Citrulline as a biomarker of bacteraemia during induction treatment for childhood acute lymphoblastic leukaemia

Pietri, Silvia; Frandsen, Thomas Leth; Christensen, Mette; Grell, Kathrine; Rathe, Mathias; Müller, Klaus

doi:10.1002/pbc.28793

Cited by 15 publications

(14 citation statements)

References 46 publications

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“…Interestingly, these metabolites showed inverse correlations with CRP, a marker of systemic inflammation suggesting that the levels of some of these metabolites increase in parallel with attenuation of CRP levels by JAK inhibition. Some reports also found low levels of arginine and citrulline in severe infectious and inflammatory states associated with elevated CRP release ( 89 , 90 ).…”

Section: Discussionmentioning

confidence: 98%

Effects of tofacitinib therapy on arginine and methionine metabolites in association with vascular pathophysiology in rheumatoid arthritis: A metabolomic approach

et al. 2022

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IntroductionRheumatoid arthritis (RA) has been associated with changes in lipid, arginine and NO metabolism with increased cardiovascular (CV) risk. The aim of this study is to evaluate the effect of tofacitinib, a Janus kinase (JAK) inhibitor, on arginine and methionine metabolism in correlation with inflammation, functional and pathological vascular changes during one-year treatment of patients with RA.Materials and methodsThirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) levels. We assessed brachial artery flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) by ultrasound at baseline and after 6 and 12 months. We also determined plasma L-arginine, L-citrulline, L-ornithine, inducible nitric oxide synthase (iNOS), asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-N-monomethyl-arginine (L-NMMA), cysteine, homocysteine, and methionine levels at these time points.ResultsTwenty-six patients (13 on each arm) completed the study. CRP, ESR and DAS28 decreased significantly during one-year treatment with tofacitinib. Arginine and ADMA showed a negative univariate correlation with CRP but not with FMD, PWV or IMT. Tofacitinib at 10 mg bid significantly increased L-arginine, L-ornithine, iNOS and methionine levels after 12 months. ADMA and SDMA levels did not change in our study. Methionine showed negative correlation with FMD at baseline and positive correlation with PWV after 12 months. No change was observed in FMD and PWV but a significant increase was measured in IMT at 6 and 12 months. Multivariate analysis indicated variable correlations of L-arginine, L-citrulline, ADMA, L-NMMA, homocysteine and methionine with DAS28, CRP, ESR and RF but not with anti-CCP after one-year treatment. With respect to vascular pathophysiology, only PWV and methionine correlated with each other.ConclusionOne-year tofacitinib treatment suppressed systemic inflammation and improved functional status in RA. FMD, PWV have not been affected by one-year tofacitinib treatment., while IMT increased further despite treatment. Increased arginine and methionine might contribute to the anti-inflammatory effects of tofacitinib. Increased arginine availability with no changing ADMA may protect FMD and PWV from deterioration. The increase of IMT in the anti-inflammatory environment cannot be explained by arginine or methionine metabolism in this study.

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Section: Discussionmentioning

confidence: 98%

Effects of tofacitinib therapy on arginine and methionine metabolites in association with vascular pathophysiology in rheumatoid arthritis: A metabolomic approach

et al. 2022

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“…wDuring induction treatment, 27 of 106 patients (25%) were diagnosed with BSI, with median debut day 12 4–29 (Figure 1). Two of 106 patients (2%) had polymicrobial BSI episodes.…”

Section: Resultsmentioning

confidence: 99%

“…The study was approved by the local ethics committee and conducted in accordance with the Declaration of Helsinki and written and oral informed consent was obtained from all patients or legal guardians. Clinical characteristics are listed in Table 1, and additional research data from a subgroup of this patient cohort has been reported previously 25–27 …”

Section: Methodsmentioning

confidence: 99%

Markers of neutrophil chemotaxis for identification of blood stream infections in children with acute lymphoblastic leukemia undergoing induction treatment

