[Invasive fungal infections in immunocompromised children in paediatric haematology: Recommendations for management in SFCE centres]. / Infections fongiques invasives chez l'enfant immunodéprimé en hématologie pédiatrique : recommandations de prise en charge au sein des centres de la SFCE.

INTRODUCTION: To date, invasive fungal infections (IFIs) are still responsible for a high mortality rate in children managed for haematological malignancy. Although Candida and Aspergillus infections remain in the majority, emerging fungal infections are increasingly common. Children differ from adults in their pathology and treatment, as well as in their prior fungal colonisation and unique pharmacokinetics. Therefore, we propose here specific paediatric management recommendations for IFIs in haematology. METHODS: We based our recommendations on a review of the literature, including the latest ECIL recommendations, an analysis of practices and a collection of expert opinions. RESULTS AND DISCUSSION: In France, approximately 5% of children treated for haematological malignancy or who have received a bone marrow allograft present an IFI. These IFIs are equally divided between yeast infections (mainly due to Candida albicans) and filamentous infections (mainly aspergillosis) and 16% are IFIs due to emerging fungi, half of which are due to Mucorales. In these recommendations, we recall the diagnostic criteria for proven or probable IFI according to the Donnelly classification, then we propose strategies for screening, diagnosing, evaluating the extension and treating these three types of IFI. We also detail the diagnostic and therapeutic management of chronic disseminated candidiasis. We also discuss prophylactic measures, including environmental measures which are of primary importance in children.

Low-dose mycophenolate mofetil improves survival in a murine model of Staphylococcus aureus sepsis by increasing bacterial clearance and phagocyte function.

Regulators of TLRs signaling pathways play an important role in the control of the pro-inflammatory response that contributes to sepsis-induced tissue injury. Mycophenolate mofetil, an immunosuppressive drug inhibiting lymphocyte proliferation, has been reported to be a regulator of TLRs signaling pathways. Whether MMF used at infra-immunosuppressive doses has an impact on survival and on innate immune response in sepsis is unknown. C57BL/6J mice were infected intraperitoneally with 108 CFU Staphylococcus aureus, and treated or not with low-dose of MMF (20mg/kg/day during 4 days). Survival rate and bacterial clearance were compared. Cytokine levels, quantitative and qualitative cellular responses were assessed. S. aureus - infected mice treated with MMF exhibited improved survival compared to non-treated ones (48% vs 10%, p<0.001). With the dose used for all experiments, MMF did not show any effect on lymphocyte proliferation. MMF treatment also improved local and systemic bacterial clearance, improved phagocytosis activity of peritoneal macrophages resulting in decreased inflammatory cytokines secretion. MMF-treated mice showed enhanced activation of NF-κB seemed with a suspected TLR4-dependent mechanism. These results suggest that infra-immunosuppressive doses of MMF improve host defense during S. aureus sepsis and protects infected mice from fatal outcome by regulating innate immune responses. The signaling pathways involved could be TLR4-dependent. This work brings new perspectives in pathogenesis and therapeutic approaches of severe infections.

[Practical management during maintenance therapy of pediatric acute lymphoblastic leukemia: Recommendations of the French Society for Childhood and Adolescent Cancer and Leukemia (SFCE)]. / Modalités pratiques de prise en charge en cours de traitement d'entretien des leucémies aiguës lymphoblastiques pédiatriques : recommandations du Comité leucémies de la Société française de lutte contre les cancers et les leucémies de l'enfant et de l'adolescent (SFCE).

Maintenance therapy is the last phase of treatment for acute lymphoblastic leukemia in children and adolescents. Although maintenance therapy is associated with toxicities and specific management issues, it is an essential phase of treatment that reduces the risk of relapse. The objective of this work is to propose a guide for the initiation, administration, and monitoring of maintenance therapy, and for the management of food, schooling, leisure, community life, risk of infection and links with family medicine.

Antifungal combination therapy for invasive fungal infections in a paediatric oncology and haematology department: A retrospective analysis of practice.

BACKGROUND: Invasive fungal infections (IFI) are an important cause of morbidity and mortality in children with leukaemia. International guidelines recommend a monotherapy for most IFI. The use of antifungal combination therapy (ACT) has been reported, but clinical data supporting these combinations are scarce, particularly in paediatrics. OBJECTIVE: To describe, among patients treated in our department, the situations in which an ACT was used. RESULTS: Between January 2017 and December 2020, 239 patients (406 hospital stays) benefited from systemic antifungals. Among them, ACT was prescribed for 14 (5.9%) patients (13 leukaemia, 1 aplastic anaemia) corresponding to 16 (3.9%) hospital stays. IFI cases treated with ACT were mainly proven (n=9) or probable (n=4). Seven cases required admission to the intensive care unit. The most commonly used antifungal agents were liposomal amphotericin B (n=13), caspofungin (n=12) and voriconazole (n=9). In 13 cases, monotherapy was prescribed as first-line therapy and changed to an ACT for an uncontrolled infection. But in 3 cases, the ACT was started immediately. The response at 12 weeks after diagnosis of proven/probable IFI was successful in 12 cases (92.3%). The only IFI-related death was attributed to disseminated mucormycosis. ACT were generally well tolerated. In 4 cases, adverse events led to the discontinuation of the offending antifungal agent. CONCLUSION: This retrospective analysis of practices shows that the use of ACT in our paediatric haemato-oncology department is rare, and concerns the most severe cases and/or those not responding to the first line treatment. In most cases, ACT was efficient and well tolerated.

