Profiling risk factors for separation of infection complications in patients with gastrointestinal and nodal diffuse large B-cell lymphoma

doi:10.21203/rs.3.rs-2863213/v1

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Research Article

Profiling risk factors for separation of infection complications in patients with gastrointestinal and nodal diffuse large B-cell lymphoma

https://doi.org/10.21203/rs.3.rs-2863213/v1

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Journal Publication

published 20 Oct, 2023

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Objective:

To identify risk factors for infection complications in patients with gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) and nodal DLBCL (N-DLBCL) during treatment, respectively.

Methods:

Total 51 GI-DLBCL patients and 80 N-DLBCL patients were included after retrieving clinical data from a single medical center in the past ten years. Logistic regression analysis was utilized to analyze patients’ data, including baseline demographics, treatments and laboratory values, to determine independent risk factors of infection.

Results:

28 of 51 patients (54.9%) in the GI-DLBCL group and 52 of 80 patients (65%) in the N-DLBCL group were observed infection events during treatment. A multivariate logistic regression model revealed that Ann-arbor stage IV (P=0.046; OR: 22.867; 95%CI: 1.053-496.508) and high serum lactic dehydrogenase (LDH) at the time of diagnosis (LDH >252U/L; P= 0.036; OR: 1.110; 95%CI: 1.105-21.456) were independent risk factors for the development of infection in patients with GI-DLBCL after systemic treatment. In the N-DLBCL group, low hemoglobin (Hb) (P= 0.037; OR: 0.970; 95%CI: 0.943-0.998) at the time of diagnosis, high serum C-reactive protein (CRP) (P= 0.046; OR: 4.869; 95%CI: 1.020-1.209) and low platelet (P= 0.016; OR: 0.991; 95%CI: 0.982-1.000) at pre-infected laboratory examination were significant factors in the infection events during treatment.

Conclusions:

Discordant impendent risk factors induced infection may be present during the treatment in patients of GI-DLBCL and N-DLBCL. Close monitoring these risk factors is likely an effective strategy to prevent microbial infections in these patients.

Infection complications

Risk factors

Gastrointestinal Diffuse Large B-cell lymphoma

Nodal DLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive Non-Hodgkin’s lymphomas arising from nodal as well as extranodal sites. Gastrointestinal (GI) tract is considered be the most common extranodal site of DLBCLs[1, 2].

Systemic treatment is well established in the patients with DLBCL. R-CHOP regiment, which includes rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone is used as a standard first-line therapy, significantly improves overall survival (OS) of DLBCL[3, 4]. The value of consolidative radio-therapy after chemotherapy has not been widely recommended, as a recent large-scale of retrospective study suggested that DLBCL patients have excellent clinical outcomes by using chemotherapy only without consolidative radio-therapy [5, 6]. In the treatment of GI-DLBCL, patients who received surgery followed by post-operation chemotherapy had a better prognosis compared with chemotherapy alone[7, 8]. Although approximately 60% of DLBCL patients benefit from treatments, severe adverse events, such as the late-onset neutropenia, post-chemotherapy pneumonia and urinary tract infection, etc., may occur, leading to reduced dosages or delayed chemo-cycles, and eventually compromise the treatment efficacies [4, 5, 9, 10]. Close monitoring the possible risk factors inducing infection in patients with DLBCL may avoid microbial infections. However, the studies separating the risk factors of infection between extranodal DLBCL (EN-DLBCL) and nodal DLBCL (N-DLBCL) patients are rare. Indeed, EN-DLBCL and N-DLBCL have their unique clinicobiological characteristics[8]. Therefore, the aim of this study was to determine the potential risk factors for infection in patients with GI-DLBCL and N-DLBCL, respectively.

Patient Information and Data Collection

Initially, a total of 139 cases of DLBCL patients (including 52 cases of GI-DLBCL and 87 cases of N-DLBCL) were retrospectively recruited in this study who were treated in the Second Affiliated Hospital of Jiaxing University between January 2013 and March 2022. The study was approved by the Institutional Review Board of the above hospital (grant no. JXEY-2022ZFYJ174), Chinese Academy of Medical Sciences and conducted in accordance with the Declaration of Helsinki.

All the patients met the following criteria: 1) Age ≥ 18 years; 2) DLBCL patients were pathologically diagnosed based on the 2016 WHO classification[11]. 3) R-CHOP or CHOP regimens are used as the first-line regimens for patients.

8 patients were excluded eventually due to meeting one of the following reasons:1) patients who diagnosed or initially treated by other hospital; 2) Patients with a large number of missing clinical data required by this study. 3) Patients with history of thoracic radiotherapy. Finally, total 131 DLBCL patients were adopted in this study including 51 patients with gastrointestinal DLBCL and 80 patients with nodal DLBCL.

All DLBCL patients were further divided into infection and non-infection subgroups. Our study only counted the occurrence of first infection events. Infection in this study was diagnosed as one of the following conditions according to previously published literatures: (1) microbiologically pathogens confirmed by all kinds of cultures, such as blood or urine. (2) Pulmonary inflammatory lesions including interstitial pneumonia or signs of inflammation at an anatomic site be identified by CT scan or radiography. (3) body temperature was higher than 38.0°C during disease course, with neutrophils < 1.0×10⁹/L [3, 12, 13]. The whole procedure of this study was present in Fig. 1.

