiotic use should be discontinued in patients with no sign of active infection and negative results on pathogen testing. Antifungal drugs were administered within 90 days of CAR-T therapy to children with previous or current fungal infections. None of the patients received preventive antiviral treatments.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using SPSS version 24.0 (IBM SPSS Statistics for windows, Armonk, NY) software. Survival analysis was used to evaluate the clinical factors associated with infections. Independent variables included age, sex, history of hematopoietic stem cell transplantation, LD chemotherapy, CAR-T dose, and CRS grade. The Cox proportional hazard model was used to evaluate the independent risk factors of infection: first, the independent variables were screened by univariate analysis, and variables with P\u0026thinsp;\u0026lt;\u0026thinsp;0.1 in univariate analysis were included in the multivariate model. The Kaplan-Meier curve was used to analyze the correlation between the CRS grade and infection.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eClinical characteristics of patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 79 children were diagnosed as R/R B-ALL and treated with CAR-Ts. The clinical features of the patient cohort, including 58 boys (73%) and 21 girls (27%)\u0026nbsp;with a median age of 8\u0026nbsp;(5\u0026ndash;11) years, are shown in Table 1. Before CAR-Ts therapy, the median number of bone marrow primordial cells was 6% (range, 3\u0026ndash;49%), and the median\u0026nbsp;bone marrow MRD was 9.34\u0026times;10\u003csup\u003e-3\u003c/sup\u003e leukemia cells (range, 1.0\u0026times;10\u003csup\u003e-4\u003c/sup\u003e\u0026ndash;2.47\u0026times;10\u003csup\u003e-1\u003c/sup\u003e leukemia cells). A total of 55.7% of the patients (n=44) were neutropenic (absolute neutrophil count [ANC] \u0026lt; 0.5\u0026times;10 \u003csup\u003e9\u003c/sup\u003e/L) and 55.7% (n=44) presented with lymphopenia (absolute lymphocyte count [ALC] \u0026lt;0.3\u0026times;10\u003csup\u003e\u0026nbsp;9\u003c/sup\u003e/L). Six\u0026nbsp;(7.6%) children\u0026nbsp;had a history of allogeneic hematopoietic stem cell transplantation. All\u0026nbsp;the patients underwent treatment with\u0026nbsp;fludarabine- and cyclophosphamide-based chemotherapy regimens\u0026nbsp;(Group A, n=11; Group B, n=68). The median infusion of CAR-Ts was 6.8\u0026times;10\u003csup\u003e\u0026nbsp;6\u003c/sup\u003e/kg (range, 5\u0026ndash;9.6 /kg). In the early phase after CAR-T infusion, the median duration of ANC \u0026lt; 0.5\u0026times;10 \u003csup\u003e9\u003c/sup\u003e/L and ALC \u0026lt; 0.3\u0026times;10 \u003csup\u003e9\u003c/sup\u003e/L was 13 days (range, 6\u0026ndash;31 days) and 6 days (range, 2\u0026ndash;11 days), respectively. Thirty-three (41.8%) patients presented with severe CRS (grade \u0026ge;3) after CAR-T infusion, while severe ICANS (grade \u0026ge;3) occurred in 9 (11.4%) patients. Fifty-one children (64.6%) were treated with IL-6 receptor antagonists, 33 (41.7%) with glucocorticoids, and 29 (36.7%) with steroids or tocilizumab to treat severe CRS and ICANS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e Clinical characteristics of the patients \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"553\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.66064981949458%\" valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.43682310469314%\" valign=\"top\"\u003e\n \u003cp\u003eN=79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.9025270758122743%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.66064981949458%\" valign=\"top\"\u003e\n \u003cp\u003eAge, years (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.43682310469314%\" valign=\"top\"\u003e\n \u003cp\u003e8 (range, 5\u0026ndash;11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.9025270758122743%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.66064981949458%\" valign=\"top\"\u003e\n \u003cp\u003eSex, male n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.43682310469314%\" valign=\"top\"\u003e\n \u003cp\u003e58 (73.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.9025270758122743%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.66064981949458%\" valign=\"top\"\u003e\n \u003cp\u003eCAR-T dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.43682310469314%\" valign=\"top\"\u003e\n \u003cp\u003e6.8 (5\u0026ndash;9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.9025270758122743%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.66064981949458%\" valign=\"top\"\u003e\n \u003cp\u003eBone marrow primordial cells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.43682310469314%\" valign=\"top\"\u003e\n \u003cp\u003e6 (3\u0026ndash;49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.9025270758122743%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.66064981949458%\" valign=\"top\"\u003e\n \u003cp\u003eMinimal Residual Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.43682310469314%\" valign=\"top\"\u003e\n \u003cp\u003e9.34\u0026times;10\u003csup\u003e-3\u0026nbsp;\u003c/sup\u003e(1 \u0026times; 10\u003csup\u003e-4\u003c/sup\u003e\u0026ndash;2.47 \u0026times; 10\u003csup\u003e-1\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.9025270758122743%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.66064981949458%\" valign=\"top\"\u003e\n \u003cp\u003ePrior autologous and / or allogeneic HCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.43682310469314%\" valign=\"top\"\u003e\n \u003cp\u003e6 (7.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.9025270758122743%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre-infusion (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eALC \u0026lt; 0.3 \u0026times; 10\u003csup\u003e9\u0026nbsp;\u003c/sup\u003e/ L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e44 (55.