Impact of hypogammaglobulinemia on bacterial infections after allogeneic hematopoietic cell transplantation

Impact of hypogammaglobulinemia on bacterial infections after allogeneic hematopoietic cell transplantation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of hypogammaglobulinemia on bacterial infections after allogeneic hematopoietic cell transplantation Hidekatsu Yae, Mitsutaka Nishimoto, Hiroshi Okamura, Hideo Miyagawa, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7344293/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Infections are major complications in patients with hematologic neoplasms. Humoral immunity plays a critical role in defense against pathogens. Although hypogammaglobulinemia can carry a risk of infection, there is no confirmed association between low immunoglobulin levels and bacterial infections after allogeneic hematopoietic cell transplantation. Methods : In this study, we assessed the association between different variables, including hypogammaglobulinemia, and the incidence of bacterial infections in 579 consecutive patients receiving allogeneic hematopoietic cell transplantation. Data obtained during three different periods post-transplantation (early, intermediate, and late) were analyzed retrospectively. Results: During the intermediate phase, the median serum trough level of IgG was significantly lower in patients with bacterial infections than in those without (5.39 vs. 6.00 g/L, respectively; p <0.01); however, there was no difference during the early (6.50 vs. 6.53 g/L, respectively; p =0.37) or late (8.60 vs. 9.30 g/L, respectively; p =0.53) phases. The incidence of bacterial infections during the intermediate phase fell as the serum IgG trough level increased (incidence rate ratio, 0.85; 95% confidence interval: 0.78–0.94, p <0.01). Hypogammaglobulinemia (incidence rate ratio, 1.70; 95% confidence interval: 1.11–2.62, p =0.02), as well as grade II–IV acute graft-versus-host disease (incidence rate ratio, 2.10; 95% confidence interval: 1.39–3.18, p <0.01), was significantly associated with bacterial infections solely during the intermediate phase. Conclusions: There was a significant association between hypogammaglobulinemia and bacterial infections solely during the intermediate phase post-transplantation. Immunoglobulin levels and recovery of innate immune cells may affect the incidence of bacterial infections. Figures Figure 1 Figure 2 Key Points Hypogammaglobulinemia was significantly associated with bacterial infections during the intermediate phase post-transplantation. Introduction Humoral immunity plays an important role in immune defense against bacterial or viral infections as well as cellular immunity. Primary immune deficiency, essentially lack of or impairment of humoral immunity, is associated with an increased risk of infection [ 1 – 3 ]. Secondary hypogammaglobulinemia caused by immunochemotherapy, bispecific antibodies, or chimeric-antigen receptor T cell therapy against hematologic neoplasms such as multiple myeloma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or non- Hodgkin lymphoma, is also associated with a high risk of infection [ 4 – 7 ]. Several studies report that immunoglobulin replacement therapy may reduce the incidence of infections in patients with primary or secondary hypogammaglobulinemia [ 2 , 3 , 4 , 7 – 9 ]. Allogeneic hematopoietic cell transplantation (allo-HCT) shows great potency against hematologic neoplasms because it induces anti-tumor activity through donor-derived immune cells; however, recipients of allo-HCT have impaired immunity against infections until their immune system is fully reconstituted. Approximately one-third of recipients experience secondary hypogammaglobulinemia due to impairment of humoral immunity [ 10 , 11 ]; however, there is little evidence supporting an association between hypogammaglobulinemia and infection after allo-HCT. In addition, a meta-analysis that included randomized control trials revealed that prophylactic immunoglobulin replacement therapy had no significant effect on the incidence of documented infections or mortality after allo-HCT [ 12 , 13 ]. Therefore, the indication of prophylactic immunoglobulin replacement therapy for allo-HCT recipients remains controversial [ 14 ]. Low immunoglobulin levels can be associated with infection, particularly those caused by bacterial pathogens. Most previous reports of patients receiving allo-HCT have focused on the early phase post-transplantation; there are no data on infections occurring during the late phase of allo-HCT. Moreover, transplantation protocols have advanced markedly over the last decade, particularly with the introduction of post-transplantation cyclophosphamide. Therefore, reassessment of factors associated with bacterial infection is needed. Evidence of an association between hypogammaglobulinemia and infections may support application of immunoglobulin replacement therapy after allo-HCT. Therefore, we comprehensively investigated the impact of several variables, including hypogammaglobulinemia, on the incidence of bacterial infection during different periods post-HCT. Patients and Methods Study design and patient selection This retrospective study was conducted at Osaka Metropolitan University Hospital, Osaka, Japan. Patients who underwent allo-HCT from January 2007 to September 2021, and who had serum IgG levels measured at least once after allo-HCT, were considered eligible. Patients with multiple myeloma were excluded from the study. Data were collected from the institutional database and from the patients’ medical records focusing on the incidence of bacterial infections during three different post-HCT periods: early (Day 0 to 59), intermediate (Day 60 to 365), and late (Day 366 to 730). Any associations between infection and the study variables, including hypogammaglobulinemia, during each observation period were determined. All participants provided broad written informed consent to participate in this study. The protocol was approved by the appropriate institutional review boards and ethics committees at Osaka Metropolitan University Graduate School of Medicine, and was conducted in accordance with the principles set out in the Declaration of Helsinki. Transplant procedures and supportive care Patients received a conditioning regimen appropriate to their age and comorbidities. Patients aged 60 years or younger, and with no comorbidities, received myeloablative conditioning except for those receiving a transplantation from a haploidentical related donor. The remainder received a reduced intensity conditioning regimen. The graft-versus-host disease (GVHD) prophylaxis administered to all patients comprised a calcineurin inhibitor and short-term methotrexate or mycophenolate mofetil, in combination with post-transplantation cyclophosphamide for haploidentical related donors or anti-thymocyte globulin for mismatched unrelated donors or haploidentical related donors. No patients received alemtuzumab or rituximab as GVHD prophylaxis. The following were administered as infection prophylactics: levofloxacin until neutrophil engraftment; fluconazole until 2 months post-transplantation; and acyclovir until discontinuation of immunosuppressants or up to 1 year post-transplantation. Trimethoprim sulfamethoxazole or atovaquone was initiated after neutrophil engraftment to prevent Pneumocystis jirovecii . Letermovir was given routinely to all patients who received allo-HCT after June 2018. In principle, immunoglobulin replacement therapy was performed if serum IgG fell below 5 g/L or if the patient developed a severe infection. Measurement of serum IgG levels Serum IgG levels were measured within the context of routine medical examinations at days 0, 30, 60, 90, 120, 150, 180, 270, 365, and 730 post-transplantation. To ensure accuracy at these evaluation points, a maximum period of deviation of 7 days was allowed for days 0, 30, and 60, and 14 days for day 90 and thereafter. Serum IgG levels were measured in a turbidimetric immunoassay (Auto Kit IgG. N; Fujifilm Wako Pure Chemical Corporation, Osaka, Japan). Reference levels were 0.05–7.5 g/L. Definitions Infectious events were defined, according to the Infectious Diseases Society of America 2010 guidelines [ 15 ], as clinically documented bacterial infections accompanied by clinical symptoms or signs, and localized to a specific anatomical site, as determined by physical examination, imaging, or laboratory findings, with or without microbiological confirmation. In cases lacking microbiological confirmation, only infections that showed a response to antibiotic therapy were included. Isolated fever without localizing signs or microbiological confirmation during the neutropenic period was excluded from the analysis. Hypogammaglobulinemia was defined as the case when a serum IgG trough level was below 5 g/L during each observation period. The serum IgG trough level for each phase was defined as the lowest measured value. Conditioning regimens were classified as myeloablative or reduced intensity in accordance with a previous consensus report [ 16 ]. The hematopoietic cell transplantation specific-comorbidity index (HCT-CI) [ 17 ], and diagnosis and severity of GVHD, were assessed according to standard criteria [ 18 , 19 ]. Statistical analysis The Mann-Whitney U test was used to compare serum IgG trough levels between the two groups (those who developed infections and those who did not) during each observation period. To evaluate repeated infectious events per patient, the incidence rates of documented infections were assessed as the “incidence density”, calculated as the