To determine the risk factors for infection, the clinical characteristics (such as gender, age, sex, Ann-arbor stage), treatments and selected hematological and biochemical parameters at the time of diagnosis and at pre-infected laboratory examination (blood indicators examined before the start of the most recent chemotherapy cycle followed by infection complications) of 131 patients were analyzed. The international prognostic index (IPI) scores were calculated 5 risk factors, including age > 60 years, stage III/IV disease, elevated lactate dehydrogenase [LDH] level, Eastern Cooperative Oncology Group [ECOG] performance status ≥ 2, more than one extranodal site of disease[14].

Statistical Analysis

Statistical Package for the Social Sciences (SPSS), version 25.0 (IBM Inc., Chicago, IL, USA) was used for data analysis. The variables were divided into dichotomous data and continuous variables based on the types of data. Dichotomous data were analyzed using the Fisher exact test or the chi square test and continuous variables with the Wilcoxon rank sum test, as appropriate. Univariate analysis was used to determine those risk factors associated with development of gastrointestinal DLBCL and nodal DLBCL infection. The factors with P < 0.2 were selected and included in the logistic regression analysis. Potential confounding factors and multicollinearity were evaluated, and the factors strongly associated with other significant factors were excluded from the multivariate analysis. Odds Ratios (ORs) and 95% Confidence Intervals (CIs) were calculated to evaluate the strength of any association. All statistical tests were two-tailed and P < 0.05 was considered statistically significant.

Clinical characteristics of 131 DLBCL patients.

The characteristics of the 131 patients with DLBCL (51 cases of GI-DLBCL patients and 80 N-DLBCL patients) were presented in Table 1. In 51 patients with GI-DLBCL, 31 (60.8%) patients were male and the median age was 67 years (range, 22-83 years).37 (72.4%) GI-DLBCL patients were categorized into Ann-arbor stage III-IV, and 32 (62.7%) patients had high level of IPI scores (IPI score >3). About half of the GI-DLBCL patients underwent surgical resection and postoperative chemotherapy. Of the 80 N-DLBCL patients, 39 (48.8%) patients were male, the median age was 64 years (range, 23-85 years), 60 (75.0%) patients were categorized into Ann-arbor stage III-IV, and 43 (53.8%) patients had high level of IPI scores (IPI score >3).

Infections were observed in 80 (61.1%) patients with DLBCL, including 28 patients with GI-DLBCL and 52 patients with N-DLBCL. The sites of infection were showed in Table 2. The most common sites of infection were respiratory tract (63.8%), followed by blood stream infection (12.5%).

The univariate analysis of 131 DLBCL patients.

In the univariate analysis, Ann-arbor stage (P<0.001), IPI scores (P=0.027), some laboratory blood examination parameters at diagnosis including CRP and hemoglobin (P=0.003 and 0.006), and some pre-infected laboratory indicators from blood biochemical examination before infection including the levels of CRP (P=0.011), erythrocyte (P=0.033), hemoglobin (P=0.004), NLR (P=0.021), platelet (P=0.015) and total bilirubin (P=0.001) were statistically significant factors associating with infection in follow up. (Table 3)

Independent risk factors of infectious events in 131 DLBCL patients

Factors which significant predictors of infection in the multivariable analysis included Ann-arbor stage III (P: 0.008; OR: 11.991; 95% CI: 1.938-74.183) and IV (P: < 0.001; OR: 64.163; 95% CI: 7.636-539.136). Patients with DLBCL who had high LDH level at the time of diagnosis (LDH ≥252 U/L) had a higher risk of infection, as compared with patients with LDH <252 U/L (P: 0.015; OR: 3.106; 95% CI: 1.241-7.773). (Table 4)

The univariate analysis of GI-DLBCL patients.

The univariate analysis of risk factors for infection in GI-DLBCL patients were summarized in Table 5. Among the 51 patients with GI-DLBCL, 28 (54.9%) patients experienced infection during treatment. Variables associated with the development of infection during treatment in this study were Ann-arbor stage (P=0.016), IPI scores (P = 0.022), the levels of LDH at diagnosis (P=0.013) and pre-infected white blood cell (WBC) (P=0.025), pre-infected neutrophils (P=0.025) and pre-infected neutrophil/lymphocyte ratio (NLR) (P=0.034). However, surgical treatment was not a risk factor as no statistically significant differences were observed between infected and non-infected groups (P >0.05) (Table 5).

The multivariate logistic regression analysis of risk factors for developing infection in GI-DLBCL patients.

The multivariate logistic regression method was used to further study the risk factors for infection in GI-DLBCL patients. The results were detailed in Table 6. Ann-arbor stage IV (P: 0.046; OR: 22.867; 95% CI: 1.053-496.508) and high LDH level at the time of diagnosis (LDH ≥252U/L; P: 0.036; OR: 1.110; 95% CI: 1.105-21.456) were identified as independent risk factors for infection in the GI-DLBCL group.

The univariate analysis of N-DLBCL patients.

The univariate analysis of possible risk factors for infection was also conducted in patients with N-DLBCL and present in Table 7. 52 of the 80 (65%) patients with N-DLBCL developed infection during treatment. Ann-arbor staging (P < 0.01), IPI scores (P = 0.005) and some pre-infected laboratory indicators including total bilirubin (P=0.001), NLR (P=0.021), erythrocyte (P=0.013) and platelets (P=0.015) were statistical different between infected group and non-infected group. Moreover, hemoglobin (Hb) and C-reactive protein (CRP) whether at diagnosis or before infection were significantly different between the infected group and the non-infected group in N-DLBCL patients (P < 0.05).