Transmission Routes of Severe Acute Respiratory Syndrome Coronavirus 2 Among Healthcare Workers of a French University Hospital in Paris, France.

In this case-control study on 564 healthcare workers of a university hospital in Paris (France), contacts without protection with coronavirus disease 2019 (COVID-19) patients or with colleagues were associated with infection with severe acute respiratory syndrome coronavirus 2, whereas working in a COVID-dedicated unit and having children kept in childcare facilities were not.

Comparing Dynamics and Determinants of Severe Acute Respiratory Syndrome Coronavirus 2 Transmissions Among Healthcare Workers of Adult and Pediatric Settings in Central Paris.

BACKGROUND: Healthcare workers (HCWs) have paid a heavy toll during the coronavirus disease 2019 (COVID-19) outbreak. Routes of transmission remain to be fully understood. METHODS: This prospective study compared a 1500-bed adult and 600-bed pediatric setting of a tertiary-care university hospital located in central Paris. From 24 February until 10 April 2020, all symptomatic HCWs were screened for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on a nasopharyngeal swab. HCWs screened positive were questioned on their profession, symptoms, and occupational and nonoccupational exposures to SARS-CoV-2. RESULTS: Among 1344 HCWs tested, 373 were positive (28%) and 336 (90%) corresponding questionnaires were completed. Three hospitalizations and no deaths were reported. Most HCWs (70%) had patient-facing occupational activities (22% in COVID-19 dedicated units). The total number of HCW cases peaked on 23 March, then decreased slowly, concomitantly with a continuous increase of compliance to preventive measures (including universal medical masking and personal protective equipment [PPE] for direct care to COVID-19 patients). Attack rates were of 3.2% and 2.3% in the adult and pediatric settings, respectively (P = .0022). In the adult setting, HCWs more frequently reported exposure to COVID-19 patients without PPE (25% vs 15%, P = .046). Report of contacts with children attending out-of-home care facilities dramatically decreased over the study period. CONCLUSIONS: Universal masking, reinforcement of hand hygiene, and PPE with medical masks for patients' care allowed protection of HCWs and containment of the outbreak. Residual transmissions were related to persistent exposures with undiagnosed patients or colleagues and not to contacts with children attending out-of-home care facilities.

Pseudomonas aeruginosa bloodstream infections in children: a 9-year retrospective study.

P. aeruginosa bloodstream infection (BSI) is associated with high hospital mortality. Empirical combination therapy is commonly used, but its benefit remains debated. The purpose of this study was to describe in a paediatric population, demographical characteristics and outcome of children treated for P. aeruginosa BSI receiving either a combined or single antibacterial therapy. We performed a retrospective, single-centre, cohort study of hospitalized children with P. aeruginosa BSI from 2007 to 2015. A total of 118 bloodstream infections (BSI) were analysed (102 (86.4%) hospital-acquired, including 52 (44.1%) hospitalized in intensive care unit). In immunocompromised children, 52% of BSI episodes were recorded. Recent medical history revealed that 68% were hospitalized, 31% underwent surgery and 67% had a prior antibiotic therapy within the last 3 months. In-hospital mortality was similar for patients receiving single or combined anti-Pseudomonas therapy (p = 0.78). In multivariate analysis, independent risk factors for in-hospital mortality were neutropenia (OR = 6.23 [1.94-20.01], hospitalization in ICU (OR = 5.24 [2.04-13.49]) and urinary tract infection (OR = 4.40 [1.02-19.25]).Conclusion: P. aeruginosa BSI mainly occurred in immunocompromised children. Most infections were hospital-acquired and associated with high mortality. Combination therapy did not improve survival. What is Known: • P. aeruginosa bloodstream infection (BSI) is associated with high hospital mortality. Empirical combination therapy is commonly used but its benefit remains debated. What is New: • This is the largest cohort of Pseudomonas aeruginosa bacteraemia in children ever published. P. aeruginosa Bloodstream mainly occurred in immunocompromised children. Most infections were hospital-acquired and associated with high mortality. Combination therapy did not improve survival.

Sepsis inhibits tumor growth in mice with cancer through Toll-like receptor 4-associated enhanced Natural Killer cell activity.

