Epidemiology, Risk Factors, and Outcomes of Neutropenic Enterocolitis in Onco-Hematological Patients According to Chemotherapy Regimen.

Neutropenic enterocolitis (NEC) is known as a life-threatening, necrotizing bowel inflammation occurring primarily in neutropenic patients undergoing intensive chemotherapy for the treatment of hematological malignancies [ 1 , 2 ]. Pathophysiological events leading to NEC result from the combined action of chemotherapy-induced mucosal damage, coagulation disorders, and profound neutropenia, promoting bacterial and fungal translocation of the resident flora [ 2 , 3 ].

The clinical manifestations of NEC overlap with those seen in other abdominal conditions, such as colitis due to Clostridioides difficile, cytomegalovirus (CMV) or ischemia, appendicitis, Ogilvie syndrome, or gastrointestinal graft-versus-host disease (GvHD) [ 2 , 4 ]. The increasing use of computed tomography (CT) has improved our ability to distinguish NEC from the other digestive syndromes. Current diagnostic criteria proposed by Gorschlüter et al [ 5 ] include an absolute neutrophil count (ANC) of less than 500 × 10 6 cells/L, fever greater than 38.3°, and bowel wall thickening (BWT) greater than 4 mm with a bowel length more than 30 mm detected by abdominal ultrasound or CT, in the absence of any other cause. The 4-mm cutoff is considered reliable as it is very rare in noninflammatory bowel disease after chemotherapy.

In the absence of a clear definition, the epidemiology of NEC has remained ill defined, with reported incidence ranging from 6% to 46% [ 2 , 5–8 ]. Recent cytotoxic chemotherapy is the most reported risk factor [ 2 , 9 ]. Pre-existing bowel abnormalities and prior episodes of NEC appear to increase the risk of relapse [ 2 ]. Altogether, patient heterogeneity and the absence of multivariate models in most studies make it difficult to determine which factors are independently associated with NEC.

The management of NEC relies mainly on expert opinion [ 5 ]. Medical treatment usually combines broad-spectrum antibiotics active against gram-negative bacteria and anaerobes [ 10 ], supportive therapy (bowel rest, intravenous fluids, parenteral nutrition), and granulocyte colony-stimulating factor (G-CSF); the benefit of empirical antifungal therapy in non–critically ill neutropenic patients with NEC is not clearly established [ 10 ]. While surgery was initially considered for all cases [ 11 , 12 ], its current use is controversial [ 13 , 14 ]. The mortality rate is high, ranging from 10% to 63% [ 3 , 5 , 7 , 15–19 ].

The goals of this study were to determine the incidence, outcomes, and risk factors for NEC in a cohort of prospectively collected onco-hematological patients.

METHODS

This study was conducted in a prospectively collected cohort of patients aged 18 years and older with hematological malignancies hospitalized within the isolation unit of Lausanne University Hospital between 1 January 2007 and 31 December 2023 (MINCO registry). It was approved by the local Ethics Committee (Swissethics 2017-01975).

Definitions

Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome with increased blasts 2 (MDS-IB2) were treated with cytarabine plus anthracycline induction according to the standard arm in ongoing K trials of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK) [ 20 ] or purine-based chemotherapy (FLAG-Ida (fludarabine, cytarabine, G-CSF, and idarubicine), CLAG-Ida (cladribine, cytarabine, G-CSF, and idarubicine)) [ 21–25 ] ( Supplementary Table 1 ). Patients with acute lymphoblastic leukemia (ALL) were treated according to ongoing protocols of the Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) [ 26 ]. Conditioning chemotherapy regimens for autologous hematopoietic stem cell transplantation (auto-HCT) were stratified as "BEAM (carmustine, etoposide, cytarabine, and melphalan) protocol" for patients with lymphoma [ 15 ] and as “other conditioning regimens,” including melphalan for multiple myeloma (MM), carmustine and thiotepa for central nervous system lymphoma, and busulfan and cyclophosphamide, for patients with AML [ 15 ]. Allogenic HCT is not performed in this hospital.

Febrile neutropenia (FN) was defined by the presence of an ANC less than 500 cells/mm 3 and a tympanic temperature of 38.5°C or greater or of 38.0°C or greater measured twice over a 2-hour period. During each episode, the investigations systematically included sets of blood cultures, cultures from urine and any suspected site of infection, and a chest X-ray. Stool cultures to check for Salmonella , Shigella , or Campylobacter species and testing for C difficile toxins were routinely performed in cases of diarrhea, as well as CMV testing in patients with relapsed acute leukemia and a history of allogeneic HCT. Broad-spectrum empiric antibiotic therapy (cefepime +/− metronidazole or piperacillin-tazobactam) is promptly started after microbiological sampling at each episode of FN. Antifungal prophylaxis during neutropenia was prescribed according to international recommendations [ 10 , 27 ].