The multivariate logistic regression analysis of risk factors for developing infection in N-DLBCL patients.

Multivariate logistic regression analysis of N-DLBCL patients was carried out and detailed in Table 8. Low level of Hb at diagnosis (P: 0.037; OR: 0.970; 95%CI: 0.943-0.998), elevated pre-infected CRP (P: 0.046; OR: 4.869; 95%CI: 1.020-1.209) and pre-infected platelet (P: 0.016; OR: 0.991; 95%CI: 0.982-1.000) were observed as independent risk factors for infection in N-DLBCL patients.

Infections are common adverse events both in patients with EN-DLBCL and N-DLBCL while undergoing systemic treatment. In accordance with previous retrospective studies, the incidence of pneumonia is about 5.6%-29.3% in DLBCL patients receiving chemotherapy [3, 15]. Infections often reduced the quality of patient's life and result in poor OS eventually[3, 12]. In addition to pulmonary infections, urinary tract, gastrointestinal tract are also common sites, with even severe infections, such as sepsis. However, to our knowledge, studies are lacking in separating the independent risk factors between the patients with GI-DLBCL and N-DLBCL. For patients with GI-DLBCL, surgical resection is considered as an initial choice followed by post-operative chemotherapy, whereas patients with N-DLBCL are mainly treated with chemotherapy only. In GI-DLBCL, whether surgical procedure serves as an independent risk factor GI-DLBCL is still required to be further illuminated. Additionally, in our study, we tried to identify risk factors for infection of GI-DLBCL and N-DLBCL patients in order to remove these risk factors by earlier intervention.

Surgical resection followed by post-operative chemotherapy is considered to be a standard treatment for the management of patients with managing GI-DLBCL[16, 17]. In our study, 28 of 51 GI-DLBCL patients received surgery combined with chemotherapy, but compared with 23 GI-DLBCL patients treated with chemotherapy only, no statistically difference was observed between two groups. Therefore, we consider that surgery is unlikely to be an independent risk factor for developing infection during GI-DLBCL treatment. But this study is based on retrospective data with a small statistical sample size, bias cannot be excluded completely. This conclusion should be further validated in a well-designed prospective study with a large sample size.

In the present study, univariate analysis revealed that in patients with GI-DLBCL, Ann-arbor staging, IPI scores, LDH levels at diagnosis and some laboratory indicators including WBC, neutrophils and NLR at pre-infected laboratory examination were associated with the development of infection during treatment. Ann-arbor stage IV and high serum levels of LDH at the time of diagnosis were observed as independent risk factors for infection complications in GI-DLBCL patients during treatment by further multivariate logistic regression analysis in this study. DLBCL patients with advanced Ann-arbor stage (stage III/IV) have poor total physical energy status compared with patients with early stage (stage I/II), particularly in stage IV patients with bone marrow metastases who are in a high risk of developing infection due to impaired hematopoietic activities and poor immune function. According to a previous study, advanced Ann-arbor stage is an independent risk factor for pneumonia in patients with DLBCL after chemo-drugs, however this study did not separate the EN-DLBCL and N-DLBCL patients[3]. In addition, elevation of LDH number is an individual risk factor of the IPI score (IPI score ≥ 3) that is frequently used to evaluate predict the poor prognosis of non-Hodgkin’s lymphoma[13, 18]. In our study, we identified that high serum levels of LDH at the time of diagnosis were an independent risk factor for infection in GI-DLBCL patients during treatment rather than high levels of IPI scores. This observation supported by a retrospective study which was showed that elevated LDH was associated with an increased risk for developing neutropenia in patients with lymphoma after chemotherapy[12]. Elevation of serum LDH has the abilities suppressing the immune system and altering the tumor microenvironment[19].

N-DLBCL is the most common subtype of DLBCLs. The univariate analysis of patients with N-DLBCL revealed that Ann-arbor staging, IPI scores, CRP levels at diagnosis, Hb levels at diagnosis, and some laboratory indicators including total bilirubin, NLR, CRP, erythrocyte, Hb and platelets at pre-infected laboratory examination were associated with the development of infection during treatment. Further multivariate logistic regression analysis showed that low levels of Hb at diagnosis, high serum levels of CRP and decreased platelets at pre-infected laboratory examination were identified independent risk factors for infection in N-DLBCL treatment in our study. These data indicate that the myelosuppressive state before chemotherapy plays a key role for the development of infection in N-DLBCL patients. DLBCL patients with advanced stage are prone to develop moderate to severe myelosuppression pre- and post-treatment. We observed advanced stage in patients with N-DLBCL in this study, as approximately 75% patients diagnosed with III/IV stage. A previous study reported that low serum levels of Hb (Hb < 12 g/dl) increase the risk of febrile neutropenia in NHL patients receiving chemotherapy[20]. Platelets have the ability to modulate the function various immune cells and participate interaction between pathogens and host defense[21, 22]. Severe thrombocytopenia increases the probability of bacteremia, tissue damage, etc.[21]. In addition, CRP is often used as a laboratory parameter for inflammatory diseases. It rises rapidly at the early stages of infection, which helps to earlier diagnose patients with latent infection[23]. Our study observed that elevated serum levels of CRP at pre-infected laboratory examination increased 4.8 times of infection and served as an independent risk factor for infection complications in N-DLBCL treatment. However, neutrophils and NLR, popular parameters used to evaluate early infection, did not showed to be independent risk factors for infection in patients with N-DLBCL in our study. This may be due to prophylactic use of colony-stimulating factor (CSF) in lots of patients and their neutrophils were maintained at normal or high levels. These data supported by previous studies showing injecting CSF can reduce the risk of infection in cancer patients with myelosuppression after chemotherapy[24, 25]. Interestingly, Ann-arbor stage and increased serum levels of LDH did not show to be independent risk factors in N-DLBCL by multivariate logistic regression analysis, which was different from GI-DLBCL. The morbidity ratio of GI-DLBCL is lower compared to N-DLBCL due to different clinical characteristics such as early clinical stage and normal serum LDH levels in patients with GI-DLBCL[26].