total number of infectious events during the observation period per patient-time of observation. The potential associations between the incidence rate of infections and serum IgG trough levels, or other variables, were analyzed using a negative binomial regression, with effect sizes reported as incidence rate ratios (IRRs) along with respective 95% confidential intervals (95% CI). Patient-time of observation was incorporated into the model as an offset variable. The association between serum IgG trough levels and the incidence rate was depicted using a scatter plot, with a fitted prediction line for each observation period. To avoid issues related to zero values, the incidence rate represents the pseudo-logarithmic transformation of infectious events per person-year. The variables analyzed were age, sex, disease status at transplantation, HCT-CI, a history of transplantation, intensity of the conditioning regimen, graft source, type of GVHD prophylaxis, a history of acute or chronic GVHD, and hypogammaglobulinemia. A history of acute or chronic GVHD was defined as the presence of acute GVHD within 60 days, or chronic GVHD within 1 year, post-transplantation, respectively. P -values below 0.05 were considered statistically significant. All statistical analyses and generation of graphs were performed using Stata/MP 16.0 (StataCorp LLC, TX, US), GraphPad Prism version 8.2.0 (GraphPad Software, La Jolla, CA, US), and EZR version 1.37 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [ 20 ]. Results Patients and infection characteristics Among the 587 consecutive allo-HCT recipients enrolled in the study, six were excluded from data analysis: one of these had multiple myeloma, and five did not have serum IgG measurements. Therefore, data from 579 patients were analyzed. Patient characteristics are summarized in Table 1 . A total of 239, 133, and 39 events of documented infections were identified during the early, intermediate, and late phase, respectively. Details regarding the sites of infection and the type of pathogen are summarized in Table 2 . Table 1 Patient characteristics Total n = 579 Age, median [range] 48.0 [16.0–72.0] Recipient sex, Male/Female, n (%) 324 (56.0)/255(44.0) Diagnosis, n (%) Acute myeloid leukemia 236 (40.8) Acute lymphoblastic leukemia 104 (18.0) Myelodysplastic syndrome 94 (16.2) Malignant lymphoma 60 (10.4) Adult T cell leukemia/lymphoma 31 (5.4) Chronic myelogenous leukemia 18 (3.1) Aplastic anemia 18 (3.1) Other 18 (3.1) Disease status at transplantation, Remission/Not remission, n (%) 298 (51.5)/ 281 (48.5) ECOG performance status, n (%) 0 292 (50.4) 1 255 (44.0) ≥ 2 32 (5.5) HCT-CI, n (%) 0 248 (42.8) 1 107 (18.5) 2 87 (15.0) ≥ 3 137 (23.7) Graft source, n (%) Bone marrow 181 (31.3) Peripheral blood 263 (45.4) Cord blood 135 (23.3) Donor type, n (%) HLA-matched related 90 (15.5) HLA-matched unrelated 151 (26.1) HLA-mismatched related 11 (1.9) HLA-mismatched unrelated 19 (3.3) Haploidentical 173 (29.9) Cord blood 135 (23.3) Previous transplantation, yes/no, n (%) 130 (22.5)/449 (77.5) Conditioning regimen, Myeloablative/Reduced intensity, n (%) 348 (60.1)/231 (39.9) Use of post-transplantation cyclophosphamide, yes/no, n (%) 207 (35.8)/372 (64.2) Use of anti-thymocyte globulin, yes/no, n (%) 63 (10.9)/516 (89.1) Table 2 Type of infection site and pathogen Observation period Total events Early phase 239 Intermediate phase 133 Late phase 39 Infection site, event (%) Pneumonia 27 (11.3) 38 (28.6) 12 (30.7) Urinary tract 1 (0.4) 8 (6.0) 3 (7.7) Gastrointestinal 36 (14.6) 18 (13.5) 5 (12.8) Bacteremia 140 (58.6) 42 (31.6) 6 (15.4) Other 35 (14.2) 27 (20.3) 13 (33.3) Pathogen, event (%) Staphylococcus spp. 90 (37.7) 33 (24.8) 4 (10.3) Streptococcus spp. 15 (6.3) 2 (1.5) 2 (5.1) Corynebacterium spp. 16 (6.7) 1 (0.8) 1 (2.6) Enterococcus spp. 20 (8.3) 9 (6.7) 1 (2.6) Escherichia Coli 6 (2.4) 6 (4.5) 0 (0.0) Clostridium difficile 34 (13.8) 11 (8.3) 0 (0.0) Pseudomonas spp. 4 (1.7) 4 (3.0) 3 (7.7) Stenotrophomonas Maltophilia 13 (5.4) 2 (1.5) 0 (0.0) Other 6 (2.5) 20 (15.0) 0 (0.0) Unspecified 35 (14.6) 45 (33.8) 28 (71.8) Serum IgG trough levels and the incidence of infection during each phase During each phase, we compared serum IgG trough levels of patients who developed bacterial infections with those of the patients who did not (Fig. 1 a–c). During the intermediate phase, the serum IgG trough level in patients with infections was significantly lower than that in those without infections (5.39 vs. 6.00 g/L, respectively; p < 0.01); however, there were no differences between the groups during the early (6.50 vs. 6.53 g/L, respectively; p = 0.37) or late (8.60 vs. 9.30 g/L, respectively; p = 0.53) phases. Next, we examined the association between the incidence rate of bacterial infections and serum IgG trough levels. Although there were no significant associations during the early (IRR, 0.97; 95% CI: 0.92–1.02, p = 0.21) and late (IRR, 0.98; 95% CI: 0.90–1.07, p = 0.67) phases, the incidence rate of bacterial infections fell as serum IgG trough levels increased during the intermediate phase (IRR, 0.85; 95% CI: 0.78–0.94, p < 0.01) (Fig. 2 a–c). Variables associated with infections during each phase Next, we examined the association between possible variables and the incidence rate of bacterial infections during each phase (Table 3 ). During the early phase, cord blood as the graft source (IRR, 1.76; 95% CI: 1.26–2.46, p < 0.01) and the high score of HCT-CI (IRR, 1.61; 95% CI: 1.22–2.13, p < 0.01) were associated with the risk of infections. Hypogammaglobulinemia was not associated with infection risk. During the intermediate phase, hypogammaglobulinemia (IRR, 1.70; 95% CI:1.11–2.62, p = 0.02) and grade II–IV acute GVHD (IRR, 2.10; 95% CI: 1.39–3.18, p < 0.01) were associated with an increased incidence of infections. During the late phase, none of the variables, including hypogammaglobulinemia, were associated with an increased incidence of infections. There was no association between the use of post-transplantation cyclophosphamide and an increased incidence of infection during any phase. Table 3 Association between variables and the incidence of bacterial infections during each observation period Early phase Intermediate phase Late phase IRR (95% CI) p value IRR (95% CI) p value IRR (95% CI) p value Age 1.01 (1.00–1.02) 0.09 1.01 (0.99–1.02) 0.44 1.00 (0.97–1.04) 0.84 Male 1.31 (1.01–1.71) 0.05 0.85 (0.56–1.30) 0.46 0.64 (0.30–1.38) 0.26 Not remission at transplantation 1.13 (0.87–1.48) 0.35 1.49 (0.98–2.26) 0.06 0.99 (0.45–2.21) 0.98 HCT-CI ≥ 3 1.61 (1.22–2.13) < 0.01 0.74 (0.44–1.26) 0.26 1.30 (0.53–3.17) 0.57 Previous transplantation 0.81 (0.57–1.16) 0.25 1.36 (0.80–2.30) 0.26 1.99 (0.70–5.64) 0.20 Myeloablative conditioning 1.25 (0.92–1.70) 0.16 1.06 (0.64–1.74) 0.83 1.07 (0.40–2.82) 0.90 Peripheral blood (vs Bone marrow) 0.86 (0.58–1.29) 0.47 1.38 (0.76–2.50) 0.28 1.38 (0.53–3.60) 0.51 Cord blood (vs Bone Marrow) 1.76 (1.26–2.46) < 0.01 1.16 (0.66–2.04) 0.60 0.72 (0.25–2.12) 0.56 Use of post-transplantation cyclophosphamide 1.26 (0.84–1.90) 0.27 0.69 (0.37–1.30) 0.25 0.63 (0.20–1.96) 0.43 Use of anti-thymocyte globulin 1.37 (0.92–2.03) 0.12 1.23 (0.62–2.41) 0.55 0.89 (0.23–3.40) 0.86 Acute GVHD with grade II–IV 2.10 (1.39–3.18) < 0.01 1.42 (0.67–3.00) 0.36 Chronic GVHD 1.85 (0.79–4.34) 0.16 Hypogammaglobulinemia 1.21 (0.89–1.65) 0.23 1.70 (1.11–2.62) 0.02 0.89 (0.28–2.77) 0.84 Abbreviations: IRR, incidence rate ratio; CI, confidence interval; HCT-CI, hematopoietic cell transplantation specific comorbidity-index; GVHD, graft-versus-host disease Discussion This retrospective single-institution study revealed a significant association between hypogammaglobulinemia and the incidence rate of bacterial infections during the intermediate phase post-allo-HCT. To the best of our knowledge, this report is the first to demonstrate the impact of hypogammaglobulinemia on the incidence of infections during a specific period after allo-HCT. Although a previous study shows that allo-HCT recipients with hypogammaglobulinemia have shorter survival times [ 21 ], and that unlike immunochemotherapy for hematologic neoplasms [ 7 , 9 , 22 ], prophylactic immunoglobulin replacement therapy does not reduce the risk of infections or mortality in the setting of allo-HCT [ 12 , 13 , 22 – 24 ]. Lacombe et al. also reported that IgG levels were not associated with the occurrence of infections within the first 100 days following allo-HCT [ 25 ]. However, these studies mainly assessed the efficacy of routine prophylactic immunoglobulin replacement therapy, or the association between IgG levels and infections during the relatively early phase post-allo-HCT. Few studies have focused on intermediate or late phases. Impairment of humoral immunity can affect the risk of infections, particularly those caused by bacterial pathogens. The function of immunoglobulins is to opsonize microbes effectively targeting them for phagocytosis and intracellular killing by neutrophils and macrophages, and for antibody-dependent cell-mediated cytotoxicity exerted by natural killer cells; immunoglobulin also neutralizes toxins and pathogens, and triggers lysis by activating the complement cascade [ 26 ]. Because phagocytosis by neutrophils, macrophages, or natural killer cells plays a central role in defense against bacterial infections, immunoglobulins may not work well if these components of the innate immune response are lacking. Thus, considering the period required for immune cell recovery after allo-HCT [ 27 ], insufficient recovery of neutrophils, macrophages, or natural killer cells during the early phase should be the principal