Data Collection

Data were extracted from the MINCO registry implemented in SecuTrial (InterActive Systems GmbH, version 5.5.0.25 (2025), Berlin), which contains an extensive range of prospectively collected data, including demographics, duration of neutropenia, characteristics of infections, treatments, outcomes, and sequential Sepsis-related Organ Failure Assessment (SOFA) and quick SOFA (qSOFA) scores [ 28 ]. All data were systematically collected by trained study nurses in a dedicated case-report form, reviewed by senior Infectious Diseases physicians and classified as microbiologically documented infection (MDI), clinically documented infection (CDI), or fever of unknown origin (FUO). Prognosis for AML was described according to the 2017 European Leukemia Network genetic categories [ 29 ]. Death occurring after hospitalization was obtained from the official death registry. The analyses were performed by chemotherapy cycles (each corresponding to a single chemotherapy and neutropenia episode), as the main risk conditions change at each cycle. The total dose of corticosteroids received during the chemotherapy episode is calculated in milligrams of prednisone equivalent [ 30 ].

The diagnosis of NEC was established when patients with FN had clinical signs and/or symptoms suggestive of abdominal infection (abdominal distension, tenderness and pain, diarrhea, vomiting, and/or bloody stools), with the presence of BWT greater than 4 mm (measured on axial CT images) over more than 30 mm of length (measured on coronal CT images) in any bowel segment, as proposed by Gorschlüter et al [ 5 ], in the absence of other well-recognized entities on CT (appendicitis, diverticulitis, cholecystitis, cholangitis, GvHD, ischemic colitis) or alternative diagnoses including enteric pathogens (such as C difficile and CMV-associated colitis). All abdominal CT examinations were reviewed by a radiologist with more than 20 years of practical experience in gastrointestinal imaging. The presence or absence of NEC was sought in the 4 quadrants of the small bowel (right upper, left upper, right lower, left lower) and the different segments of colon (cecum, ascending colon, transverse colon, descending colon, sigmoid, rectum). The maximal wall thickness for each segment and the percentage of involvement of the analyzed bowel segment were measured. Episodes of NEC occurring within 10 days of C difficile colitis were excluded.

Statistical Analysis

Statistical analysis was performed using Stata version 18.0 software (StataCorp, College Station, TX). Risk factors for developing NEC were assessed in homogeneous groups of patients by using univariate and multivariate logistic regression models. Factors that were or tended to be associated with the endpoint on univariate analysis were entered into multivariate analysis and selected by using backward stepwise regression. Kaplan-Meier survival analyses were performed using the STS graph function with a landmark approach. Differences were considered significant for P values less than .05.

RESULTS

Study Population

A total of 1963 chemotherapy courses were analyzed in 1259 patients ( Table 1 ). The patients’ median age was 58 years (Percentile 75 minus percentile 25 [P75-P25]: 17 years) and 60.0% were men. Most frequent malignancies were AML and MDS-IB2 (n = 379; 30.1%), MM (n = 374; 29.7%), lymphoma (n = 351; 27.9%), and ALL (n = 80; 6.4%). Of the 1963 chemotherapy courses, 665 were for the treatment of AML (“AML population,” including 231 first and 180 second standard inductions and 254 purine-based inductions or salvage) and 776 were conditioning regimen for auto-HCT (“auto-HCT population,” including 289 with a BEAM and 487 with another conditioning protocol; eg, melphalan). The other chemotherapy episodes included 47 ALL inductions and 475 chemotherapies for other hematological malignancies (detailed in Supplementary Table 2 ).

Characteristics of Neutropenic Enterocolitis

A total of 178 episodes of NEC were diagnosed during 1963 courses of chemotherapy (9.1%) ( Supplementary Table 3 ). The vast majority (93.3% of NEC episodes) occurred in the AML (n = 92; 13.8% of courses) and the auto-HCT (n = 74; 9.5%) populations. Yet, the incidence of NEC varied within these 2 groups after stratification according to specific chemotherapeutic regimen ( Figure 1 ). In the AML population, this incidence was much higher during induction with a standard (“7 + 3”) protocol (18.6% for the first and 17.8% for the second induction) than during purine-based chemotherapy (6.7%). In the auto-HCT population, it was higher among patients receiving a BEAM protocol (15.2%) compared with those receiving another protocol (6.2%). The incidence of NEC was 8.5% during ALL induction and only 1.7% during other chemotherapies.