Our study suggests that there are discordant impendent risk factors inducing infection during GI-DLBCL and N-DLBCL treatment. In GI-DLBCL patients, surgical procedure is unlikely to be an independent risk factor for developing infection during treatment. It may be valuable for monitoring risk factors for infection in GI-DLBCL and N-DLBCL separately.

GI-DLBCL	Gastrointestinal diffuse large B-cell lymphoma
N-DLBCL	Nodal diffuse large B-cell lymphoma
DLBCL	Diffuse large B-cell lymphoma
LDH	High serum lactic dehydrogenase
OS	Overall survival
IPI	International prognostic index
ECOG	Eastern cooperative oncology group
SPSS	Statistical package for the social sciences
ORs	Odds ratios
CIs	Confidence intervals
WBC	White blood cell
NLR	Neutrophil/lymphocyte ratio
CRP	C-reactive protein
Hb	Hemoglobin
CSF	Colony-stimulating factor

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki. This study has been approved by the Ethics Committee of the Second Affiliated Hospital of Jiaxing University and the related informed consent has been received (grant no. JXEY-2022ZFYJ174). All authors read and approved the final manuscript.

Consent for publication

Not applicable.

Availability of data and material

All data generated or analyzed during this study are included in this published article.

Competing interests

The authors report there are no competing interests to declare.

Funding

This work was supported by the Science and Technology Bureau of Jiaxing (grant no. 2021AY30019).

Authors' contributions

Min Xue performed clinical data collection, analyses, and the manuscript writing. ML Yan, ZZ Gao reviewed and analyzed partial data. Y Bao designed this study and mentored Min Xue clinical data collection and revised the manuscript. All authors read and approved the final manuscript.