risk factor for bacterial infections, irrespective of immunoglobulin levels. However, once neutrophil, macrophage, and natural killer cell have recovered during the intermediate phase, hypogammaglobulinemia can impact the risk of bacterial infections. When immunoglobulin levels have recovered (usually about 1 year post-transplantation), the optimal level of immunoglobulins reduces the impact on the risk of bacterial infections. Therefore, it seems that immunoglobulin levels can be a major determinant of the risk of bacterial infections during the intermediate phase after allo-HCT as it is the period between after the recovery of neutrophil, macrophage, or natural killer cell and before recovery of B cell or immunoglobulin. The data presented herein suggest that the beneficial effects of immunoglobulin replacement therapy might be maximal during intermediate phase after allo-HCT. Indeed, this hypothesis is supported, at least in part, by a single-institution study demonstrating the possible efficacy of subcutaneous immunoglobulin replacement therapy after 60 days of transplantation [ 28 ]. This study has several limitations. First, this was a retrospective single-institution study. Second, immunoglobulin replacement therapy may affect serum IgG levels; however, as our institutional strategy is to administered immunoglobulins when serum IgG level is below 5 g/L, immunoglobulin replacement therapy would minimize the influence of hypogammaglobulinemia (defined as a trough level below 5 g/L). Third, the frequency of infectious events during the late phase was relatively low. Any future study should use a larger sample size to increase the accuracy of the analysis. In conclusion, we found a significant association between hypogammaglobulinemia and the incidence of bacterial infections during the intermediate phase after allo-HCT. This may be due to a combination of immunoglobulin levels and recovery of innate immune cells during this phase; thus, the beneficial effects of immunoglobulin replacement therapy might be maximal at this time. Further studies are warranted to establish the optimal strategy of immunoglobulin replacement therapy for allo-HCT recipients. Declarations Potential conflicts of interest M.H. has received research funding from Takeda Pharmaceuticals and the Japan Blood Products Organization, as well as speaker’s honoraria from Takeda Pharmaceuticals. H.N. has received research funding and speaker’s honoraria from Takeda Pharmaceuticals. H.O. has received research funding from Takeda Pharmaceuticals. M. Nishimoto has received speaker’s honoraria from CSL Behring. The other authors have no conflicts of interest to disclose. Competing Interests M.H. has received research funding from Takeda Pharmaceuticals and the Japan Blood Products Organization, as well as speaker’s honoraria from Takeda Pharmaceuticals. H.N. has received research funding and speaker’s honoraria from Takeda Pharmaceuticals. H.O. has received research funding from Takeda Pharmaceuticals. M. Nishimoto has received speaker’s honoraria from CSL Behring. The other authors have no conflicts of interest to disclose. Funding The authors did not receive support from any organization for the submitted work. Author Contribution M. Nishimoto conceived the study; H.Y., M. Nishimoto, H. K-M., M. Nakamae, and H.O. performed clinical data analysis; H.Y. and M. Nishimoto wrote the manuscript with help from all other authors. All authors discussed the results and commented on the manuscript. Acknowledgement We thank the patients and their families, and all nurses and data managers, for their contribution to the study. Data Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. References Durandy A, Kracker S, Fischer A (2013) Primary antibody deficiencies. Nat Rev Immunol 13(7):519–533 Aguilar C, Malphettes M, Donadieu J, Chandesris O, Coignard-Biehler H, Catherinot E et al (2014) Prevention of infections during primary immunodeficiency. Clin Infect Dis 59(10):1462–1470 Syed MN, Kutac C, Miller JM, Marsh R, Sullivan KE, Cunningham-Rundles C et al (2022) Risk Factors of Pneumonia in Primary Antibody Deficiency Patients Receiving Immunoglobulin Therapy: Data from the US Immunodeficiency Network (USIDNET). J Clin Immunol 42(7):1545–1552 Patel SY, Carbone J, Jolles S (2019) The Expanding Field of Secondary Antibody Deficiency: Causes, Diagnosis, and Management. Front Immunol 10:33 Wudhikarn K, Perales MA (2022) Infectious complications, immune reconstitution, and infection prophylaxis after CD19 chimeric antigen receptor T-cell therapy. Bone Marrow Transpl 57(10):1477–1488 Zugmaier G, Topp MS, Alekar S, Viardot A, Horst HA, Neumann S et al (2014) Long-term follow-up of serum immunoglobulin levels in blinatumomab-treated patients with minimal residual disease-positive B-precursor acute lymphoblastic leukemia. Blood Cancer J 4(9):244 Oscier D, Dearden C, Eren E, Fegan C, Follows G, Hillmen P et al (2012) Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia. Br J Haematol 159(5):541–564 Orange JS, Grossman WJ, Navickis RJ, Wilkes MM (2010) Impact of trough IgG on pneumonia incidence in primary immunodeficiency: A meta-analysis of clinical studies. Clin Immunol 137(1):21–30 Vacca A, Melaccio A, Sportelli A, Solimando AG, Dammacco F, Ria R (2018) Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial. Clin Immunol 191:110–115 Arai Y, Yamashita K, Mizugishi K, Kondo T, Kitano T, Hishizawa M et al (2014) Risk factors for hypogammaglobulinemia after allo-SCT. Bone Marrow Transpl 49(6):859–861 Karakulska-Prystupiuk E, Dwilewicz-Trojaczek J, Drozd-Sokołowska J, Kmin E, Chlebus M, Szczypińska K et al (2021) Prevalence of hypogammaglobulinemia and its management with subcutaneous immunoglobulin supplementation in patients after allogeneic hematopoietic stem cell transplantation-a single-center analysis. Ann Hematol 100(12):3007–3016 Ahn H, Tay J, Shea B, Hutton B, Shorr R, Knoll GA et al (2018) Effectiveness of immunoglobulin prophylaxis in reducing clinical complications of hematopoietic stem cell transplantation: a systematic review and meta-analysis. Transfusion 58(10):2437–2452 Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O (2009) Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and meta-analysis. J Clin Oncol 27(5):770–781 Ohmoto A, Fuji S, Shultes KC, Savani BN, Einsele H (2022) Controversies about immunoglobulin replacement therapy in HSCT recipients with hypogammaglobulinemia. Bone Marrow Transpl 57(6):874–880 Freifeld A, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA et al (2011) Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 52(4):e56–93 Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al (2009) Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transpl 15(12):1628–1633 Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al (2005) Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106(8):2912–2919 Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al (1995) 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. ;15(6):825-8 Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al (2015) National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transpl 21(3):389–401e1 Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transpl 48(3):452–458 Norlin AC, Sairafi D, Mattsson J, Ljungman P, Ringdén O, Remberger M (2008) Allogeneic stem cell transplantation: low immunoglobulin levels associated with decreased survival. Bone Marrow Transpl 41(3):267–273 Ueda M, Berger M, Gale RP, Lazarus HM (2018) Immunoglobulin therapy in hematologic neoplasms and after hematopoietic cell transplantation. Blood Rev 32(2):106–115 Cordonnier C, Chevret S, Legrand M, Rafi H, Dhédin N, Lehmann B et al (2003) Should immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, double-blind, dose effect, placebo-controlled, multicenter trial. Ann Intern Med 139(1):8–18 Howell JE, Gulbis AM, Champlin RE, Qazilbash MH (2012) Retrospective analysis of weekly intravenous immunoglobulin prophylaxis versus intravenous immunoglobulin by IgG level monitoring in hematopoietic stem cell transplant recipients. Am J Hematol 87(2):172–174 Lacombe V, Nunes Gomes C, Robin JB, Thépot S, François S, Cottin L et al (2021) Risk of infection according to the gamma globulin level in the 100 days following allogeneic stem cell transplantations. Eur J Haematol 107(4):489–496 Pedraza-Sánchez S, Cruz-González A, Palmeros-Rojas O, Gálvez-Romero JL, Bellanti JA, Torres M (2022) Polyvalent human immunoglobulin for infectious diseases: Potential to circumvent antimicrobial resistance. Front Immunol 13:987231 Storek J (2008) Immunological reconstitution after hematopoietic cell transplantation - its relation to the contents of the graft. Expert Opin Biol Ther 8(5):583–597 Suga M, Fuji S, Tada Y, Tsutsumi K, Kida S, Shibata K et al (2024) A single-institution pre-post comparison of subcutaneous immunoglobulin replacement therapy in allogeneic haematopoietic cell transplantation recipients. Br J Haematol 204(1):260–267 Additional Declarations Competing interest reported. M.H. has received research funding from Takeda Pharmaceuticals and the Japan Blood Products Organization, as well as speaker’s honoraria from Takeda Pharmaceuticals. H.N. has received research funding and speaker’s honoraria from Takeda Pharmaceuticals. H.O. has received research funding from Takeda Pharmaceuticals. M. Nishimoto has received speaker’s honoraria from CSL Behring. The other authors have no conflicts of interest to disclose. