Background Gram-negative bacteremia (GNB) is a major cause of illness and death after hematopoietic stem cell transplantation (HSCT), and updated epidemiological investigation is advisable. Methods We prospectively evaluated the epidemiology of pre-engraftment GNB in 1118 allogeneic HSCTs (allo-HSCTs) and 1625 autologous HSCTs (auto-HSCTs) among 54 transplant centers during 2014 (SIGNB-GITMO-AMCLI study). Using logistic regression methods. we identified risk factors for GNB and evaluated the impact of GNB on the 4-month overall-survival after transplant. Results The cumulative incidence of pre-engraftment GNB was 17.3% in allo-HSCT and 9% in auto-HSCT. Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most common isolates. By multivariate analysis, variables associated with GNB were a diagnosis of acute leukemia, a transplant from a HLA-mismatched donor and from cord blood, older age, and duration of severe neutropenia in allo-HSCT, and a diagnosis of lymphoma, older age, and no antibacterial prophylaxis in auto-HSCT. A pretransplant infection by a resistant pathogen was significantly associated with an increased risk of posttransplant infection by the same microorganism in allo-HSCT. Colonization by resistant gram-negative bacteria was significantly associated with an increased rate of infection by the same pathogen in both transplant procedures. GNB was independently associated with increased mortality at 4 months both in allo-HSCT (hazard ratio, 2.13; 95% confidence interval, 1.45–3.13; P <.001) and auto-HSCT (2.43; 1.22–4.84; P = .01). Conclusions Pre-engraftment GNB is an independent factor associated with increased mortality rate at 4 months after auto-HSCT and allo-HSCT. Previous infectious history and colonization monitoring represent major indicators of GNB. Clinical Trials registration NCT02088840.

Background The onset of acute Graft-versus-Host Disease (aGvHD) has been correlated with the gut microbiota (GM) composition, but experimental observations are still few, mainly involving cohorts of adult patients. In the current scenario where fecal microbiota transplantation has been used as a pioneer therapeutic approach to treat steroid-refractory aGvHD, there is an urgent need to expand existing observational studies of the GM dynamics in Hematopoietic Stem Cell Transplantation (HSCT). Aim of the present study is to explore the GM trajectory in 36 pediatric HSCT recipients in relation to aGvHD onset. Methods Thirty-six pediatric patients, from four transplantation centers, undergoing HSCT were enrolled in the study. Stools were collected at three time points: before HSCT, at time of engraftment and > 30 days following HSCT. Changes in the GM phylogenetic structure were studied by 16S rRNA gene Illumina sequencing and phylogenetic assignation. Results Children developing gut aGvHD had a dysbiotic GM layout before HSCT occurred. This putative aGvHD-predisposing ecosystem state was characterized by (i) reduced diversity, (ii) lower Blautia content , (iii) increase in Fusobacterium abundance. At time of engraftment, the GM structure underwent a deep rearrangement in all patients but, regardless of the occurrence of aGvHD and its treatment, it reacquired a eubiotic configuration from day 30. Conclusions We found a specific GM signature before HSCT predictive of subsequent gut aGvHD occurrence. Our data may open the way to a GM-based stratification of the risk of developing aGvHD in children undergoing HSCT, potentially useful also to identify patients benefiting from prophylactic fecal transplantation. Electronic supplementary material The online version of this article (10.1186/s12920-019-0494-7) contains supplementary material, which is available to authorized users.

About two-thirds of pediatric patients with PP-IFI survived, regardless of whether the infection occurred after frontline chemotherapy, reinduction chemotherapy for disease relapse, or after HSCT. Further prospective studies are needed to define the impact of antifungal prophylaxis and early combination therapy on short-term overall survival.

Summary Background Invasive mucormycosis is a rare but frequently fatal fungal disease. The acute and rapidly progressive evolution causes unfavourable outcome in 22%‐59% of patients and its treatment represents a clinical challenge, especially in immunocompromised patients. Current data in paediatric oncological patients are limited. Objectives The infection Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) analysed the episodes of invasive mucormycosis occurred between 2009 and 2016. Patients Fifteen cases of proven mucormycosis (male/female 8/7; median age 14.1 years, range 7.7‐18.6) were reported after chemotherapy for acute leukaemia and lymphoma (12) and allogeneic stem cell transplantation (3). The aetiology was Rhizopus oryzae 4, Lichtheimia corymbifera 3 and Mucor spp. 8. Results Paranasal sinus was the primary site of infection in 14/15 patients combined with orbital involvement (9), central nervous system (8), lung (4), thyroid gland and kidney (1). All patients received liposomal Amphotericin B (L‐AmB) (3‐10 mg/kg), with surgical debridement in 14/15 cases. Eleven patients received maintenance treatment with posaconazole (9) or isavuconazole (2). Eight out of fifteen patients (53.3%) died, after 3‐6 months. Conclusions Mucormycosis involved mainly the sinu‐orbital site and affected children >10 years. Despite aggressive treatment with high‐dose L‐AmB and timely surgical debridement, the mortality rate remains still high.