Acknowledgments: Not applicable

Shi Y, Han Y, Yang J, Liu P, He X, Zhang C, Zhou S, Zhou L, Qin Y, Song Y et al. Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin: Analysis of 1,085 WHO classified cases in a single institution in China. Chin J Cancer Res 2019, 31(1):152-161.
Li P, Chai J, Chen Z, Liu Y, Wei J, Liu Y, Zhao D, Ma J, Wang K, Li X et al. Genomic Mutation Profile of Primary Gastrointestinal Diffuse Large B-Cell Lymphoma. Front Oncol 2021, 11:622648.
Wang J, Liu F, Tang X. Incidence and risk factors of pneumonia in diffuse large B-cell lymphoma patients receiving first line R-CHOP/R-CHOP-like immunochemotherapy: a retrospective study of 287 patients in single center. Ann Palliat Med 2021, 10(11):11931-11938.
Wang L, Li LR. R-CHOP resistance in diffuse large B-cell lymphoma: biological and molecular mechanisms. Chin Med J (Engl) 2020, 134(3):253-260.
Sehn LH, Salles G. Diffuse Large B-Cell Lymphoma. N Engl J Med 2021, 384(9):842-858.
Freeman CL, Savage KJ, Villa DR, Scott DW, Srour L, Gerrie AS, Brown MJ, Slack GW, Farinha P, Skinnider B et al. Long-term results of PET-guided radiation in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP. Blood 2021, 137(7):929-938.
Zhao F, Qin Y, Yang J, Liu P, He X, Zhou L, Zhou S, Gui L, Zhang H, Wang X et al. R-CHOP immunochemotherapy plus surgery is associated with a superior prognosis in Chinese primary intestinal diffuse large B-cell lymphoma. Asia Pac J Clin Oncol 2020, 16(6):385-391.
Fan X, Zang L, Zhao BB, Yi HM, Lu HY, Xu PP, Cheng S, Li QY, Fang Y, Wang L et al. Development and validation of prognostic scoring in primary intestinal diffuse large B-cell lymphoma: a single-institution study of 184 patients. Ann Transl Med 2021, 9(20):1542.
Bai Z, Zhou Y. A systematic review of primary gastric diffuse large B-cell lymphoma: Clinical diagnosis, staging, treatment and prognostic factors. Leuk Res 2021, 111:106716.
Ram R, Ben-Bassat I, Shpilberg O, Polliack A, Raanani P. The late adverse events of rituximab therapy--rare but there! Leuk Lymphoma 2009, 50(7):1083-1095.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016, 127(20):2375-2390.
Yildiz A, Albayrak M, Pala C, Sahin O, Afacan Ozturk HB, Gunes G, Maral S, Okutan H. Infections in patients with lymphoma: An analysis of incidence, relationship and risk factors. J Infect Dev Ctries 2018, 12(9):741-747.
Dendle C, Gilbertson M, Spelman T, Stuart RL, Korman TM, Thursky K, Opat S, McQuilten Z. Infection is an Independent Predictor of Death in Diffuse Large B Cell Lymphoma. Sci Rep 2017, 7(1):4395.
Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, Klasa R, Savage KJ, Shenkier T, Sutherland J et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007, 109(5):1857-1861.
Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S et al. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica 2017, 102(11):1913-1922.
Kim SJ, Kang HJ, Kim JS, Oh SY, Choi CW, Lee SI, Won JH, Kim MK, Kwon JH, Mun YC et al. Comparison of treatment strategies for patients with intestinal diffuse large B-cell lymphoma: surgical resection followed by chemotherapy versus chemotherapy alone. Blood 2011, 117(6):1958-1965.
Wang M, Ma S, Shi W, Zhang Y, Luo S, Hu Y. Surgery shows survival benefit in patients with primary intestinal diffuse large B-cell lymphoma: A population-based study. Cancer Med 2021, 10(10):3474-3485.
Bobillo S, Joffe E, Lavery JA, Sermer D, Ghione P, Noy A, Caron PC, Hamilton A, Hamlin PA, Horwitz SM et al. Clinical characteristics and outcomes of extranodal stage I diffuse large B-cell lymphoma in the rituximab era. Blood 2021, 137(1):39-48.
Ding J, Karp JE, Emadi A. Elevated lactate dehydrogenase (LDH) can be a marker of immune suppression in cancer: Interplay between hematologic and solid neoplastic clones and their microenvironments. Cancer Biomark 2017, 19(4):353-363.
Lyman GH, Morrison VA, Dale DC, Crawford J, Delgado DJ, Fridman M, Group OW, Group ANCS. Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin's lymphoma receiving CHOP chemotherapy. Leuk Lymphoma 2003, 44(12):2069-2076.
Page MJ, Pretorius E. A Champion of Host Defense: A Generic Large-Scale Cause for Platelet Dysfunction and Depletion in Infection. Semin Thromb Hemost 2020, 46(3):302-319.
Solomon Tsegaye T, Gnirss K, Rahe-Meyer N, Kiene M, Kramer-Kuhl A, Behrens G, Munch J, Pohlmann S. Platelet activation suppresses HIV-1 infection of T cells. Retrovirology 2013, 10:48.
Li S, Gu J, Nan W, Zhang N, Qin L, Su M, Jia M. Procalcitonin and C-reactive protein predict infection in hematopoietic stem cell transplantation patients. Leuk Res 2021, 105:106574.
Bennett CL, Djulbegovic B, Norris LB, Armitage JO. Colony-stimulating factors for febrile neutropenia during cancer therapy. N Engl J Med 2013, 368(12):1131-1139.
Rastogi S, Kalaiselvan V, Ali S, Ahmad A, Guru SA, Sarwat M. Efficacy and Safety of Filgrastim and Its Biosimilars to Prevent Febrile Neutropenia in Cancer Patients: A Prospective Study and Meta-Analysis. Biology (Basel) 2021, 10(10).
Lal A, Bhurgri Y, Vaziri I, Rizvi NB, Sadaf A, Sartajuddin S, Islam M, Kumar P, Adil S, Kakepoto GN et al. Extranodal non-Hodgkin's lymphomas--a retrospective review of clinico-pathologic features and outcomes in comparison with nodal non-Hodgkin's lymphomas. Asian Pac J Cancer Prev 2008, 9(3):453-458.

Table 1 Clinical characteristics of the 131 DLBCL patients.

	Total	GI-DLBCL	N- DLBCL
	(n=131)	(n=51)	(n=80)
Sex(male)	61(46.6%)	31(60.8%)	39(48.8%)
Age(years)	66[22,85]	67[22,83]	64[23,85]
Smoking status	29(22.1%)	14(27.5%)	15(18.8%)
Hypertension	47(35.9%)	17(33.3%)	30(37.5%)
Type 2 diabetes mellitus	16(12.2%)	7(13.7%)	9(11.3%)
Ann-arbor stage
I	11(8.4%)	9(17.6%)	2(2.5%)
II	23(17.5%)	5(10.0%)	18(22.5%)
III	55(42.0%)	16(31.4%)	39(48.8%)
IV	42(32.1%)	21(41.0%)	21(26.2%)
IPI score
< 3	58(44.3%)	19(37.3%)	37(46.2%)
>3	73(55.7%)	32(62.7%)	43(53.8%)
Surgery	28(21.4%)	28(54.9%)	0
Chemo-drugs	130(99.2%)	50(98.0%)	80(100%)
Targeted drug-rituximab	65(49.6%)	23(45.1%)	42(52.5%)
Infection	80(61.1%)	28(54.9%)	52(65.0%)

Data are median and number (%).

Table 2 All infectious episodes– Sites of infection.

Sites	Number (Percent)
	DLBCL (n=80)	GI-DLBCL (n=28)	N-DLBCL (n=52)
respiratory tract	51(63.8%)	13(46.4%)	38(73.1%)
Blood stream infection	10 (12.5%)	4(14.3%)	6(11.5%)
Gastrointestinal	1(1.2%)	1(3.6%)	0
Urogenital	7(8.7%)	4(14.3%)	3(5.8%)
Skin and Soft tissue	2(2.5%)	0	2(3.8%)
Other	9(11.3%)	6(21.4%)	3(5.8%)

Table 3 Clinical characteristics of the 131 patients with DLBCL.