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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-7344293","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":523866044,"identity":"16c75a7e-f98c-4de6-82df-c8abedfb23a9","order_by":0,"name":"Hidekatsu Yae","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hidekatsu","middleName":"","lastName":"Yae","suffix":""},{"id":523866045,"identity":"842f78de-5aec-4af9-894a-14223fefa851","order_by":1,"name":"Mitsutaka Nishimoto","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYDACZgY2hgQGBjkEn1gtxiRoYQBqAYLEBqLdZc7O/uzBwxyb9H6xMwYMP2oY2M0JabFs5jE3SNyWljtzdo4BY88xBmZLQvYZHOZhk0jcdjh3w+0cAwbeBgZmgwMEtbA/A2lJNwBqYfxLnBYGM5CWBJAWZiJt4QFpSTOcOTut4LDMMQki/HL++DPJn9ts5Pmlkzc+fFNjk0wwxFAA0EkSyQYkaQEBO9K1jIJRMApGwXAHAPCgONu+SST0AAAAAElFTkSuQmCC","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Mitsutaka","middleName":"","lastName":"Nishimoto","suffix":""},{"id":523866047,"identity":"df404b3a-af62-4aab-9a89-b9ecd4034e90","order_by":2,"name":"Hiroshi Okamura","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Okamura","suffix":""},{"id":523866049,"identity":"37114b2b-99b6-421b-bb45-4978c2f91c6e","order_by":3,"name":"Hideo Miyagawa","email":"","orcid":"","institution":"Osaka Metropolitan University","correspondingAuthor":false,"prefix":"","firstName":"Hideo","middleName":"","lastName":"Miyagawa","suffix":""},{"id":523866050,"identity":"ecc2b8d9-55d2-47bc-8e59-89ff3767c8f5","order_by":4,"name":"Mika Nakamae","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Mika","middleName":"","lastName":"Nakamae","suffix":""},{"id":523866052,"identity":"4a8bb4c9-331d-424a-8135-2c757c4de542","order_by":5,"name":"Yasuhiro Nakashima","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yasuhiro","middleName":"","lastName":"Nakashima","suffix":""},{"id":523866054,"identity":"6e85d687-2e73-4159-bac6-b10113143349","order_by":6,"name":"Masayuki Hino","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masayuki","middleName":"","lastName":"Hino","suffix":""},{"id":523866055,"identity":"9092f936-a998-452e-88c2-224befe5e56b","order_by":7,"name":"Hirohisa Nakamae","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hirohisa","middleName":"","lastName":"Nakamae","suffix":""}],"badges":[],"createdAt":"2025-08-11 08:53:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7344293/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7344293/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":92737863,"identity":"c73fa028-28d0-4651-8b4e-743c6018af6a","added_by":"auto","created_at":"2025-10-03 16:47:20","extension":"tif","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":74994,"visible":true,"origin":"","legend":"","description":"","filename":"Fig1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7344293/v1/ddfb8abf4612fa9c2b0cc00b.tif"},{"id":92738897,"identity":"1eb19f48-3ee1-47b4-95ce-f73f8f4b12ee","added_by":"auto","created_at":"2025-10-03 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16:55:21","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":18375,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7344293/v1/d7f8d0abb42e2f3dbfad6e2a.png"},{"id":92737875,"identity":"38336a60-bb04-4dde-948d-1a9cb345e8fd","added_by":"auto","created_at":"2025-10-03 16:47:21","extension":"xml","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97260,"visible":true,"origin":"","legend":"","description":"","filename":"5c5c2b1af4ed44429049764fbe348f7c1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7344293/v1/2b8bb59ee8a9a08c1db981ca.xml"},{"id":92737876,"identity":"fd9bd9e8-0e45-433b-ab41-0e9eaf573ea9","added_by":"auto","created_at":"2025-10-03 16:47:21","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":107776,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7344293/v1/4e669ae17c626287e984f8c5.html"},{"id":92737862,"identity":"566dfc0d-1f00-44b6-b609-2b3ba1c44382","added_by":"auto","created_at":"2025-10-03 16:47:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":31902,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of serum IgG trough level in recipients with or without bacterial infections during the early (a), intermediate (b), and late (c) phase after allo-HCT.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum IgG trough levels of recipients with bacterial infections during the intermediate phase are significantly lower than those in recipients without bacterial infections (5.39 \u003cem\u003evs.\u003c/em\u003e 6.00 g/L, respectively; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.01).\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-7344293/v1/4b73e31c064aecd204b48e7d.png"},{"id":92739285,"identity":"875b6390-5aee-4f38-ac9f-2bc2d5323ad3","added_by":"auto","created_at":"2025-10-03 17:03:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":74328,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociation between serum IgG trough levels and incidence rates of bacterial infections during the early (a), intermediate (b), late (c) phase after allo-HCT.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum IgG trough levels are associated significantly with the incidence rate of bacterial infections during the intermediate phase (incidence rate ratio, 0.85; 95% confidence interval: 0.78–0.94, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.01). The incidence rate represents the pseudo-logarithmic transformation of the number of infectious events per person-year. The solid line shows predictions based on a negative binomial model, and the gray-shaded area represents the 95% confidence interval.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7344293/v1/93f78f3e4136b6a4a455e983.png"},{"id":95528316,"identity":"8b4f148e-2204-468e-8a9f-f590cf44a85d","added_by":"auto","created_at":"2025-11-10 10:15:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1054032,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7344293/v1/2ae56814-f95b-4442-974a-94632618a83f.pdf"}],"financialInterests":"Competing interest reported. M.H. has received research funding from Takeda Pharmaceuticals and the Japan Blood Products Organization, as well as speaker’s honoraria from Takeda Pharmaceuticals. H.N. has received research funding and speaker’s honoraria from Takeda Pharmaceuticals. H.O. has received research funding from Takeda Pharmaceuticals. M. Nishimoto has received speaker’s honoraria from CSL Behring. The other authors have no conflicts of interest to disclose.","formattedTitle":"Impact of hypogammaglobulinemia on bacterial infections after allogeneic hematopoietic cell transplantation","fulltext":[{"header":"Key Points","content":"\u003cp\u003eHypogammaglobulinemia was significantly associated with bacterial infections during the intermediate phase post-transplantation.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eHumoral immunity plays an important role in immune defense against bacterial or viral infections as well as cellular immunity. Primary immune deficiency, essentially lack of or impairment of humoral immunity, is associated with an increased risk of infection [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Secondary hypogammaglobulinemia caused by immunochemotherapy, bispecific antibodies, or chimeric-antigen receptor T cell therapy against hematologic neoplasms such as multiple myeloma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or non- Hodgkin lymphoma, is also associated with a high risk of infection [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Several studies report that immunoglobulin replacement therapy may reduce the incidence of infections in patients with primary or secondary hypogammaglobulinemia [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAllogeneic hematopoietic cell transplantation (allo-HCT) shows great potency against hematologic neoplasms because it induces anti-tumor activity through donor-derived immune cells; however, recipients of allo-HCT have impaired immunity against infections until their immune system is fully reconstituted. Approximately one-third of recipients experience secondary hypogammaglobulinemia due to impairment of humoral immunity [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]; however, there is little evidence supporting an association between hypogammaglobulinemia and infection after allo-HCT. In addition, a meta-analysis that included randomized control trials revealed that prophylactic immunoglobulin replacement therapy had no significant effect on the incidence of documented infections or mortality after allo-HCT [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Therefore, the indication of prophylactic immunoglobulin replacement therapy for allo-HCT recipients remains controversial [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eLow immunoglobulin levels can be associated with infection, particularly those caused by bacterial pathogens. Most previous reports of patients receiving allo-HCT have focused on the early phase post-transplantation; there are no data on infections occurring during the late phase of allo-HCT. Moreover, transplantation protocols have advanced markedly over the last decade, particularly with the introduction of post-transplantation cyclophosphamide. Therefore, reassessment of factors associated with bacterial infection is needed. Evidence of an association between hypogammaglobulinemia and infections may support application of immunoglobulin replacement therapy after allo-HCT. Therefore, we comprehensively investigated the impact of several variables, including hypogammaglobulinemia, on the incidence of bacterial infection during different periods post-HCT.