The analysis of abdominal CT examinations revealed that NEC involved more than 1 intestinal segment in 91% of cases (median number of segments = 3, IQR = 3), with the small intestine situated in the upper left abdominal quadrant (50.0% of cases) and the ascending colon (48.9%) being the most frequently affected localization ( Figure 2 ). The median maximal BWT ranged from 8 mm (IQR = 3 mm) in the right lower quadrant of the small intestine to 15 mm (IQR = 8 mm) in the cecum.

Risk Factors

In the AML population, independent risk factors for NEC included high-dose corticosteroids (>100 mg prednisone equivalent; odds ratio [OR] = 2.07; 95% CI: 1.29–3.30; P = .002), elevated circulating blast count at the time of AML diagnosis (>50 G/L; OR = 2.02; 95% CI: 1.15–3.56; P = .02) ( Table 2 ), and concomitant use of azacitidine, a pyrimidine analogue (OR = 2.45; 95% CI: 1.01–5.90; P = .05). Purine-based chemotherapy instead of standard induction was an independent protective factor (OR = .27; 95% CI: .15–.47; P < .001). Additional risk factors emerged when the analyses were further limited to patients receiving standard AML induction, the group with the highest incidence of NEC, by entering specific regimens into the multivariate models ( Table 3 ). In addition to high-dose corticosteroids (prednisone equivalent >100 mg; OR = 2.77; 95% CI: 1.57–4.88; P < .001), elevated circulating blast counts (OR = 2.64; 95% CI: 1.37–5.08; P = .004 for blasts 20–50 G/L; OR = 2.25; 95% CI: 1.08–4.69; P = .03 for blasts >50 G/L, compared with blasts <20 G/L), and the use of azacitidine (OR = 3.29; 95% CI: 1.03–10.5; P = .04), the analysis also identified a previous NEC (OR = 3.65; 95% CI: 1.48–9.04; P = .005), as well as the use of regimens containing idarubicine (OR = 2.66; 95% CI: 1.31–5.41; P = .007) and amsacrine (OR = 3.24; 95% CI: 1.54–6.84; P = .002), versus cytarabine alone or in combination with daunorubicine, as independent risk factors for NEC.

In the auto-HCT population, the only 2 factors independently associated with NEC were conditioning with BEAM protocol (OR = 3.28; 95% CI: 1.98–5.43; P < .001) ( Table 4 ) versus another regimen and increasing age (OR = 1.03 per year; 95% CI: 1.01–1.06; P = .007). In the ALL population, no significant risk factor for NEC was identified, but the number of such episodes was quite small (n = 4) ( Supplementary Table 4 ). In the other chemotherapies, the only independent risk factor for NEC was previous NEC (OR = 5.76; 95% CI: 1.08–30.73; P < .001) ( Supplementary Table 5 ) despite the small number of NEC cases (n = 8).

Treatment and Outcome

Broad-spectrum antibiotics were administered to all NEC cases (100%), as an initial empirical therapy in 99 cases in whom NEC appeared as the first episode of neutropenic fever (55.6%) or as a switch from (n = 84; 47.2%), or continuation of (n = 15; 8.4%), ongoing antibiotics, when NEC was preceded by 1 or several episode(s) of neutropenic fever ( Supplementary Table 3 ). Antifungals were administered in 119 out of 178 cases of NEC (66.9%), as an initial antifungal therapy (n = 49; 27.6%) or as a switch from (n = 18; 10.1%), or maintenance of (n = 52; 29.2%), antifungals previously given as prophylaxis or treatment. Abdominal surgery with resection was performed in 3 episodes of NEC, only 1 of whom had perforation.