	DLBCL
	Total	Infection group	Non-infection group	P
	(n=131)	(n=80)	(n=51)
Sex(male)	61(46.6%)	37(46.3%)	24(47.1%)	0.928
Age(years)	66[22,85]	66[23,83]	65[22,85]	0.704
Ann-arbor stage				＜0.001*
I	11(8.4%)	2(2.5%)	9(30.5%)
II	23(17.5%)	7(8.7%)	16(17.4%)
III	55(42.0%)	34(42.5%)	21(30.4%)
IV	42(32.1%)	37(46.3%)	5(21.7%)
IPI score				0.002*
< 3	58(44.3%)	27(33.7%)	31(60.8%)
>3	73(55.7%)	53(66.3%)	20(39.2%)
Chemo-drugs	128(97.7%)	77(96.3%)	51(100%)	0.281
Targeted drug-rituximab	65(49.6%)	42(52.5%)	23(45.1%)	0.409
Smoking status	29(22.1%)	21(26.3%)	8(15.7%)	0.156
Hypertension	47(35.9%)	28(35.0%)	19(37.3%)	0.793
Type 2 diabetes mellitus	16(12.2%)	11(13.8%)	5(9.8%)	0.501
CRP¹(mg/L)	15.9(3.8,44.9)	22.4(4.6,51.3)	7.5(2.5,25.2)	0.005*
Erythrocyte¹(×10¹²/L)	4.2(3.7,4.4)	4.1(3.8,4.4)	4.3(3.7,4.6)	0.292
Hemoglobin¹(g/L)	119.8(107,130)	117.5(107,127)	124(108,137.5)	0.022*
WBC¹ (×10⁹/L)	6.4(4.9,7.8)	6.4(4.6,7.5)	6.3(5.2,7.9)	0.711
Neutrophil¹ (×10⁹/L)	4.3(3.1,5.4)	4.3(2.9,5.4)	4.4(3.4,5.4)	0.345
Lymphocyte¹(×10⁹/L)	1.2(0.8,1.4)	1.1(0.8,1.4)	1.2(0.8,1.4)	0.962
NLR¹	4.2(2.5,6.0)	4.5(2.4,6.0)	4.0(2.9,5.9)	0.770
Monocyte¹(×10⁹/L)	0.5(0.3,0.6)	0.5(0.4,0.7)	0.5(0.3,0.5)	0.067
Platelet¹(×10⁹/L)	215(157,262)	212(155,262)	222(169,260)	0.421
Total bilirubin¹(umol/L)	10.8(8.1,15.6)	10.9(7.8,15.7)	10.4(8.5,15.5)	0.834
LDH¹(≥252U/L)	73(55.7%)	52(65.0%)	21(41.2%)	0.007*
CRP² (mg/L)	3.9(1.7,15.3)	7.0(1.9,25.1)	3.0(1.5,8.6)	0.021*
Erythrocyte²(×10¹²/L)	3.9(3.6,4.3)	3.9(3.4,4.1)	4.1(3.8,4.5)	0.010*
Hemoglobin²(g/L)	115(103,125)	112(99,123)	118.6(109.5,132)	0.010*
WBC²(×10⁹/L)	5.1(3.4,6.6)	5.6(3.9,7.1)	4.1(3.0,5.9)	0.009*
Neutrophils²(×10⁹/L)	3.6(2.2,5.6)	4.3(2.6,6.2)	2.7(1.8,4.2)	0.004*
Lymphocyte²(×10⁹/L)	0.9(0.5,1.2)	0.8(0.4,1.1)	0.9(0.6,1.2)	0.161
NLR²	3.6(2.7,7.5)	4.8(3.1,8.0)	3.0(2.3,5.5)	0.002*
Monocyte²(×10⁹/L)	0.4(0.2,0.6)	0.4(0.1,0.6)	0.4(0.2,0.5)	0.597
Platelet²(×10⁹/L)	184(138,247)	173(130,222)	206(169.5,254)	0.082
Total bilirubin²(umol/L)	10.1(7.7,15.1)	11.2(8.6,16.4)	8.8(7.2,10.7)	0.002*
LDH²(≥252U/L)	45(34.4%)	33(41.3%)	12(23.5%)	0.038*

Data are median, number (%) or median and quartile, M(P25, P75). *P< 0.05. CRP, C-reactive protein; WBC, white blood cell; NLR, neutrophil/lymphocyte ratio. ¹ tests at the time of diagnosis. ² tests before infection.

Table 4 Univariate analysis and multivariate analyses of risk factors for infections in 131 patients with DLBCL.

	Univariate analysis	Multivariate analyses
	P	P	OR	95%CI
Ann-arbor stage	＜0.001
II	0.453
III	0.017	0.008	11.991	1.938-74.183
IV	＜0.001	＜0.001	64.163	7.636-539.136
IPI score (>3)	0.003
Smoking status	0.160
CRP¹(mg/L)	0.052
Hemoglobin¹(g/L)	0.036
Monocyte¹(×10⁹/L)	0.051
LDH¹(≥252U/L)	0.008	0.015	3.106	1.241-7.773
Erythrocyte² (×10¹²/L)	0.034
Hemoglobin²(g/L)	0.036
WBC²(×10⁹/L)	0.048
Neutrophils²(×10⁹/L)	0.652
Lymphocyte²(×10⁹/L)	0.551
NLR²	0.537
Platelet²(×10⁹/L)	0.176
Total bilirubin²(umol/L)	0.019
LDH²(≥252U/L)	0.039

OR, odds ratio; CI, confidence interval

Table 5 Univariate analysis of risk factors for infection in 51 patients with GI-DLBCL.