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and patient selection\u003c/h2\u003e\u003cp\u003eThis retrospective study was conducted at Osaka Metropolitan University Hospital, Osaka, Japan. Patients who underwent allo-HCT from January 2007 to September 2021, and who had serum IgG levels measured at least once after allo-HCT, were considered eligible. Patients with multiple myeloma were excluded from the study. Data were collected from the institutional database and from the patients\u0026rsquo; medical records focusing on the incidence of bacterial infections during three different post-HCT periods: early (Day 0 to 59), intermediate (Day 60 to 365), and late (Day 366 to 730). Any associations between infection and the study variables, including hypogammaglobulinemia, during each observation period were determined. All participants provided broad written informed consent to participate in this study. The protocol was approved by the appropriate institutional review boards and ethics committees at Osaka Metropolitan University Graduate School of Medicine, and was conducted in accordance with the principles set out in the Declaration of Helsinki.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTransplant procedures and supportive care\u003c/h3\u003e\n\u003cp\u003ePatients received a conditioning regimen appropriate to their age and comorbidities. Patients aged 60 years or younger, and with no comorbidities, received myeloablative conditioning except for those receiving a transplantation from a haploidentical related donor. The remainder received a reduced intensity conditioning regimen. The graft-versus-host disease (GVHD) prophylaxis administered to all patients comprised a calcineurin inhibitor and short-term methotrexate or mycophenolate mofetil, in combination with post-transplantation cyclophosphamide for haploidentical related donors or anti-thymocyte globulin for mismatched unrelated donors or haploidentical related donors. No patients received alemtuzumab or rituximab as GVHD prophylaxis. The following were administered as infection prophylactics: levofloxacin until neutrophil engraftment; fluconazole until 2 months post-transplantation; and acyclovir until discontinuation of immunosuppressants or up to 1 year post-transplantation. Trimethoprim sulfamethoxazole or atovaquone was initiated after neutrophil engraftment to prevent \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e. Letermovir was given routinely to all patients who received allo-HCT after June 2018. In principle, immunoglobulin replacement therapy was performed if serum IgG fell below 5 g/L or if the patient developed a severe infection.\u003c/p\u003e\n\u003ch3\u003eMeasurement of serum IgG levels\u003c/h3\u003e\n\u003cp\u003eSerum IgG levels were measured within the context of routine medical examinations at days 0, 30, 60, 90, 120, 150, 180, 270, 365, and 730 post-transplantation. To ensure accuracy at these evaluation points, a maximum period of deviation of 7 days was allowed for days 0, 30, and 60, and 14 days for day 90 and thereafter. Serum IgG levels were measured in a turbidimetric immunoassay (Auto Kit IgG. N; Fujifilm Wako Pure Chemical Corporation, Osaka, Japan). Reference levels were 0.05\u0026ndash;7.5 g/L.\u003c/p\u003e\n\u003ch3\u003eDefinitions\u003c/h3\u003e\n\u003cp\u003eInfectious events were defined, according to the Infectious Diseases Society of America 2010 guidelines [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], as clinically documented bacterial infections accompanied by clinical symptoms or signs, and localized to a specific anatomical site, as determined by physical examination, imaging, or laboratory findings, with or without microbiological confirmation. In cases lacking microbiological confirmation, only infections that showed a response to antibiotic therapy were included. Isolated fever without localizing signs or microbiological confirmation during the neutropenic period was excluded from the analysis. Hypogammaglobulinemia was defined as the case when a serum IgG trough level was below 5 g/L during each observation period. The serum IgG trough level for each phase was defined as the lowest measured value. Conditioning regimens were classified as myeloablative or reduced intensity in accordance with a previous consensus report [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The hematopoietic cell transplantation specific-comorbidity index (HCT-CI) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], and diagnosis and severity of GVHD, were assessed according to standard criteria [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe Mann-Whitney U test was used to compare serum IgG trough levels between the two groups (those who developed infections and those who did not) during each observation period. To evaluate repeated infectious events per patient, the incidence rates of documented infections were assessed as the \u0026ldquo;incidence density\u0026rdquo;, calculated as the total number of infectious events during the observation period per patient-time of observation. The potential associations between the incidence rate of infections and serum IgG trough levels, or other variables, were analyzed using a negative binomial regression, with effect sizes reported as incidence rate ratios (IRRs) along with respective 95% confidential intervals (95% CI). Patient-time of observation was incorporated into the model as an offset variable. The association between serum IgG trough levels and the incidence rate was depicted using a scatter plot, with a fitted prediction line for each observation period. To avoid issues related to zero values, the incidence rate represents the pseudo-logarithmic transformation of infectious events per person-year. The variables analyzed were age, sex, disease status at transplantation, HCT-CI, a history of transplantation, intensity of the conditioning regimen, graft source, type of GVHD prophylaxis, a history of acute or chronic GVHD, and hypogammaglobulinemia. A history of acute or chronic GVHD was defined as the presence of acute GVHD within 60 days, or chronic GVHD within 1 year, post-transplantation, respectively. \u003cem\u003eP\u003c/em\u003e-values below 0.05 were considered statistically significant. All statistical analyses and generation of graphs were performed using Stata/MP 16.0 (StataCorp LLC, TX, US), GraphPad Prism version 8.2.0 (GraphPad Software, La Jolla, CA, US), and EZR version 1.37 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003ePatients and infection characteristics\u003c/h2\u003e\u003cp\u003eAmong the 587 consecutive allo-HCT recipients enrolled in the study, six were excluded from data analysis: one of these had multiple myeloma, and five did not have serum IgG measurements. Therefore, data from 579 patients were analyzed. Patient characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A total of 239, 133, and 39 events of documented infections were identified during the early, intermediate, and late phase, respectively. Details regarding the sites of infection and the type of pathogen are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal n\u0026thinsp;=\u0026thinsp;579\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, median [range]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e48.0 [16.0\u0026ndash;72.0]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRecipient sex, Male/Female, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e324 (56.0)/255(44.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiagnosis, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcute myeloid leukemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e236 (40.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcute lymphoblastic leukemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e104 (18.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMyelodysplastic syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e94 (16.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMalignant lymphoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e60 (10.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult T cell leukemia/lymphoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e31 (5.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic myelogenous leukemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18 (3.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAplastic anemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18 (3.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18 (3.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease status at transplantation, Remission/Not remission, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e298 (51.5)/ 281 (48.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eECOG performance status, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e292 (50.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e255 (44.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e32 (5.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHCT-CI, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e248 (42.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e107 (18.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e87 (15.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e137 (23.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGraft source, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone marrow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e181 (31.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeripheral blood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e263 (45.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCord blood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e135 (23.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDonor type, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHLA-matched related\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e90 (15.