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eANC \u0026lt; 0.5 \u0026times; 10\u003csup\u003e9\u0026nbsp;\u003c/sup\u003e/ L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e44 (55.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymphodepleting preparative regimen, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eGroup A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e11 (13.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eGroup B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e68 (86.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCRS, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eGrade \u0026lt; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e46 (58.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eGrade \u0026ge; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e33 (41.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eICANS, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eGrade \u0026lt; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e70 (88.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eGrade \u0026ge; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e9 (11.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUse of glucocorticoid\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e33 (41.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e46 (58.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUse of tocilizumab\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e51 (64.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"71.79023508137432%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.209764918625677%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e28 (35.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eCAR-T\u0026nbsp;\u003c/em\u003echimeric antigen receptor T cell\u003cem\u003e; HCT\u0026nbsp;\u003c/em\u003eHematopoietic stem cell transplantation; \u003cem\u003eANC\u003c/em\u003e Absolute neutrophil count; \u003cem\u003eALC\u003c/em\u003e absolute lymphocyte count;\u003cem\u003e\u0026nbsp;CRS\u003c/em\u003e Cytokine release syndrome, \u003cem\u003eICANS\u0026nbsp;\u003c/em\u003eImmune effector cell-associated neurotoxicity syndrome\u003c/p\u003e\n\u003cp\u003eIn Group A, the total dose of cyclophosphamide was \u0026gt; 1 g/m\u003csup\u003e2\u003c/sup\u003e,\u0026nbsp;and the total dose of fludarabine was \u0026gt; 0.12 g/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eGroup B: the total dose of cyclophosphamide \u0026le;1\u0026nbsp;g/m\u003csup\u003e2\u003c/sup\u003e, the total dose of fludarabine \u0026le;0.12\u0026nbsp;g/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInfections post CAR-T Therapy\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cumulative incidence of the first infection\u0026nbsp;within 90 days of CAR-T infusion is shown in Figure 1. The cumulative incidence of the first infection was 32.9% (95% confidence interval [CI]:\u0026nbsp;19.5\u0026ndash;55.8%) by day 7, 44.3% (95% CI: 32.1\u0026ndash;55.8%) by day 30, and 67.1% (95% CI: 58.9\u0026ndash;74.0%) by day 90\u0026nbsp;after CAR-T therapy. The median time to the first infection was 8 days (range, 4\u0026ndash;55 days) after infusion, and most infections occurred in the early phase, with an infection density of 1.94. In contrast, infection density was 0.84 in the late phase. Bacterial infections mainly occurred in the early phase (n=20), whereas viral infections\u0026nbsp;were more common in the late phase (n=7) (Table 2).\u003c/p\u003e\n\u003cp\u003eIn the LD chemotherapy phase, 10 patients experienced 11 infectious episodes, and no bacterial or viral infections were detected. In the early phase, 46 infections occurred in 35 children, and pathogens were identified in 20 infections, all of which were bacterial. Thirteen children had 14 episodes of bacteremia, of which six were gram-positive bacteria, eight were gram-negative bacteria, and all these children had neutropenia. Four children were admitted to the ICU for treatment because of infection, and one died because of grade 4 CRS complicated by \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e infection of the respiratory tract and \u003cem\u003eStaphylococcus aureus\u003c/em\u003e bacteremia. In the late phase, 29 children had a total of 40 infectious episodes, and pathogens were detected in 11 cases, including seven viral (herpes virus and human parvovirus detected in plasma by PCR), three bacterial (one gram-positive bacterium and two gram-negative bacteria), and one fungal (urinary tract infection caused by \u003cem\u003eTrichosporon asahii\u003c/em\u003e) infection. Details of the pathogens are presented in Table 3. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e Pathogens of infection *\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"728\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.543328748280604%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eType of Infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.40990371389271%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eThe phase of LD chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.436038514442917%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eDays 0-30 Post CAR-T (the early phase)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.61072902338377%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eDays 31-90 Post CAR-T (the late phase)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.681892332789559%\" valign=\"top\"\u003e\n \u003cp\u003eTotal Episodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.6394779771615%\" valign=\"top\"\u003e\n \u003cp\u003ePatients