Neutropenic episodes complicated by NEC compared with those without NEC were characterized by a longer hospitalization (median [P75-25]: 34 [25] days vs 32 [17] days; P = .03 for AML induction; median [P75-P25]: 26 [8] days vs 20 [6] days; P < .001 for auto-HCT) ( Table 5 ), a higher occurrence of sepsis (qSOFA ≥2: 19.6% vs 11.3%, P = .03, for AML induction; 23.0% vs 5.4%, P <.001, for auto-HCT; SOFA >10: 4.3% vs 1.0% for AML induction, P = .03; 4.1% vs 0.4%, P = .003 for auto-HCT), and a higher need for transfer to the intensive care unit (ICU) (14.1% vs 7.3%, P = .03, for AML induction; 18.9% vs 2.1%, P < .001, for auto-HCT). Neutropenic enterocolitis was associated with a higher rate of fungemia (6.5% vs 0.7%, P < .001, during AML induction; 4.1% vs 0.6%, P = .01, during auto-HCT), and during AML induction but not auto-HCT, a higher rate of bacteremia due to gram-positive cocci (38.0% vs 25.7%; P = .01). Finally, NEC was associated with a higher rate of in-hospital mortality during AML induction (6.5% vs 2.4%; P = .04), particularly after purine-based chemotherapy (17.6% vs 2.5%; P = .005) ( Supplementary Table 6 ), but not during auto-HCT ( P = .3). However, overall, long-term survival was not affected by NEC (log-rank test: P = .7 for AML and P = .5 for auto-HCT) ( Figure 3 ).

DISCUSSION

Although NEC is considered to be a life-threatening condition, its exact incidence and outcome have long remained undefined, probably due to the lack of a standard definition, inhomogeneity, and limited size of study populations and retrospective nature of most reports [ 2 , 5 ]. To our knowledge, this is the largest NEC cohort study and the first to stratify risk factor analyses by chemotherapeutic regimen.

Historically, NEC was associated with the use of cytarabine [ 6 , 7 , 9 ], which induces mucosal damages in the gastrointestinal tract [ 31 ]. Yet, this observation is not useful for predicting which patients with AML are likely to develop NEC, since this drug is part of virtually all regimens used for AML induction [ 6 , 7 , 9 ]. We show for the first time that the incidence of NEC can greatly vary among patients receiving cytarabine. The incidence of NEC was quite elevated after both a first (18.6%) and a second (17.8%) induction with a standard (“7 + 3”) regimen, while cytarabine doses greatly differ among these protocols (200 mg/m 2 /d, days 1–7, vs 2000 mg/m 2 /d, days 1–6, respectively). Furthermore, purine-based therapy (regardless of its use as front-line or salvage therapy) was associated with a lower rate of NEC compared with standard “7 + 3” induction despite elevated doses of cytarabine (2000 mg/m 2 /d, days 1–5 for FLAG). This suggests that cytarabine bowel toxicity may not much rely on its dosage but rather on factors such as the number of days it is administered, its daily infusion mode (1 vs 2 times per day, long vs short administration), and/or the type of associated chemotherapeutic drug. In standard AML induction, the incidence of NEC was higher when cytarabine was combined with idarubicine, a semi-synthetic glycoside analogue of daunorubicine with slightly different pharmacokinetic properties, or amsacrine compared with cytarabine alone or combined with daunorubicine, suggesting a potentiating role for these drugs, as previously reported with amsacrine [ 32 ]. The use of upfront G-CSF, which is systematic in purine-based regimens (eg FLAG-Ida), may have contributed to reduce neutropenia duration and the risk of NEC in this group. Nevertheless, G-CSF was not a significant protective factor for NEC during standard AML induction. The other relevant risk factor for NEC in our AML population was a previous NEC and the high level of circulating blasts (>50 Giga/L) at admission. A likely mechanism is the presence is leukemic infiltration of the bowel at the beginning of chemotherapy, which plays a role in the pathogenesis of NEC, as previously suggested [ 3 ], although this has not been confirmed histologically [ 33 ].

The second regimen associated with NEC was auto-HCT conditioning with a BEAM protocol, with a global incidence of 15% (16% for Non-Hodgkin lymphoma (NHL) and 13% for Hodgkin lymphoma (HL)); this is consistent with a smaller report of 25 episodes of NEC occurring in 179 BEAM recipients (14%), although the proportion of NEC differed according to the underlying disease in this study (19% for NHL and 9% for HL) [ 15 ]. In a recent prospective study of 129 patients with lymphoma conditioned with BEAM, NEC incidence was even higher (31%), but the diagnosis was obtained by ultrasonography, a technique that is more subjective and far less reproducible than CT [ 34 ]. Since the doses of melphalan and cytarabine are lower in the BEAM protocol than in the conditioning regimen for MM and purine-based AML regimens, respectively, NEC may result from a potentiating effect of the other drugs used in these regimens—namely, carmustine and etoposide.