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHLA-matched unrelated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e151 (26.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHLA-mismatched related\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11 (1.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHLA-mismatched unrelated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19 (3.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHaploidentical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e173 (29.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCord blood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e135 (23.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious transplantation, yes/no, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e130 (22.5)/449 (77.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConditioning regimen, Myeloablative/Reduced intensity, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e348 (60.1)/231 (39.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUse of post-transplantation cyclophosphamide, yes/no, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e207 (35.8)/372 (64.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUse of anti-thymocyte globulin, yes/no, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e63 (10.9)/516 (89.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eType of infection site and pathogen\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eObservation period\u003c/p\u003e\u003cp\u003eTotal events\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEarly phase\u003c/p\u003e\u003cp\u003e239\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIntermediate phase\u003c/p\u003e\u003cp\u003e133\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLate phase\u003c/p\u003e\u003cp\u003e39\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eInfection site, event (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePneumonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e27 (11.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e38 (28.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12 (30.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUrinary tract\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8 (6.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (7.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGastrointestinal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e36 (14.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e18 (13.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (12.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBacteremia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e140 (58.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e42 (31.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (15.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e35 (14.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e27 (20.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13 (33.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003ePathogen, event (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eStaphylococcus\u003c/em\u003e spp.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e90 (37.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e33 (24.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (10.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eStreptococcus\u003c/em\u003e spp.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15 (6.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2 (1.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (5.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eCorynebacterium\u003c/em\u003e spp.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e16 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eEnterococcus\u003c/em\u003e spp.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e20 (8.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e9 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eEscherichia Coli\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6 (2.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6 (4.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eClostridium difficile\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e34 (13.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e11 (8.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003ePseudomonas\u003c/em\u003e spp.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4 (1.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4 (3.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (7.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eStenotrophomonas Maltophilia\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e13 (5.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2 (1.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6 (2.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e20 (15.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnspecified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e35 (14.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e45 (33.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e28 (71.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSerum IgG trough levels and the incidence of infection during each phase\u003c/h3\u003e\n\u003cp\u003eDuring each phase, we compared serum IgG trough levels of patients who developed bacterial infections with those of the patients who did not (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea\u0026ndash;c). During the intermediate phase, the serum IgG trough level in patients with infections was significantly lower than that in those without infections (5.39 \u003cem\u003evs.\u003c/em\u003e 6.00 g/L, respectively; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01); however, there were no differences between the groups during the early (6.50 \u003cem\u003evs.\u003c/em\u003e 6.53 g/L, respectively; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.37) or late (8.60 \u003cem\u003evs.\u003c/em\u003e 9.30 g/L, respectively; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.53) phases. Next, we examined the association between the incidence rate of bacterial infections and serum IgG trough levels. Although there were no significant associations during the early (IRR, 0.97; 95% CI: 0.92\u0026ndash;1.02, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.21) and late (IRR, 0.98; 95% CI: 0.90\u0026ndash;1.07, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.67) phases, the incidence rate of bacterial infections fell as serum IgG trough levels increased during the intermediate phase (IRR, 0.85; 95% CI: 0.78\u0026ndash;0.94, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea\u0026ndash;c).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eVariables associated with infections during each phase\u003c/h2\u003e\u003cp\u003eNext, we examined the association between possible variables and the incidence rate of bacterial infections during each phase (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). During the early phase, cord blood as the graft source (IRR, 1.76; 95% CI: 1.26\u0026ndash;2.46, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and the high score of HCT-CI (IRR, 1.61; 95% CI: 1.22\u0026ndash;2.13, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) were associated with the risk of infections. Hypogammaglobulinemia was not associated with infection risk. During the intermediate phase, hypogammaglobulinemia (IRR, 1.70; 95% CI:1.11\u0026ndash;2.62, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) and grade II\u0026ndash;IV acute GVHD (IRR, 2.10; 95% CI: 1.39\u0026ndash;3.18, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) were associated with an increased incidence of infections. During the late phase, none of the variables, including hypogammaglobulinemia, were associated with an increased incidence of infections. There was no association between the use of post-transplantation cyclophosphamide and an increased incidence of infection during any phase.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAssociation between variables and the incidence of bacterial infections during each observation period\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eEarly phase\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eIntermediate phase\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003eLate phase\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIRR (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIRR (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eIRR (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.01 (1.00\u0026ndash;1.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.01 (0.99\u0026ndash;1.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.00 (0.97\u0026ndash;1.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.31 (1.01\u0026ndash;1.71)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.85 (0.56\u0026ndash;1.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.64 (0.30\u0026ndash;1.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNot remission at transplantation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.13 (0.87\u0026ndash;1.48)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.49 (0.98\u0026ndash;2.26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.99 (0.45\u0026ndash;2.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.98\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHCT-CI\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1.61\u003c/b\u003e (1.22\u0026ndash;2.