Affected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.94453507340946%\" valign=\"top\"\u003e\n \u003cp\u003eTotal Episodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.965742251223492%\" valign=\"top\"\u003e\n \u003cp\u003ePatients Affected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.33442088091354%\" valign=\"top\"\u003e\n \u003cp\u003eTotal Episodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" valign=\"top\"\u003e\n \u003cp\u003ePatients Affected\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.56473829201102%\" valign=\"top\"\u003e\n \u003cp\u003eBacterial Infections\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.049586776859504%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.325068870523417%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.947658402203857%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.56473829201102%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.56473829201102%\" valign=\"top\"\u003e\n \u003cp\u003eViral Infections\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.049586776859504%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.325068870523417%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.947658402203857%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.56473829201102%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.56473829201102%\" valign=\"top\"\u003e\n \u003cp\u003eFungal Infections\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.049586776859504%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.325068870523417%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.947658402203857%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.56473829201102%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eLD\u003c/em\u003e lymphodepletion; \u003cem\u003eCAR-T\u003c/em\u003e Chimeric antigen receptor T cell\u003c/p\u003e\n\u003cp\u003e* Pathogens were detected in 31 infections, including 23 bacterial, seven viral, and one fungal infection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e Microbiological description of infection events\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"604\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003ePhase of LD chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003eEarly phase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003eLate phase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eStreptococcus pneumoniae\u003c/em\u003e（blood）+EBV（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eStenotrophomonas maltophilia\u003c/em\u003e（urine）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eStaphylococcus warneri\u003c/em\u003e（blood）+ \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e（sputum）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eStaphylococcus\u003c/em\u003e（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eHaemophilus influenzae\u003c/em\u003e（blood）+ \u003cem\u003eS. pneumoniae\u003c/em\u003e（blood）+ \u003cem\u003eStenotrophomonas maltophilia\u003c/em\u003e（Stool）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003eCMV（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eEscherichia coli\u003c/em\u003e（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eStaphylococcus aureus\u003c/em\u003e（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eH. influenzae\u003c/em\u003e（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eStaphylococcus capitis\u003c/em\u003e（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003eVB19（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e（sputum）+ \u003cem\u003eStaphylococcus epidermidis\u003c/em\u003e（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003eCMV（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eS. pneumoniae\u003c/em\u003e（sputum）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eS. pneumoniae\u003c/em\u003e\u003cem\u003e（\u003c/em\u003eblood）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eE. coli\u003c/em\u003e（urine）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eStaphylococcus hominis\u003c/em\u003e（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTrichosporon asahii\u003c/em\u003e\u003cem\u003e（\u003c/em\u003eUrine）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003eCMV（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003eSalmonella（stool）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eK. pneumoniae\u003c/em\u003e（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eS. hominis\u003c/em\u003e（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003eVB19（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.396694214876034%\" valign=\"top\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.702479338842975%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.14876033057851%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.75206611570248%\" valign=\"top\"\u003e\n \u003cp\u003eVB19（blood）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eEBV\u003c/em\u003e Epstein\u0026ndash;Barr Virus; \u003cem\u003eCMV\u003c/em\u003e cytomegalovirus; \u003cem\u003eVB19\u0026nbsp;\u003c/em\u003eparvovirus B19\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFactors associated with the occurrence of infections\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnivariate and multivariate Cox regression analyses were performed on the clinical factors of\u0026nbsp;the 79 patients,\u0026nbsp;and the risk factors for CAR-T therapy-related infections were assessed (Table 4). Univariate analysis showed that the proportion of bone marrow primordial cells (pre-infusion), MRD of the bone marrow (pre-infusion), lymphopenia (pre-infusion),\u0026nbsp;lymphocyte count before infusion, duration of neutrophil deficiency and lymphocyte reduction after infusion, CRS and ICANS grades, use of IL-6 receptor antagonists and glucocorticoids,\u0026nbsp;ICU admission, and peak value of the Treg proportion (within one week after infusion)\u0026nbsp;were associated with the presence of infection (P \u0026lt; 0.05). Multivariate analysis showed that CRS \u0026ge;3 was an independent risk factor for CAR-T therapy-related infection (hazard ratio = 2.41, 95% CI: 1.08\u0026ndash;5.36, P = 0.031) and the infection risk of patients with CRS \u0026ge; 3 after CAR-T infusion increased by 2.41-fold (Figure 2).