	GI-DLBCL
	Total	Infection group	Non-infection group	P
	(n=51)	(n=28)	(n=23)
Sex(male)	31(60.8%)	16(57.1%)	15(65.2%)	0.557
Age(years)	67[22,83]	63.5[50,82]	64[22,83]	0.857
Hypertension	17(33.3%)	9(32.1%)	8(34.8%)	0.842
Type 2 diabetes mellitus	7(13.7%)	4(14.3%)	3(13.0%)	1.000
Primary site				0.115
Stomach	19(37.3%)	12(42.8%)	7(30.4%)
Intestine	11(21.5%)	8(28.6%)	3(13.1%)
Colon and rectum	21(41.2%)	8(28.6%)	13(56.5%)
Ann-arbor stage				0.016*
I	9(17.6%)	2(7.1%)	7(30.5%)
II	5(10.0%)	1(3.6)	4(17.4%)
III	16(31.4%)	9(32.1%)	7(30.4%)
IV	21(41.0%)	16(57.2%)	5(21.7%)
IPI score				0.022*
< 3	19(37.3%)	6(21.4%)	13(56.5%)
>3	32(62.7%)	22(78.6%)	10(43.5%)
Surgery	28(54.9%)	16(57.1%)	12(52.2%)	0.723
Chemo-drugs	50(98.0%)	27(96.4%)	23(100%)	0.360
Targeted drug-rituximab	23(45.1%)	16(57.1%)	7(30.4%)	0.056
CRP¹(mg/L)	22.3(7.6,50.3)	32.0(9.4,62.8)	17.9(5.9,29.0)	0.176
Erythrocyte¹(×10¹²/L)	4.2(3.8,4.4)	4.2(3.9,4.3)	4.3(3.6,4.6)	0.835
Hemoglobin¹(g/L)	116.5(106,127)	116.5(109,123)	116.5(104,133)	0.820
WBC¹ (×10⁹/L)	6.8(5.3,7.5)	7.0(5.3,7.6)	6.5(5.4,7.4)	0.940
Neutrophil¹ (×10⁹/L)	5.1(3.8,5.4)	5.2(3.8,6.1)	4.6(3.9,5.2)	0.683
Lymphocyte¹(×10⁹/L)	1.2(0.8,1.4)	1.2(0.7,1.3)	1.2(0.8,1.4)	0.569
NLR¹	4.5(3.3,6.2)	4.5(4.1,6.0)	4.5(3.1,6.2)	0.595
Monocyte¹(×10⁹/L)	0.5(0.3,0.6)	0.5(0.3,0.6)	0.4(0.3,0.5)	0.477
Platelet¹(×10⁹/L)	251(211,290)	251(228,300)	231(202,264)	0.232
Total bilirubin¹(umol/L)	8.9(7.2,11.3)	8.9(6.5,12.5)	8.9(7.6,9.9)	0.691
LDH¹(≥252U/L)	23(45.1%)	17(60.7%)	6(26.1%)	0.013*
CRP² (mg/L)	4.4(1.4,15.0)	5.4(1.8,15.0)	4.4(1.0,14.9)	0.583
Erythrocyte²(×10¹²/L)	3.9(3.5,4.3)	3.7(3.4,4.1)	4.0(3.8,4.6)	0.100
Hemoglobin²(g/L)	111.9(99,124)	111.9(101,123)	113(100,128.5)	0.449
WBC²(×10⁹/L)	5.1(3.1,6.6)	5.6(4.6,8.0)	3.7(2.8,5.8)	0.025*
Neutrophils²(×10⁹/L)	3.7(1.9,6.5)	5.2(3.3,6.7)	2.4(1.7,5.3)	0.025*
Lymphocyte²(×10⁹/L)	0.8(0.5,1.1)	0.9(0.4,1.1)	0.8(0.5,0.9)	0.940
NLR²	4.9(3.0,7.9)	6.8(3.6,8.7)	3.2(2.7,6.9)	0.034*
Monocyte²(×10⁹/L)	0.3(0.2,0.4)	0.3(0.2,0.6)	0.3(0.2,0.4)	0.432
Platelet²(×10⁹/L)	216.7(160,281)	216.7(160,300)	194(172,261)	0.513
Total bilirubin²(umol/L)	8.0(6.2,11.1)	8.5(5.7,12.2)	7.8(6.6,10.2)	0.726
LDH²(≥252U/L)	8(15.7%)	5(17.9%)	3(13.0%)	0.715

Table 6 Univariate and multivariate logistic regression analyses of risk factors for infections in GI-DLBCL patients.

	Univariate analysis	Multivariate analyses
	P	P	OR	95%CI
Ann-arbor stage	0.032
II	0.923
III	0.112
IV	0.011	0.046	22.867	1.053-496.508
IPI score (>3)	0.025
Targeted drug-rituximab	0.060
CRP¹(mg/L)	0.107
LDH¹(≥252U/L)	0.016	0.036	4.869	1.105-21.456
Erythrocyte²(×10¹²/L)	0.923
WBC²(×10⁹/L)	0.104
Neutrophils²(×10⁹/L)	0.522
NLR²	0.832

Table 7 Univariate analysis of risk factors for infection in 80 patients with N-DLBCL.