Weischendorff

Pietri

Rathe

et al. 2023

European J of Haematology

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Background: Although neutropenic fever is frequently observed during chemotherapy, only a minor proportion is caused by blood stream infections (BSI). This study investigated measurements of neutrophil chemotaxis as risk markers for BSI in children with acute lymphoblastic leukemia (ALL). Methods:The chemokines CXCL1 and CXCL8 were measured weekly in 106 children with ALL during induction treatment. Information regarding BSI episodes was collected from the patients' medical records.Results: During induction treatment, 102 (96%) patients developed profound neutropenia and 27 (25%) were diagnosed with BSI, debuting on median day 12 (range: 4-29). Patients developing BSI had increased levels of CXCL1 on days 8 and 15 as well as increased CXCL8 on days 8, 15, 22, and 29 compared to patients without BSI (all p < 0.05). Patients with BSI < day 12 exhibited increased CXCL1 and CXCL8 levels as early as day 8 (81 vs. 4 pg/mL, p = 0.031 and 35 vs. 10 pg/mL, p < 0.0001, respectively), while CXCL1 and CXCL8 were increased on day 15 (215 vs. 57 pg/mL, p = 0.022 and 68 vs. 17 pg/mL, p = 0.0002) and after (all p < 0.01) in patients with BSI ≥ day 12. Conclusion:The markers of neutrophil chemotaxis, CXCL1, and CXCL8 may help to identify patients at increased risk of BSI during chemotherapy-induced neutropenia.

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“…Plasma citrulline is produced by enterocytes [ 38 ]. Lower levels of citrulline correspond to cell loss and thus to tissue damage and inflammation [ 72 ]. Mucositis was also introduced as marker for an increased risk of bacteremia in ALL [ 72 ].…”

Section: Microbiome In Allmentioning

confidence: 99%

“…Lower levels of citrulline correspond to cell loss and thus to tissue damage and inflammation [ 72 ]. Mucositis was also introduced as marker for an increased risk of bacteremia in ALL [ 72 ]. Furthermore, plasma C-reactive protein level acts as an indicator for inflammation, and its direct increase at sites of infection was also correlated with the increase in specific bacteria at different therapy time points [ 38 ].…”

Section: Microbiome In Allmentioning

confidence: 99%

The Microbiome in Childhood Acute Lymphoblastic Leukemia

Oldenburg

Rüchel

Gössling

2021

Cancers

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For almost 30 years, the term “holobiont” has referred to an ecological unit where a host (e.g., human) and all species living in or around it are considered together. The concept highlights the complex interactions between the host and the other species, which, if disturbed may lead to disease and premature aging. Specifically, the impact of microbiome alterations on the etiology of acute lymphoblastic leukemia (ALL) in children is not fully understood, but has been the focus of much research in recent years. In ALL patients, significant reductions in microbiome diversity are already observable at disease onset. It remains unclear whether such alterations at diagnosis are etiologically linked with leukemogenesis or simply due to immunological alteration preceding ALL onset. Regardless, all chemotherapeutic treatment regimens severely affect the microbiome, accompanied by severe side effects, including mucositis, systemic inflammation, and infection. In particular, dominance of Enterococcaceae is predictive of infections during chemotherapy. Long-term dysbiosis, like depletion of Faecalibacterium, has been observed in ALL survivors. Modulation of the microbiome (e.g., by fecal microbiota transplant, probiotics, or prebiotics) is currently being researched for potential protective effects. Herein, we review the latest microbiome studies in pediatric ALL patients.

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Citrulline as a biomarker of bacteraemia during induction treatment for childhood acute lymphoblastic leukaemia

Cited by 15 publications

References 46 publications

Effects of tofacitinib therapy on arginine and methionine metabolites in association with vascular pathophysiology in rheumatoid arthritis: A metabolomic approach

Effects of tofacitinib therapy on arginine and methionine metabolites in association with vascular pathophysiology in rheumatoid arthritis: A metabolomic approach

Markers of neutrophil chemotaxis for identification of blood stream infections in children with acute lymphoblastic leukemia undergoing induction treatment

The Microbiome in Childhood Acute Lymphoblastic Leukemia

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