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\" width=\"644\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"6\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTable 4\u003c/strong\u003e Association of chimeric antigen receptor T cell (CAR-T) therapy variables with time to first infection post CAR-T therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003eUnivariate Hazard Ratio (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003eMultivariate Hazard Ratio (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGeneral information\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eSex (F vs. M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.41 (0.79\u0026ndash;2.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e1.06 (0.98\u0026ndash;1.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e0.114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre-CAR-T variables\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eDose of CAR-T cells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e0.91 (0.83\u0026ndash;1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.063\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e0.98 (0.87\u0026ndash;1.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.721\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eBone marrow primordial cells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e1.01 (1.00\u0026ndash;1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e1.01 (0.99\u0026ndash;1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eMRD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e3.91 (1.38\u0026ndash;11.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.010\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e0.59 (0.10\u0026ndash;3.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.545\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eANC\u0026nbsp;\u0026lt;\u0026nbsp;0.5 (Yes vs. No）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e1.51 (0.86\u0026ndash;2.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e0.147\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eALC\u0026nbsp;\u0026lt;\u0026nbsp;0.3 (Yes vs. No）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e1.99 (1.13\u0026ndash;3.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.016\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e1.77 (0.90\u0026ndash;3.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.097\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eHistory of HCT (Yes vs. No）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e1.66 (0.65\u0026ndash;4.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e0.281\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eLD chemotherapy (Group A vs. Group B）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e2.10 (1.05\u0026ndash;4.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.035\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e2.01(0.92\u0026ndash;4.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.077\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-CAR-T variables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eDuration of ANC\u0026nbsp;\u0026lt;\u0026nbsp;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e1.03 (1.01\u0026ndash;1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e0.99 (0.96\u0026ndash;1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.841\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eDuration of ALC\u0026nbsp;\u0026lt; 0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e1.03 (1.00\u0026ndash;1.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e0.99 (0.95\u0026ndash;1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.621\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eCRS grade\u0026nbsp;（\u0026ge;\u0026nbsp;3 vs.\u0026nbsp;\u0026lt;\u0026nbsp;3）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e3.41 (1.95\u0026ndash;5.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e2.41 (1.08\u0026ndash;5.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.031\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eICANS grade\u0026nbsp;（\u0026ge;\u0026nbsp;3 vs.\u0026nbsp;\u0026lt;\u0026nbsp;3）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e2.62 (1.22\u0026ndash;5.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.013\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e1.64 (0.66\u0026ndash;4.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.285\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eUse of IL-6 receptor antagonists (yes vs. no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e1.87 (1.02\u0026ndash;3.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.040\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e1.06 (0.50\u0026ndash;2.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.874\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eUse of glucocorticoids (yes vs. no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e2.07 (1.20\u0026ndash;3.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e1.05 (0.55\u0026ndash;2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.875\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003eAdmission to ICU (yes vs. no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e3.63 (2.07\u0026ndash;6.