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Background: Early antibiotic discontinuation has been advocated in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment., Methods: This non-inferiority, open-label, multicentre, randomised trial was done in six hospitals in the Netherlands. Adult patients (≥18 years) who were treated with intensive chemotherapy or haematopoietic stem-cell transplantation (HSCT) for a haematological malignancy, and had fever of unknown origin during high-risk neutropenia (<0·5 × 10 9 /L expected for ≥7 days) were eligible. After onset of fever, patients received either 500 mg intravenous imipenem-cilastatin four times a day or 1000 mg intravenous meropenem three times a day. Between 48 h and 72 h of treatment, participants were randomly assigned (1:1) by a computer-generated sequence to receive a short-term (72 h [60-84]; short treatment group) or extended (≥9 days until being afebrile for 5 days or neutrophil recovery; extended treatment group) carbapenem regimen. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock or respiratory failure or death from day 4 until neutrophil recovery. The study was designed to assess the non-inferiority of the short treatment compared with the extended treatment regimen, with a non-inferiority margin of 10%. The primary outcome was adjudicated by an independent outcome committee, who were masked to treatment allocation, and was analysed in the intention-to-treat and per-protocol populations. The trial is completed and registered with ClinicalTrials.gov, NCT02149329., Findings: Between Dec 1, 2014, and July 1, 2019, 281 patients were included in the intention-to-treat analysis: 144 (51%) patients were assigned to the short treatment group and 137 (49%) to the extended treatment group. Median age was 59 years (IQR 52-65); 109 (39%) patients were women and 172 (61%) were men; 205 (73%) patients received HSCT. In the intention-to-treat analysis, 28 (19%) of 144 patients in the short treatment group versus 21 (15%) of 137 patients in the extended treatment group had treatment failure (adjusted risk difference [ARD] 4·0% [90% CI -1·7% to 9·7%]; p=0·25). In the per-protocol analysis (n=225), 24 (23%) of 104 patients in the short treatment group and 19 (16%) of 121 patients in the extended treatment group had treatment failure (ARD 7·3% [0·3% to 14·9%]; p=0·11). The most common grade 3-5 infection-related adverse events were mucositis (23 [20%] of 114 adverse events in the short treatment group vs 28 [29%] of 98 adverse events in the extended treatment group), fever of unknown origin (20 [18%] vs 16 [16%] events), and bacteraemia (15 [13%] vs 13 [13%] events). The number of serious adverse events were higher in the short treatment group (23 [16%] of 144 patients) than in the extended treatment group (14 [10%] of 137 patients), due to an increased rate of readmission (17 [12%] patients in the short treatment group vs ten [7%] in the extended treatment group). Death before 30 days after neutrophil recovery occurred in five (3%) participants in the short treatment group: two due to progressive leukaemia, two due to candidaemia, and one due to Enterococcus faecium bacteraemia and drug-induced pneumonitis. One (1%) patient died in the extended treatment group due to candidaemia. None of the deaths were related to carbapenem-sensitive infections., Interpretation: Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are persistantly febrile the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating., Funding: The Netherlands Organisation for Health Research and Development and Fonds NutsOhra., Competing Interests: Declaration of interests NAdJ, JJS, SZ, AB, PY, AHH, WV, AdK, JLLMC, BL-W, MHHK, MAvA, and JJWMJ received grants from ZonMw and Fonds NutsOhra for the execution of this study. We declare no other competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Metamizole can be used in both short- and long-term pain relief therapies and has a relatively favourable safety profile compared with classic NSAIDs. Metamizole is also infamous because of its potential fatal adverse drug reaction, agranulocytosis. Although this risk varies, it is estimated to occur in less than one million metamizole prescriptions. We describe a case of a 68-year-old patient who developed leukopenia after using metamizole.