	N-DLBCL
	Total	Infection group	Non-infection group	P
	(n=80)	(n=52)	(n=28)
Sex(male)	39(48.8%)	27(51.9%)	12(42.9%)	0.870
Age(years)	64[23,85]	67.5[23,83]	66.5[33,85]	0.428
Hypertension	30(37.5%)	19(36.5%)	11(39.3%)	0.468
Type 2 diabetes mellitus	9(11.3%)	7(13.5%)	2(7.1%)	0.795
Ann-arbor stage				＜0.001*
I	2(2.5%)	0	2(7.1%)
II	18(22.5%)	6(11.5%)	12(42.9%)
III	39(48.8%)	25(48.1%)	14(50%)
IV	21(26.2%)	21(40.4%)	0
IPI score				0.005*
< 3	37(46.2%)	19(36.5%)	18(64.3%)
>3	43(53.8%)	33(63.5%)	10(35.7%)
Chemo-drugs	80(100%)	52(100%)	28(100%)	1.000
Targeted drug-rituximab	42(52.5%)	26(50.0%)	16(57.1%)	0.542
CRP¹(mg/L)	8.4(2.8,31.4)	21.2(4.2,36.7)	4.2(1.6,10.0)	0.003*
Erythrocyte¹(×10¹²/L)	4.1(3.7,4.5)	4.1(3.6,4.5)	4.2(3.9,4.6)	0.195
Hemoglobin¹(g/L)	121.5(108,132)	119(103,129)	127(122.8,138)	0.006*
WBC¹ (×10⁹/L)	5.9(4.4,7.9)	5.9(4.4,7.4)	6.0(4.8,8.1)	0.774
Neutrophil¹ (×10⁹/L)	4.0(2.8,5.4)	3.8(2.5,4.9)	4.1(2.9,5.5)	0.306
Lymphocyte¹(×10⁹/L)	1.0(0.8,1.5)	1.1(0.9,1.6)	1.0(0.8,1.4)	0.569
NLR¹	3.5(2.2,5.8)	3.2(2.0,6.0)	3.7(2.9,5.4)	0.353
Monocyte¹(×10⁹/L)	0.5(0.4,0.7)	0.6(0.4,0.8)	0.5(0.3,0.5)	0.066
Platelet¹(×10⁹/L)	185.9(136,247)	176(126,223)	207(142,257)	0.155
Total bilirubin¹(umol/L)	12.4(9.1,16.6)	11.7(8.3,16.3)	14.2(10.8,17.0)	0.218
LDH¹(≥252U/L)	50(62.5%)	35(67.3%)	15(53.6%)	0.226
CRP² (mg/L)	3.8(1.8,16.5)	7.9(2.1,29.7)	3.0(1.7,4.5)	0.011*
Erythrocyte²(×10¹²/L)	3.9(3.6,4.3)	3.9(3.4,4.2)	4.1(3.8,4.5)	0.033*
Hemoglobin²(g/L)	116(105,126)	114.1(99,122)	121.5(115,131)	0.004*
WBC²(×10⁹/L)	5.1(3.6,6.6)	5.6(3.8,6.8)	4.7(3.6,6.0)	0.178
Neutrophils²(×10⁹/L)	3.5(2.3,4.9)	3.9(2.3,6.7)	3.0(2.4,3.9)	0.075
Lymphocyte²(×10⁹/L)	0.9(0.5,1.2)	0.8(0.5,1.1)	1.1(0.7,1.2)	0.050
NLR²	3.4(2.4,6.3)	3.8(2.9,7.8)	2.9(2.1,5.1)	0.021*
Monocyte²(×10⁹/L)	0.4(0.2,0.6)	0.4(0.1,0.6)	0.4(0.3,0.6)	0.888
Platelet²(×10⁹/L)	172.8(130,235.3)	159(112,200)	207.5(165,252)	0.015*
Total bilirubin²(umol/L)	11.0(8.8,16.4)	12.4(10,18.4)	9.6(7.8,12.5)	0.001*
LDH²(≥252U/L)	37(46.3%)	28(53.8%)	9(32.1%)	0.063

Table 8 Univariate and multivariate logistic regression analyses of risk factors for infections in N-DLBCL patients.

	Univariate analysis	Multivariate analyses
	P	P	OR	95%CI
Smoking status	0.067
Ann-arbor stage	0.214
II	0.999
III	0.999
IV	0.999
IPI score (>3)	0.030
CRP¹(mg/L)	0.153
Erythrocyte¹ (×10¹²/L)	0.140
Hb¹(g/L)	0.026	0.037	0.970	0.943-0.998
Monocyte¹(×10⁹/L)	0.038
Platelet¹(×10⁹/L)	0.344
CRP² (mg/L)	0.013	0.016	1.110	1.020-1.209
Erythrocyte² (×10¹²/L)	0.083
Hb²(g/L)	0.032
WBC²(×10⁹/L)	0.208
Neutrophils²(×10⁹/L)	0.195
Lymphocyte²(×10⁹/L)	0.645
NLR²	0.159
Platelet²(×10⁹/L)	0.029	0.046	0.991	0.982-1.000
Total bilirubin²(umol/L)	0.052
LDH²(≥252U/L)	0.066

No competing interests reported.

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Profiling risk factors for separation of infection complications in patients with gastrointestinal and nodal diffuse large B-cell lymphoma

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