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e1.75 (0.77\u0026ndash;3.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.69565217391305%\"\u003e\n \u003cp\u003ePeak value of Tregs proportion*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.496894409937887%\"\u003e\n \u003cp\u003e1.02 (1.00\u0026ndash;1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.248447204968944%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.026\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.049689440993788%\"\u003e\n \u003cp\u003e1.00 (0.98\u0026ndash;1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.509316770186336%\" colspan=\"2\"\u003e\n \u003cp\u003e0.574\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"94.57364341085271%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eCox proportional hazards model. \u003cstrong\u003e\u003cem\u003eM\u003c/em\u003e\u003c/strong\u003e male; \u003cstrong\u003e\u003cem\u003eF\u003c/em\u003e\u003c/strong\u003e female; \u003cstrong\u003e\u003cem\u003eCAR-T\u003c/em\u003e\u003c/strong\u003e chimeric antigen receptor T cell; \u003cstrong\u003e\u003cem\u003eMRD\u003c/em\u003e\u003c/strong\u003e Minimal residual disease; \u003cstrong\u003e\u003cem\u003eANC\u003c/em\u003e\u003c/strong\u003e Absolute neutrophil count; \u003cstrong\u003e\u003cem\u003eALC\u003c/em\u003e\u003c/strong\u003e Absolute lymphocyte count; \u003cstrong\u003e\u003cem\u003eCRS\u003c/em\u003e\u003c/strong\u003e Cytokine release syndrome; \u003cstrong\u003e\u003cem\u003eICANS\u003c/em\u003e\u003c/strong\u003e Immune effector cell-associated neurotoxicity syndrome; \u003cstrong\u003e\u003cem\u003eHCT\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eHematopoietic stem cell transplantation; \u003cstrong\u003e\u003cem\u003eTregs\u003c/em\u003e\u003c/strong\u003e regulatory T-cells. * Peak value of regulatory T cell proportion within one week after CAR-T therapy..\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.426356589147287%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eCAR-T therapy can effectively improve the remission and survival rates of patients with R/R B-ALL. However, adverse events, including CRS, ICANS, infections, and hematological toxicity are associated with CAR-T therapy. In recent years, CAR-T therapy-related infections have attracted increasing attention. In some prospective clinical trials and retrospective studies, the incidence of infection was approximately 18\u0026ndash;60% [\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Our research suggests that the cumulative infection rate within 90 days after CAR-T transfusion was 67.1%, the early infection density was 1.94, and the late infection density was 0.8, which were similar to recent reports [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNeutropenia is an important risk factor for bacterial infection, and early bacterial infection with CAR-T therapy may be related to multiple neutropenic episodes during this period. Neutropenia is more common after CAR-T therapy, which can be caused by many factors (including CRS and LD chemotherapy) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In a clinical study of CAR-T therapy in patients with relapsed/refractory lymphoma, the incidence of neutropenia was 71%, and most of these cases (98%) occurred in the early phase after CAR-T therapy [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Fried et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] reported that 72% patients (n\u0026thinsp;=\u0026thinsp;38) with R/R B-ALL had severe neutropenia (grade\u0026thinsp;\u0026ge;\u0026thinsp;3) and the median occurrence time of neutropenia was by day 17 after the initiation of CAR-T therapy. Our data suggest that 16 children developed infections following CAR-T therapy, with a total of 20 bacterial infections in the early phase. All 16 children developed neutropenia, and seven of these patients had persistent neutropenia (lasting\u0026thinsp;\u0026gt;\u0026thinsp;20 days). Therefore, antibiotics may be used preventively to reduce the risk of bacterial infections in children with neutropenia. In addition, patients could receive granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) treatment to decrease the duration of neutropenia and thus decrease the risk of bacterial infection, although this approach remains controversial [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Studies have shown that GM-CSF is associated with the occurrence of CRS and ICANS. The incidence and severity of CRS and ICANS can be reduced by inhibition of GM-CSF after CAR-T treatment; meanwhile, it does not affect the proliferation or antitumor activity of CAR-Ts in vivo [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Conversely, another single-center study on R/R diffuse large B-cell lymphoma (DLBCL) showed that the use of G-CSF in the early phase of reinfusion did not increase the risk of severe CRS and ICANS or interfere with the expansion of CAR-Ts [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. None of the children in our center were treated with GM-CSF or G-CSF; the incidence of CRS and ICANS was 90% and 30%, respectively, and the cumulative incidence of infection in the early phase was 47.4%. Some studies including patients treated with G-CSF or GM-CSF have reported a CRS incidence of 72.7\u0026ndash;97% and ICANS incidence of 27\u0026ndash;65%, with an incidence of infection of 33.3\u0026ndash;45% [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The infection rate in patients treated with G-CSF or GM-CSF was significantly reduced. Therefore, the use of G-CSF or GM-CSF at the proper time may help reduce the incidence of infection. However, further research is needed to determine the optimal time and duration of this treatment.