Infection remains one of the most prominent complications after cytotoxic treatment for cancer. The connection between neutropenia and both infections and fever has long been designated as 'febrile neutropenia', but treatment with antimicrobial agents and haematopoietic growth factors has failed to significantly reduce its incidence. Moreover, emerging antimicrobial resistance is becoming a concern that necessitates the judicious use of available antimicrobial agents. In addition to neutropenia, patients who receive cytotoxic therapy experience mucosal barrier injury (MBI) or 'mucositis'. MBI creates a port-de-entrée for resident micro-organisms to cause blood stream infections and contributes directly to the occurrence of fever by disrupting the highly regulated host-microbe interactions, which, even in the absence of an infection, can result in strong inflammatory reactions. Indeed, MBI has been shown to be a pivotal factor in the occurrence of inflammatory complications after cytotoxic therapy. Hence, the concept 'febrile neutropenia' alone may no longer suffice and a new concept 'febrile mucositis' should be recognized as the two are at least complementary. This review we summarizes the existing evidence for both paradigms and proposes new therapeutic approaches to tackle the perturbed host-microbe interactions arising from cytotoxic therapy-induced tissue damage in order to reduce fever in neutropenic patients with cancer., (© 2014 John Wiley & Sons Ltd.)

Background: In the 1960s, it was reported that infectious complications were the main cause of fever during neutropenia that followed hematopoietic stem cell transplant (HSCT). More recently, mucositis has become recognized as an important determinant of the inflammatory response and infectious complications., Methods: The objective of this prospective study was to determine the impact of intestinal mucositis, as measured by plasma citrulline, and neutropenia on the systemic inflammatory response (C-reactive protein) and the occurrence of bacteremia among 2 cohorts of HSCT recipients: 1 composed of 18 patients who had been treated with a myeloablative (MA) regimen (high-dose melphalan) and the other involving 19 patients who had received the non-myeloablative (NMA) regimen (fludarabine and cyclophosphamide). Blood cultures were obtained for surveillance from admission onwards as well as at the onset of fever., Results: The MA regimen induced severe intestinal mucositis manifest by citrullinemia <10 μmol/L, which was accompanied by an inflammatory response, and bacteremia affected 8 (44%) of 18 patients and coincided with the nadir of citrullinemia. By contrast, those who had been treated with the NMA regimen did not develop severe intestinal mucositis, had a moderate inflammatory response, and only 2 (11%) of the 19 patients developed bacteremia. However, both groups experienced profound neutropenia and its duration was significantly longer for those receiving the NMA regimen., Conclusion: This study suggests that severe intestinal mucositis, i.e., citrullinemia <10 μmol/L, defines the period of risk of bacteremia better than does neutropenia, and that measuring plasma citrulline may prove useful in deciding who needs empirical antimicrobial therapy and when., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The matched-control study failed to show a clinical relevant impact of palifermin on intestinal mucositis, although there was a reduced inflammatory response and less febrile neutropenia among patients who had no bacteraemia.

Gastrointestinal (GI) mucositis is a common side effect of intense chemotherapy to prepare patients for hematopoietic SCT. Measuring intestinal damage objectively remains difficult, and clinicians often rely on albumin levels as an indicator of GI mucositis, but citrulline might be a more specific marker, which has in the past been shown to correlate with clinical signs of GI mucositis. We evaluated the courses of albumin and citrulline following different conditioning regimens for SCT and studied their relatedness to the subsequent inflammatory response using C-reactive protein. Patterns of albumin and citrulline differed significantly between myeloablative and non-myeloablative conditioning regimens. After myeloablative regimens, decreasing citrulline levels preceded the occurrence of inflammation unlike albumin levels, which decreased thereafter. Albumin levels were greatly influenced by inflammation, confirming it to be a 'negative acute-phase protein', whereas citrulline levels were not. Citrulline appeared to be a better biomarker of GI mucositis than albumin. Measuring citrulline might prove useful in clinical decision making, in identifying GI mucositis, and it would also be of interest to see how it compares with other biomarkers in the setting of acute GI GVHD.

Background: Stem cell transplantation (SCT) is still complicated by the occurrence of fever and inflammatory complications attributed to neutropenia and subsequent infectious complications. The role of mucosal barrier injury (MBI) of the intestinal tract therein has received little attention., Methods: We performed a retrospective analysis in 163 SCT recipients of which data had been collected prospectively on intestinal damage (citrulline), inflammation (C-reactive protein), and neutrophil count. Six different conditioning regimens were studied; 5 myeloablative (MA) and 1 non-myeloablative (NMA). Linear mixed model multivariate and AUC analyses were used to define the role of intestinal damage in post-SCT inflammation. We also studied the relationship between the degree of intestinal damage and the occurrence of early post-SCT complications., Results: In the 5 MA regimen there was a striking pattern of inflammatory response that coincided with the occurrence of severe intestinal damage. This contrasted with a modest inflammatory response seen in the NMA regimen in which intestinal damage was limited. With linear mixed model analysis the degree of intestinal damage was shown the most important determinant of the inflammatory response, and both neutropenia and bacteremia had only a minor impact. AUC analysis revealed a strong correlation between citrulline and CRP (Pearson correlation r = 0.96). Intestinal damage was associated with the occurrence of bacteremia and acute lung injury, and influenced the kinetics of acute graft-versus-host disease., Conclusion: The degree of intestinal damage after myeloablative conditioning appeared to be the most important determined the inflammatory response following SCT, and was associated with inflammatory complications. Studies should explore ways to ameliorate cytotoxic therapy-induced intestinal damage in order to reduce complications associated with myeloablative conditioning therapy.