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.74 (0.44\u0026ndash;1.26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.30 (0.53\u0026ndash;3.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious transplantation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.81 (0.57\u0026ndash;1.16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.36 (0.80\u0026ndash;2.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.99 (0.70\u0026ndash;5.64)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.20\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMyeloablative conditioning\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.25 (0.92\u0026ndash;1.70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.06 (0.64\u0026ndash;1.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.07 (0.40\u0026ndash;2.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.90\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeripheral blood (vs Bone marrow)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.86 (0.58\u0026ndash;1.29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.38 (0.76\u0026ndash;2.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.38 (0.53\u0026ndash;3.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCord blood (vs Bone Marrow)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1.76\u003c/b\u003e (1.26\u0026ndash;2.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.16 (0.66\u0026ndash;2.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.72 (0.25\u0026ndash;2.12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUse of post-transplantation cyclophosphamide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.26 (0.84\u0026ndash;1.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.69 (0.37\u0026ndash;1.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.63 (0.20\u0026ndash;1.96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUse of anti-thymocyte globulin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.37 (0.92\u0026ndash;2.03)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.23 (0.62\u0026ndash;2.41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.89 (0.23\u0026ndash;3.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcute GVHD with grade II\u0026ndash;IV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e2.10\u003c/b\u003e (1.39\u0026ndash;3.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.42 (0.67\u0026ndash;3.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic GVHD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.85 (0.79\u0026ndash;4.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypogammaglobulinemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.21 (0.89\u0026ndash;1.65)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e1.70\u003c/b\u003e (1.11\u0026ndash;2.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.89 (0.28\u0026ndash;2.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eAbbreviations: IRR, incidence rate ratio; CI, confidence interval; HCT-CI, hematopoietic cell transplantation specific comorbidity-index; GVHD, graft-versus-host disease\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis retrospective single-institution study revealed a significant association between hypogammaglobulinemia and the incidence rate of bacterial infections during the intermediate phase post-allo-HCT. To the best of our knowledge, this report is the first to demonstrate the impact of hypogammaglobulinemia on the incidence of infections during a specific period after allo-HCT.\u003c/p\u003e\u003cp\u003eAlthough a previous study shows that allo-HCT recipients with hypogammaglobulinemia have shorter survival times [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], and that unlike immunochemotherapy for hematologic neoplasms [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], prophylactic immunoglobulin replacement therapy does not reduce the risk of infections or mortality in the setting of allo-HCT [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Lacombe et al. also reported that IgG levels were not associated with the occurrence of infections within the first 100 days following allo-HCT [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. However, these studies mainly assessed the efficacy of routine prophylactic immunoglobulin replacement therapy, or the association between IgG levels and infections during the relatively early phase post-allo-HCT. Few studies have focused on intermediate or late phases.\u003c/p\u003e\u003cp\u003eImpairment of humoral immunity can affect the risk of infections, particularly those caused by bacterial pathogens. The function of immunoglobulins is to opsonize microbes effectively targeting them for phagocytosis and intracellular killing by neutrophils and macrophages, and for antibody-dependent cell-mediated cytotoxicity exerted by natural killer cells; immunoglobulin also neutralizes toxins and pathogens, and triggers lysis by activating the complement cascade [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Because phagocytosis by neutrophils, macrophages, or natural killer cells plays a central role in defense against bacterial infections, immunoglobulins may not work well if these components of the innate immune response are lacking. Thus, considering the period required for immune cell recovery after allo-HCT [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], insufficient recovery of neutrophils, macrophages, or natural killer cells during the early phase should be the principal risk factor for bacterial infections, irrespective of immunoglobulin levels. However, once neutrophil, macrophage, and natural killer cell have recovered during the intermediate phase, hypogammaglobulinemia can impact the risk of bacterial infections. When immunoglobulin levels have recovered (usually about 1 year post-transplantation), the optimal level of immunoglobulins reduces the impact on the risk of bacterial infections. Therefore, it seems that immunoglobulin levels can be a major determinant of the risk of bacterial infections during the intermediate phase after allo-HCT as it is the period between after the recovery of neutrophil, macrophage, or natural killer cell and before recovery of B cell or immunoglobulin. The data presented herein suggest that the beneficial effects of immunoglobulin replacement therapy might be maximal during intermediate phase after allo-HCT. Indeed, this hypothesis is supported, at least in part, by a single-institution study demonstrating the possible efficacy of subcutaneous immunoglobulin replacement therapy after 60 days of transplantation [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis study has several limitations. First, this was a retrospective single-institution study. Second, immunoglobulin replacement therapy may affect serum IgG levels; however, as our institutional strategy is to administered immunoglobulins when serum IgG level is below 5 g/L, immunoglobulin replacement therapy would minimize the influence of hypogammaglobulinemia (defined as a trough level below 5 g/L). Third, the frequency of infectious events during the late phase was relatively low. Any future study should use a larger sample size to increase the accuracy of the analysis.\u003c/p\u003e\u003cp\u003eIn conclusion, we found a significant association between hypogammaglobulinemia and the incidence of bacterial infections during the intermediate phase after allo-HCT. This may be due to a combination of immunoglobulin levels and recovery of innate immune cells during this phase; thus, the beneficial effects of immunoglobulin replacement therapy might be maximal at this time. Further studies are warranted to establish the optimal strategy of immunoglobulin replacement therapy for allo-HCT recipients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003ePotential conflicts of interest\u003c/h2\u003e\n\u003cp\u003eM.H. has received research funding from Takeda Pharmaceuticals and the Japan Blood Products Organization, as well as speaker\u0026rsquo;s honoraria from Takeda Pharmaceuticals. H.N. has received research funding and speaker\u0026rsquo;s honoraria from Takeda Pharmaceuticals. H.O. has received research funding from Takeda Pharmaceuticals. M. Nishimoto has received speaker\u0026rsquo;s honoraria from CSL Behring. The other authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003ch2\u003eCompeting Interests\u003c/h2\u003e\n\u003cp\u003eM.H. has received research funding from Takeda Pharmaceuticals and the Japan Blood Products Organization, as well as speaker\u0026rsquo;s honoraria from Takeda Pharmaceuticals. H.N. has received research funding and speaker\u0026rsquo;s honoraria from Takeda Pharmaceuticals. H.O. has received research funding from Takeda Pharmaceuticals. M. Nishimoto has received speaker\u0026rsquo;s honoraria from CSL Behring. The other authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eM. Nishimoto conceived the study; H.Y., M. Nishimoto, H. K-M., M. Nakamae, and H.O. performed clinical data analysis; H.Y. and M. Nishimoto wrote the manuscript with help from all other authors. All authors discussed the results and commented on the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eWe thank the patients and their families, and all nurses and data managers, for their contribution to the study.