\u003c/p\u003e \u003cp\u003eViral infections mostly occur in the late phase after CAR-T infusion, which may be related to B cell aplasia and hypogammaglobulinemia [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The \u0026ldquo;off-target\u0026rdquo; effect of CAR-Ts (CAR-Ts not only kill malignant B cells, but also target normal B cells) leads to the failure of B cell regeneration, inducing hypogammaglobulinemia. The incidence of hypogammaglobulinemia varies across treatment centers, with reports indicating an incidence of 20\u0026ndash;90% due to differences in research objects, definitions of hypogammaglobulinemia, and methods of immunoglobulin determination [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In our study, 53 children had complete humoral immunity data including 27 (50.9%) with late-phase hypogammaglobulinemia. Among the 27 children with hypogammaglobulinemia, 11 developed infections, and the pathogens were identified in four children, of which three were viral infections. The infection density in the late phase was lower than that in the early phase, which may be related to the routine monthly infusion of gamma globulin for patients in our center after CAR-T therapy (until 6 months after treatment), which reduces the incidence of hypogammaglobulinemia. Moreover, lymphocyte and neutrophil counts recovered over time in most cases. In our study, lymphocyte and neutrophil counts recovered in 54 (54/60, 90%) and 48 (48/71, 67.6%) children, respectively, in the late phase. At present, most reports show that respiratory viruses (including influenza virus, parainfluenza virus, metapneumovirus, and respiratory syncytial virus [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]) are the most common pathogens in the late phase of reinfusion, and only a small number of herpes viruses are observed. The reported incidence of cytomegalovirus (CMV) infection is 1\u0026ndash;2%, with viremia constituting most cases, whereas organ damage is rare. However, an increasing number of fatal cases of viral infections have been reported in recent years [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Respiratory tract infection was the most common in our study; however, the etiological examination of respiratory tract infection has not been checked routinely; CMV and human parvovirus B19 were commonly detected in our data, although patients without clinical symptoms were not treated with antiviral therapy.\u003c/p\u003e \u003cp\u003eFungal infections after CAR-T therapy are rare, with an incidence between 1% and 5% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], which may be related to persistent neutropenia or the long-term use of glucocorticoids. Our center usually administers antifungal treatment to children with fungal infections during CAR-T treatment. Only one case of urinary tract fungal infection (\u003cem\u003eT. asahii\u003c/em\u003e) was detected and the infection was successfully treated with voriconazole. The child had long-term cytopenia, neutropenia lasting up to 30 days, a history of glucocorticoid use, and persistent application of broad-spectrum antibiotics. These factors increase the risk of fungal infection in children. Therefore, antifungal drugs should be used preventively in children with high-risk factors.\u003c/p\u003e \u003cp\u003eAlthough infections following CAR-T therapy are common, life-threatening infections are rare. Hill et al. performed a retrospective analysis of 133 patients who underwent CD19 CAR-T therapy, and found that 30 children had 43 infectious episodes, but only two led to death [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. A report on CAR-T treatment in children and adolescents showed that two of 39 patients died of colibacillosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In this study, only one child died of Grade 4 CRS complicated by infection, which was caused by \u003cem\u003eA. baumannii\u003c/em\u003e infection in the respiratory tract and \u003cem\u003eStaphylococcus wallichii\u003c/em\u003e bacteremia. Following treatment with imipenem, amikacin, and voriconazole, the oxygen saturation and blood pressure could not be maintained at stable levels and the patient died of multiple organ dysfunction syndrome and septic shock. The low mortality rate of CAR-T therapy-related infections is associated with early identification of infection and active anti-infection treatment. Therefore, when children have symptoms of infection, we should promptly identify the infection site, conduct pathogen identification, actively and empirically use broad-spectrum antibiotics, regularly evaluate the severity of infection, and adjust antibiotics according to the pathogen test results.\u003c/p\u003e \u003cp\u003eWe also analyzed the clinical factors related to infection and found that they were related to pre-infusion tumor load, intensity of LD chemotherapy, lymphocyte count before infusion, duration of neutrophil deficiency and lymphocyte reduction after infusion, CRS and ICANS grades, use of IL-6 receptor antagonists and glucocorticoids, admission to the ICU, and peak value of the Treg proportion (within one week after infusion). High tumor load and intensive lymphocyte clearance usually lead to an increased incidence of severe CRS and ICANS [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and patients with severe CRS have a higher risk of infection [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. CRS is one of the most common adverse reactions after CAR-T therapy and typically occurs 1\u0026ndash;14 days after CAR-T infusion for a duration of approximately 1\u0026ndash;10 days, with an incidence of 