Background: Currently, objective tests are lacking that enable the extent and duration of intestinal mucosal damage induced by myeloablative chemotherapy to be determined. To address this problem, we explored a citrulline-based assessment score as this amino acid is a simple quantitative marker of intestinal failure., Patients and Methods: From March 2004 to June 2007, citrulline concentrations were determined at baseline and at least once weekly after the start of myeloablative chemotherapy until 30 days thereafter among 94 allogeneic or autologous haematopoietic stem-cell transplant recipients. The patients were divided into three groups according to the regimen they received: (i) carmustine, etoposide, cytarabine and melphalan/high-dose melphalan, (ii) cyclophosphamide and total body irradiation +/- antithymocyte globulin and (iii) idarubicin-containing regimens. Intestinal mucosal damage was described either by level of citrulline on each day, on the basis of different thresholds of citrulline indicating the severity of villous atrophy, or by area under the curve using reciprocal value of 10/citrulline., Results: Regimens that incorporated idarubicin induced the most severe intestinal toxicity. Scores based on the level of citrulline, using severity thresholds, and on the area under the reciprocal curve are able to discriminate between the damage induced by different high-dose chemotherapy regimens., Conclusion: A citrulline-based assessment score appears objective, validated, reproducible, reliable, specific and sensitive making it a suitable first choice for measuring and monitoring intestinal mucositis.

Mucosal damage to the intestines induced by myeloablative conditioning for allogeneic PBSC transplant (PBSCT) can be determined by the concentration of citrulline, which is a functional marker of small intestinal enterocytes. Low citrulline concentrations in blood coincide with and are a response to severe mucosal barrier injury. We treated 29 patients with high-dose melphalan 200 mg/m(2) (Mel-200) to prepare for an autologous PBSCT and collected plasma samples from each patient starting before the myeloablative regimen and three times per week thereafter until discharge. The baseline citrulline concentration was 27.6 mM+/-4.0 (mean+/-95% confidence interval; CI), and citrulline concentrations declined rapidly thereafter reaching a nadir averaging 6.7 mM+/-2.7, 12 days after starting Mel-200. Citrulline concentrations, only increased gradually and were still low (12 mM+/-4) at discharge. A total of 20 patients developed fever, which was associated with bacteraemia in 10 cases. Their mean citrulline concentrations were lower at 5.5 mM+/-1.5 than were those of patients without bacteraemia (10.2 mM+/-3.9). Importantly, neither the number of preceding neutropenic days nor the mean C-reactive protein (CRP) concentration at the onset of fever was different between these two groups. In conclusion, citrulline concentrations rapidly decline after Mel-200 reflecting intestinal mucosal barrier injury. Low citrulline, rather than the duration of neutropenia, is associated with bacteraemia indicating the importance of an intact mucosal barrier in neutropenic patients.

We report a 73-year-old man presenting with fatigue, lymphadenopathy and weight loss. He had no abdominal pain, fever or night sweats. Physical examination revealed a palpable 1.4-cm hard nontender lymph node behind the left sternocleidomastoid muscle and a palpable 2-cm lymph node in the left axilla. Bone marrow examination and excisional biopsy of the lymph node behind the left sterno-cleidomastoid muscle showed a CLL-type non-Hodgkin's lymphoma (CLL-type NHL). Staging by CT scanning revealed, besides axillary and mediastinal adenopathy, an unexpected mass in the stomach. Gastroscopy and pathological evaluation showed a gastrointestinal stromal tumour (GIST) with immunohistochemical staining for CD 34 and CD 117. The patient was treated with imatinib. CLL-type NHL and GIST both tend to occur in middle-aged and older patients. A double-tumour consisting of both these tumours is rare: the incidence is estimated to be 3 per 10 billion people.