This study is the first to identify steroids as a risk factor for NEC. Cumulative doses greater than 100 mg of prednisone equivalent significantly increased this risk during AML induction, and higher doses (>250 mg) also tended to do so during auto-HCT. A smaller study of 52 episodes of typhlitis failed to detect such an association, but the results are difficult to interpret in the absence of dose reporting [ 9 ]. Since steroids are increasingly administered within or in addition to chemotherapy regimens to prevent gastrointestinal side effects or to treat severe cutaneous and/or digestive damage secondary to high doses of cytarabine, the identification of their role as a risk factor for NEC is clinically relevant.

While earlier studies reported NEC mortality rates of more than 50% [ 5 , 7 ], 30-day mortality rates ranged from 9% to 30% in more recent reports [ 3 , 15–18 , 35 ]. In-hospital mortality (6.5% for AML induction and 2.4% for auto-HCT) was even lower in our study. Such differences may be due to several factors. First, the literature is often limited to case reports or small case series, with a potential publication bias towards severe cases [ 5 , 35 , 36 ]. Second, clinical screening, diagnostic procedures, and criteria definitions for NEC have evolved and differ among centers, making it difficult to compare NEC incidence and mortality rates. Finally, close monitoring since the first sepsis signs, as illustrated by our high ICU transfer rate, and prompt management of septic shock [ 37 ] may have contributed to limit mortality [ 2 , 33 , 38 ]. In rare cases, NEC was associated with severe infections, such as candidemia, with high mortality [ 36 ].

Conservative management has become the standard of care in most institutions [ 35 ]. Our data confirm the efficacy of a conservative approach, including broad-spectrum empiric antimicrobial therapy promptly started at the onset of fever [ 10 ] and general supportive care. Surgical management was reserved for situations of clinical deterioration despite optimal medical treatment, as proposed by Shamberger et al [ 14 ]. Indeed, a recent meta-analysis still favors surgery for patients with severe NEC requiring intensive care management [ 13 ].

This study has limitations, including its retrospective design and the fact that CT examination was decided by the treating physician. However, all patients were prospectively included, and data systematically reported in real-time. In auto-HCT patients, physicians may have been less prone to perform a CT scan, as neutropenia is of short duration and NEC is usually diagnosed just before neutrophil recovery. This may have contributed to underestimate the incidence of NEC in patients with auto-HCT with BEAM conditioning (14%), compared to the incidence observed in another study (31%), in which abdominal ultrasonography was performed systematically [ 34 ].

In conclusion, NEC is a common complication in neutropenic patients receiving standard AML induction chemotherapy or BEAM conditioning for auto-HCT. It requires close monitoring and abdominal CT examination in these groups, particularly in patients with AML with elevated circulating blast counts at diagnosis, high-dose corticosteroids, and/or previous NEC. Our results emphasize the effectiveness of medical management with a low 30-day mortality and the absence of a direct impact on long-term survival.

Supplementary Material

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Author Contributions. P.-Y. B., C. S., and A.-S. B. designed the study. C. S. collected specific NEC data. S. A. and M. G. collected specific hematologic data. A.-S. B. designed the full clinical database under the supervision of P.-Y. B., with the contribution of O. M. for the period 2007–2014. M. F. drew up the treatment plans and validated the pharmacotherapy analyses. S. S. and K. M. reviewed all abdominal CT examinations. P.-Y. B. and A.-S. B. performed statistical analyses. P.-Y. B., A.-S. B., C. S., M. G., M. F., and O. S. contributed to the interpretation of the data. A.-S. B., P.-Y. B., and C. S. drafted the original manuscript. All authors revised and approved the final version of the manuscript.

Acknowledgments. The authors thank the patients who participated in the study. They thank Galia Santos for her outstanding contribution to data collection. She tragically passed away at the beginning of this study. They acknowledge the contribution of Corine Guyat-Jacques for their important contribution in collecting clinical data as well as Fady Fares for data maintenance. They thank Eleftheria Kampouri for important advice for survival analyses.

Data availability. Study data can be made available to investigators under specific data transfer agreement.

Financial support. This work was supported by the Promex Stiftung für die Forschung (via Carigest SA) (to A.-S. B.); the Swiss National Science Foundation (grant numbers 31CA30_196036, 33IC30_179636, and 314730_192616) (to P.-Y. B.); the Leenaards Foundation to P.-Y. B.; and the Santos-Suarez Foundation (to P.-Y. B).

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