30\u0026ndash;100% while the incidence of CRS grade\u0026thinsp;\u0026ge;\u0026thinsp;3 being approximately 10\u0026ndash;30% [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. CRS is mainly characterized by fever, hypotension, decreased pulse oxygen, and toxicity of various organs [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. CRS is a systemic inflammatory response syndrome caused by excessive activation of immune cells and the production of a large amount of cytokines, which leads to microvascular endothelial damage, increased vascular permeability, capillary leakage syndrome, and disseminated intravascular hemolysis. These manifestations are often difficult to distinguish from sepsis caused by bacterial infection. Some studies have attempted to distinguish between CRS and infection by analyzing cytokines. Park et al. identified the cytokines related to CRS, notably interferon γ (IFN-γ), tumor necrosis factor α, IL-6, IL-10, and IL-15; however, no difference was found between these cytokines and those of patients with infection [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Luo et al. [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] noted that subtle differences exist between CRS and infection inflammatory indicators; for example, both ferritin and IL-6 levels increase in CRS, whereas only IL-6 levels increase during infection, with ferritin remaining normal. The authors built a prediction model including three cytokines (IL-8, IL-1β, and IFN-γ) to predict severe infection. However, further data are required to corroborate this model and verify its applicability in the clinic. Patients with severe CRS often require admission to the ICU. Indwelling catheters (central venous catheters, urinary catheters, and tracheal catheters) in the ICU increase the risk of infection, and patients often require glucocorticoid and/or IL-6 receptor antagonist treatment, which may inhibit the ability of the patient\u0026rsquo;s immune system to respond effectively to pathogens [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. A single-center study on rheumatoid arthritis showed that the use of IL-6 receptor antagonists was associated with an increase in infection [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. However, Frigault et al. noted that IL-6 receptor antagonist use in patients after CAR-T treatment was not associated with the occurrence of infection [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Regarding the association between glucocorticoid use and infection risk, current findings have yielded conflicting results with some studies showing no increased infection risk [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and others demonstrating an increased infection risk [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. These contradictory results may be due to the selection bias of different studies as different research centers have different standards for the selection of research participants, definition of infection, and use of antibacterial drugs. In summary, owing to the comprehensive effects of many factors, severe CRS increases the risk of infection in patients.\u003c/p\u003e \u003cp\u003eInterestingly, we also found that Tregs were related to infections after CAR-T therapy, and the risk of infection increased with an increase in the peak value of the Treg proportion. Tregs are a subset of T cells with strong negative immunoregulatory functions that actively inhibit the activation, amplification, and function of other immune cells, thus regulating the intensity and duration of the immune response and maintaining immune homeostasis in vivo [\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Sustained high expression of Tregs inhibit the activation and expansion of tumor antigen-specific effector T cells, affecting the curative effect of CAR-Ts, further aggravating the immune deficiency of patients, and increasing the risk of infection. Therefore, inhibiting the activation of Tregs, when necessary, may promote the tumor-killing effect of CAR-Ts and reduce the risk of infection. We intend to explore this intriguing aspect in our future clinical work.\u003c/p\u003e \u003cp\u003eAfter the remission of CAR-T therapy in our center, most children underwent hematopoietic stem cell transplantation within approximately 90 days, and long-term infection after CAR-T transfusion could not be tracked. Further research is required to generate robust data on etiology and immunology to address this limitation.\u003c/p\u003e \u003cp\u003eThe incidence, pathogens, and severity of infection after CAR-T therapy are affected by many factors. Therefore, integrating the experience of CAR-T therapy for various hematological diseases is important to better understand related infectious complications and formulate the optimal infection management strategy to improve the safety and effectiveness of CAR-T therapy for children with R/R B-ALL.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXCW thanks the staff and faculty of the department of hematology at Children\u0026apos;s Hospital of Soochow University for tireless work caring for the patients involved in this study, especially appreciating Jinran Li and Qi Ji for their assistance during this study. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDesign of the study and collection, analysis and interpretation of data by fund from Medical Research Project of Jiangsu Provincial Health and Family Planning Commission (Key Project ZD2021006), National Natural Science Foundation of China (Nos. 81770193, 82100229, and 81970163), Jiangsu Project (No. BE2021654), Suzhou Enterprise Technology Innovation\u0026apos;s project, Suzhou Key Laboratory of Childhood Leukemia (SZS201615).