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDurandy A, Kracker S, Fischer A (2013) Primary antibody deficiencies. Nat Rev Immunol 13(7):519\u0026ndash;533\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAguilar C, Malphettes M, Donadieu J, Chandesris O, Coignard-Biehler H, Catherinot E et al (2014) Prevention of infections during primary immunodeficiency. Clin Infect Dis 59(10):1462\u0026ndash;1470\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSyed MN, Kutac C, Miller JM, Marsh R, Sullivan KE, Cunningham-Rundles C et al (2022) Risk Factors of Pneumonia in Primary Antibody Deficiency Patients Receiving Immunoglobulin Therapy: Data from the US Immunodeficiency Network (USIDNET). J Clin Immunol 42(7):1545\u0026ndash;1552\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePatel SY, Carbone J, Jolles S (2019) The Expanding Field of Secondary Antibody Deficiency: Causes, Diagnosis, and Management. Front Immunol 10:33\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWudhikarn K, Perales MA (2022) Infectious complications, immune reconstitution, and infection prophylaxis after CD19 chimeric antigen receptor T-cell therapy. Bone Marrow Transpl 57(10):1477\u0026ndash;1488\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZugmaier G, Topp MS, Alekar S, Viardot A, Horst HA, Neumann S et al (2014) Long-term follow-up of serum immunoglobulin levels in blinatumomab-treated patients with minimal residual disease-positive B-precursor acute lymphoblastic leukemia. Blood Cancer J 4(9):244\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOscier D, Dearden C, Eren E, Fegan C, Follows G, Hillmen P et al (2012) Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia. Br J Haematol 159(5):541\u0026ndash;564\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOrange JS, Grossman WJ, Navickis RJ, Wilkes MM (2010) Impact of trough IgG on pneumonia incidence in primary immunodeficiency: A meta-analysis of clinical studies. Clin Immunol 137(1):21\u0026ndash;30\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVacca A, Melaccio A, Sportelli A, Solimando AG, Dammacco F, Ria R (2018) Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial. Clin Immunol 191:110\u0026ndash;115\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArai Y, Yamashita K, Mizugishi K, Kondo T, Kitano T, Hishizawa M et al (2014) Risk factors for hypogammaglobulinemia after allo-SCT. Bone Marrow Transpl 49(6):859\u0026ndash;861\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKarakulska-Prystupiuk E, Dwilewicz-Trojaczek J, Drozd-Sokołowska J, Kmin E, Chlebus M, Szczypińska K et al (2021) Prevalence of hypogammaglobulinemia and its management with subcutaneous immunoglobulin supplementation in patients after allogeneic hematopoietic stem cell transplantation-a single-center analysis. Ann Hematol 100(12):3007\u0026ndash;3016\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAhn H, Tay J, Shea B, Hutton B, Shorr R, Knoll GA et al (2018) Effectiveness of immunoglobulin prophylaxis in reducing clinical complications of hematopoietic stem cell transplantation: a systematic review and meta-analysis. Transfusion 58(10):2437\u0026ndash;2452\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRaanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O (2009) Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and meta-analysis. J Clin Oncol 27(5):770\u0026ndash;781\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOhmoto A, Fuji S, Shultes KC, Savani BN, Einsele H (2022) Controversies about immunoglobulin replacement therapy in HSCT recipients with hypogammaglobulinemia. Bone Marrow Transpl 57(6):874\u0026ndash;880\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFreifeld A, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA et al (2011) Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 52(4):e56\u0026ndash;93\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al (2009) Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transpl 15(12):1628\u0026ndash;1633\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al (2005) Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 106(8):2912\u0026ndash;2919\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePrzepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al (1995) 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. ;15(6):825-8\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al (2015) National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transpl 21(3):389\u0026ndash;401e1\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transpl 48(3):452\u0026ndash;458\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNorlin AC, Sairafi D, Mattsson J, Ljungman P, Ringd\u0026eacute;n O, Remberger M (2008) Allogeneic stem cell transplantation: low immunoglobulin levels associated with decreased survival. Bone Marrow Transpl 41(3):267\u0026ndash;273\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUeda M, Berger M, Gale RP, Lazarus HM (2018) Immunoglobulin therapy in hematologic neoplasms and after hematopoietic cell transplantation. Blood Rev 32(2):106\u0026ndash;115\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCordonnier C, Chevret S, Legrand M, Rafi H, Dh\u0026eacute;din N, Lehmann B et al (2003) Should immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, double-blind, dose effect, placebo-controlled, multicenter trial. Ann Intern Med 139(1):8\u0026ndash;18\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHowell JE, Gulbis AM, Champlin RE, Qazilbash MH (2012) Retrospective analysis of weekly intravenous immunoglobulin prophylaxis versus intravenous immunoglobulin by IgG level monitoring in hematopoietic stem cell transplant recipients. Am J Hematol 87(2):172\u0026ndash;174\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLacombe V, Nunes Gomes C, Robin JB, Th\u0026eacute;pot S, Fran\u0026ccedil;ois S, Cottin L et al (2021) Risk of infection according to the gamma globulin level in the 100 days following allogeneic stem cell transplantations. Eur J Haematol 107(4):489\u0026ndash;496\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePedraza-S\u0026aacute;nchez S, Cruz-Gonz\u0026aacute;lez A, Palmeros-Rojas O, G\u0026aacute;lvez-Romero JL, Bellanti JA, Torres M (2022) Polyvalent human immunoglobulin for infectious diseases: Potential to circumvent antimicrobial resistance. Front Immunol 13:987231\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStorek J (2008) Immunological reconstitution after hematopoietic cell transplantation - its relation to the contents of the graft. Expert Opin Biol Ther 8(5):583\u0026ndash;597\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSuga M, Fuji S, Tada Y, Tsutsumi K, Kida S, Shibata K et al (2024) A single-institution pre-post comparison of subcutaneous immunoglobulin replacement therapy in allogeneic haematopoietic cell transplantation recipients. Br J Haematol 204(1):260\u0026ndash;267\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7344293/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7344293/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Infections are major complications in patients with hematologic neoplasms. Humoral immunity plays a critical role in defense against pathogens. Although hypogammaglobulinemia can carry a risk of infection, there is no confirmed association between low immunoglobulin levels and bacterial infections after allogeneic hematopoietic cell transplantation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: In this study, we assessed the association between different variables, including hypogammaglobulinemia, and the incidence of bacterial infections in 579 consecutive patients receiving allogeneic hematopoietic cell transplantation. Data obtained during three different periods post-transplantation (early, intermediate, and late) were analyzed retrospectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e During the intermediate phase, the median serum trough level of IgG was significantly lower in patients with bacterial infections than in those without (5.39 \u003cem\u003evs.\u003c/em\u003e 6.00 g/L, respectively; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.01); however, there was no difference during the early (6.50 \u003cem\u003evs.\u003c/em\u003e 6.53 g/L, respectively; \u003cem\u003ep\u003c/em\u003e=0.37) or late (8.60 \u003cem\u003evs.\u003c/em\u003e 9.30 g/L, respectively; \u003cem\u003ep\u003c/em\u003e=0.53) phases. The incidence of bacterial infections during the intermediate phase fell as the serum IgG trough level increased (incidence rate ratio, 0.85; 95% confidence interval: 0.78–0.94, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.01). Hypogammaglobulinemia (incidence rate ratio, 1.70; 95% confidence interval: 1.11–2.62, \u003cem\u003ep\u003c/em\u003e=0.02), as well as grade II–IV acute graft-versus-host disease (incidence rate ratio, 2.10; 95% confidence interval: 1.39–3.18, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.01), was significantly associated with bacterial infections solely during the intermediate phase.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThere was a significant association between hypogammaglobulinemia and bacterial infections solely during the intermediate phase post-transplantation. Immunoglobulin levels and recovery of innate immune cells may affect the incidence of bacterial infections.\u003c/p\u003e","manuscriptTitle":"Impact of hypogammaglobulinemia on bacterial infections after allogeneic hematopoietic cell transplantation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-03 16:47:16","doi":"10.21203/rs.3.rs-7344293/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"232659e9-cabe-4aba-9518-becc136f9638","owner":[],"postedDate":"October 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-09T15:08:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-03 16:47:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7344293","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7344293","identity":"rs-7344293","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}