Sepsis-induced immune dysfunctions are likely to impact on malignant tumor growth. Sequential sepsis-then-cancer models of tumor transplantation in mice recovering from sepsis have shown that the post-septic immunosuppressive environment was able to promote tumor growth. We herein addressed the impact of sepsis on pre-established malignancy in a reverse cancer-then sepsis experimental model. Mice previously inoculated with MCA205 fibrosarcoma cells were subjected to septic challenges by polymicrobial peritonitis induced by cecal ligation and puncture or endotoxinic shock. The anti-tumoral immune response was assessed through the distribution of tumor-infiltrating immune cells, as well as the functions of cytotoxic cells. As compared to sham surgery, polymicrobial sepsis dampened malignant tumor growth in wild-type (WT) mice, but neither in Toll-like receptor 4 (Tlr4)-/- nor in Myd88-/- mice. Similar tumor growth inhibition was observed following a LPS challenge in WT mice, suggesting a regulatory role of Tlr4 in this setting. The low expression of MHC class 1 onto MCA205 cells suggested the involvement of Natural Killer (NK) cells in sepsis-induced tumor inhibition. Septic insults applied to mice with cancer promoted the main anti-tumoral NK functions of IFNγ production and degranulation. The anti-tumoral properties of NK cells obtained from septic mice were exacerbated when cultured with MHC1low MCA205 or YAC-1 cells. These results suggest that sepsis may harbor dual effects on tumor growth depending on the sequential experimental model. When applied in mice with cancer, sepsis prevents tumor growth in a Tlr4-dependent manner by enhancing the anti-tumoral functions of NK cells.

Salvage Strategy for Long-Term Central Venous Catheter-Associated Staphylococcus aureus Infections in Children.

Introduction: Current international guidelines strongly recommend catheter removal in case of S. aureus central line-associated bloodstream infection (CLASBI), but a catheter salvage strategy may be considered in children given age-related specificities. No data is available regarding the outcome of this strategy in children. This study aims to evaluate catheter salvage strategy in children with S. aureus CLABSI, and to determine treatment failure rates and associated risk factors. Methods: We retrospectively analyzed data for all children <18 years having S. aureus CLABSI on a long-term central venous catheter in a tertiary hospital from 2010 to 2014. We defined catheter salvage strategy as a central venous catheter left in place ≥3 days after initiation of empiric treatment for suspected bacteremia, and catheter salvage strategy failure as the persistence or relapse of bacteremia with a S. aureus strain harboring the same antibiotic susceptibility pattern, or the occurrence or the worsening of local or systemic infectious complication between 72 h and 28 days after the first positive blood culture. Results: During the study period, 49 cases of S. aureus CLABSI on long-term central venous catheters were observed in 41 children (including 59% with long-term parenteral nutrition) and 6 (15%) isolates were resistant to methicillin. A catheter salvage strategy was chosen in 37/49 (76%) cases and failed in 12/37 (32%) cases. Initial presence of bloodstream co-infection, serum concentration of vancomycin under the targeted value and inadequate empiric treatment were significantly associated with catheter salvage therapy failure. Conclusions: The catheter salvage strategy of S. aureus CLABSI on a long-term central venous catheter was frequent in the studied hospital and failed only in one third of cases.

Trichosporon: another yeast-like organism responsible for immune reconstitution inflammatory syndrome in patients with hematological malignancy.

Trichosporon has recently emerged as a life-threatening opportunistic fungal pathogen, notably in patients with hematological malignancy. Fungemia, sometimes associated with cutaneous lesions and/or pneumonitis, is the major clinical form. Here, we report two cases of patients suffering from acute leukaemia who developed hepatic and/or splenic lesions apart from Trichosporon positive blood cultures. The appearance of hepatic and splenic lesions following the recovery from neutropenia is highly suggestive of a chronic disseminated infection, now considered as an immune reconstitution inflammatory syndrome. Treatment with corticosteroid therapy led to clinical improvement in both cases. Copyright © 2016 John Wiley & Sons, Ltd.

Sepsis-induced expansion of granulocytic myeloid-derived suppressor cells promotes tumour growth through Toll-like receptor 4.

Severe sepsis remains a frequent and dreaded complication in cancer patients. Beyond the often fatal short-term outcome, the long-term sequelae of severe sepsis may also impact directly on the prognosis of the underlying malignancy in survivors. The immune system is involved in all stages of tumour development, in the detection of transforming and dying cells and in the prevention of tumour growth and dissemination. In fact, the profound and sustained immune defects induced by sepsis may constitute a privileged environment likely to favour tumour growth. We investigated the impact of sepsis on malignant tumour growth in a double-hit animal model of polymicrobial peritonitis, followed by subcutaneous inoculation of MCA205 fibrosarcoma cells. As compared to their sham-operated counterparts, post-septic mice exhibited accelerated tumour growth. This was associated with intratumoural accumulation of CD11b(+) Ly6G(high) polymorphonuclear cells (PMNs) that could be characterized as granulocytic myeloid-derived suppressor cells (G-MDSCs). Depletion of granulocytic cells in post-septic mice inhibited the sepsis-enhanced tumour growth. Toll-like receptor (TLR)-4 (Tlr4) and Myd88 deficiencies prevented sepsis-induced expansion of G-MDSCs and tumour growth. Our results demonstrate that the myelosuppressive environment induced by severe bacterial infections promotes malignant tumour growth, and highlight a critical role of CD11b(+) Ly6G(high) G-MDSCs under the control of TLR-dependent signalling. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.