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003eXCW, ZMC and ZHC analyzed data and wrote the manuscript. YW, HLH and PFX reviewed that data and edited the manuscript. SYH, BSL and JL guided the study, proposed the study protocol, supervised its implementation, and provided funding. All authors approved the final manuscript prior to submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e All procedures performed in studies involving human participants were approved by the Ethics Committee of Children\u0026apos;s Hospital affiliated to Suzhou University, which is in line with the guidelines of Helsinki Declaration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e Informed consent was obtained from all individual participants included in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e The authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSterner RC, Sterner RM. 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Current status and perspectives of regulatory T cell-based therapy. J Genet Genomics. Jul 2022;49(7):599\u0026ndash;611. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jgg.2022.05.005\u003c/span\u003e\u003cspan address=\"10.1016/j.jgg.2022.05.005\" 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":"clinical-and-experimental-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clem","sideBox":"Learn more about [Clinical and Experimental Medicine](https://www.springer.com/journal/10238)","snPcode":"10238","submissionUrl":"https://submission.nature.com/new-submission/10238/3","title":"Clinical and Experimental Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Infectious complications, CAR-T, Children","lastPublishedDoi":"10.21203/rs.3.rs-3805105/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3805105/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eChimeric antigen receptor T cell (CAR-T) therapy is effective in the treatment of relapsed/refractory acute B-lymphoblastic leukemia (R/R B-ALL); however, patients who receive CAR-T therapy are predisposed to infections, with considerable detrimental effects on long-term survival rates and the quality of life of patients. This study retrospectively analyzed infectious complications in 79 pediatric patients with R/R B-ALL treated with CAR-T cells at our institution. Overall, 53 patients developed 97 infections. Ten patients experienced 11 infections during lymphodepletion chemotherapy, 34 experienced 46 infections during the early phase (days 0 to +\u0026thinsp;30 after infusion), and 29 experienced 40 infections during the late phase (day\u0026thinsp;+\u0026thinsp;31 to +\u0026thinsp;90 after infusion). Pathogens were identified in 31 infections, including 23 bacteria, seven viruses, and one fungus. Four patients were admitted to the intensive care unit for infection and one died. The following factors were associated with infection: pre-infusion tumor load, intensity of lymphodepleting chemotherapy, lymphocyte count before infusion, duration of neutrophil deficiency and lymphocyte reduction after infusion, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome grades, use of interleukin-6 receptor antagonists and glucocorticoids, intensive care unit admission, and peak value of regulatory T cell proportion within one week after infusion (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). CRS\u0026thinsp;\u0026ge;\u0026thinsp;grade 3 was identified as a risk factor for infection (hazard ratio\u0026thinsp;=\u0026thinsp;2.41, 95% confidence interval: 1.08\u0026ndash;5.36, P\u0026thinsp;=\u0026thinsp;0.031). Therefore, actively reducing the CRS grade may decrease the risk of infection and improve the long-term quality of life of these patients.\u003c/p\u003e","manuscriptTitle":"Infectious complications in pediatric patients undergoing CD19+CD22+ chimeric antigen receptor T-cell therapy for relapsed/refractory B-lymphoblastic leukemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-02 17:18:16","doi":"10.21203/rs.3.rs-3805105/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-02-21T12:57:07+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-22T19:18:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"24baf9cb-5d91-409d-9a96-96061e8a7ef7","date":"2024-01-22T17:16:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-18T14:50:02+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-26T05:11:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-12-26T05:11:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical and Experimental Medicine","date":"2023-12-25T15:50:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-and-experimental-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clem","sideBox":"Learn more about [Clinical and Experimental Medicine](https://www.springer.com/journal/10238)","snPcode":"10238","submissionUrl":"https://submission.nature.com/new-submission/10238/3","title":"Clinical and Experimental Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"44204154-bcf5-4cc1-9aa8-0a5aa458a3fd","owner":[],"postedDate":"January 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-01T22:00:31+00:00","versionOfRecord":{"articleIdentity":"rs-3805105","link":"https://doi.org/10.1007/s10238-024-01339-7","journal":{"identity":"clinical-and-experimental-medicine","isVorOnly":false,"title":"Clinical and Experimental Medicine"},"publishedOn":"2024-04-25 22:00:31","publishedOnDateReadable":"April 25th, 2024"},"versionCreatedAt":"2024-01-02 17:18:16","video":"","vorDoi":"10.1007/s10238-024-01339-7","vorDoiUrl":"https://doi.org/10.1007/s10238-024-01339-7","workflowStages":[]},"version":"v1","identity":"rs-3805105","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3805105","identity":"rs-3805105","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}