Summary Invasive fungal infections (IFI) of the Central Nervous System (IFI‐CNS) and Paranasal Sinuses (IFI‐PS) are rare, life‐threatening infections in haematologic patients, and their management remains a challenge despite the availability of new diagnostic techniques and novel antifungal agents. In addition, analyses of large cohorts of patients focusing on these rare IFI are still lacking. Between January 2010 and December 2016, 89 consecutive cases of Proven (53) or Probable (36) IFI‐CNS (71/89) and IFI‐PS (18/89) were collected in 34 haematological centres. The median age was 40 years (range 5‐79); acute leukaemia was the most common underlying disease (69%) and 29% of cases received a previous allogeneic stem cell transplant. Aspergillus spp. were the most common pathogens (69%), followed by mucormycetes (22%), Cryptococcus spp. (4%) and Fusarium spp. (2%). The lung was the primary focus of fungal infection (48% of cases). The nervous system biopsy was performed in 10% of IFI‐CNS, and a sinus biopsy was performed in 56% of IFI‐PS (P = 0.03). The Galactomannan test on cerebrospinal fluid has been performed in 42% of IFI‐CNS (30/71), and it was positive in 67%. Eighty‐four pts received a first‐line antifungal therapy with Amphotericine B in 58% of cases, Voriconazole in 31% and both in 11%. Moreover, 58% of patients received 2 or more lines of therapy and 38% were treated with a combination of 2 or more antifungal drugs. The median duration of antifungal therapy was 60 days (range 5‐835). A surgical intervention was performed in 26% of cases but only 10% of IFI‐CNS underwent neurosurgical intervention. The overall response rate to antifungal therapy (complete or partial response) was 57%, and 1‐year overall survival was 32% without significant differences between IFI‐CNS and IFI‐PS. The overall mortality was 69% but the IFI attributable mortality was 33%. Mortality of IFI‐CNS/PS remains high but, compared to previous historical data, it seems to be reduced probably due to the availability of newer antifungal drugs. The results arising from this large contemporary cohort of cases may allow a more effective diagnostic and therapeutic management of these very rare IFI complications in haematologic patients.

PBM is a safe, feasible, and effective treatment for children affected by chemotherapy-induced OM, as it accelerates mucosal recovery and reduces pain.

We analyzed the use of isavuconazole (ISA) as treatment or prophylaxis for invasive fungal disease (IFD) in children with hemato-oncologic diseases. A multicentric retrospective analysis was performed among centers belonging to the Italian Association for Pediatric Hematology and Oncology (AIEOP). Pharmacokinetic (PK) monitoring was applied by a high-performance liquid chromatography-tandem mass spectrometry (HLPC-MS/MS) assay. Twenty-nine patients were studied: 10 during chemotherapy and 19 after allogeneic hematopoietic stem cell transplantation (HSCT). The patients consisted of 20 males and 9 females with a median age of 14.5 years (age range, 3 to 18 years) and a median body weight of 47 kg (body weight range, 15 to 80 kg). ISA was used as prophylaxis in 5 patients and as treatment in 24 cases (20 after therapeutic failure, 4 as first-line therapy). According to European Organization for Research and Treatment of Cancer (EORTC) criteria, we registered 5 patients with proven IFD, 9 patients with probable IFD, and 10 patients with possible IFD. Patients with a body weight of <30 kg received half the ISA dose; the others received ISA on the adult schedule (a 200-mg loading dose every 8 h on days 1 and 2 and a 200-mg/day maintenance dose); for all but 10 patients, the route of administration switched from the intravenous route to the oral route during treatment. ISA was administered for a median of 75.5 days (range, 6 to 523 days). The overall response rate was 70.8%; 12 patients with IFD achieved complete remission, 5 achieved partial remission, 5 achieved progression, and 3 achieved stable IFD. No breakthrough infections were registered. PK monitoring of 17 patients revealed a median ISA steady-state trough concentration of 4.91 mg/liter (range, 2.15 to 8.54 mg/liter) and a concentration/dose (in kilograms) ratio of 1.13 (range, 0.47 to 3.42). Determination of the 12-h PK profile was performed in 6 cases. The median area under the concentration-time curve from 0 to 12 h was 153.16 mg·h/liter (range, 86.31 to 169.45 mg·h/liter). Common Terminology Criteria for Adverse Events grade 1 to 3 toxicity (increased transaminase and/or creatinine levels) was observed in 6 patients, with no drug-drug interactions being seen in patients receiving immunosuppressants. Isavuconazole may be useful and safe in children with hemato-oncologic diseases, even in the HSCT setting. Prospective studies are warranted.

Toxoplasmosis is a rare but severe complication after allogenic hematopoietic stem cell transplantation (allo-HSCT) that, in the vast majority of cases, develops as a reactivation of a latent infection; 1,2 however primary infection is also possible. 2-4 Patients who were toxoplasmosis seropositive before transplantation are at higher risk when the donor is seronegative. 1,4,5 Toxoplasmosis disease is associated with high morbidity and mortality rate in~60-90% when the onset is early after transplantation. 4-6 In most cases, patients develop localised central nervous system infection, but disseminated disease is also possible. 1,5,7 In adult patients who undergo HSCT, the reported incidence of toxoplasmosis is~1% with an important variability between geographic areas depending on seroprevalence. 1 When screening PCR is performed in patients at high risk of infectious complications, the incidence of infection (without disease) is 12-18%. 1-3 Here, we report the frequency of toxoplasmosis disease, its presentation, diagnosis and outcome in paediatric patients who underwent allogeneic HSCT in the Paediatric Haematology and Oncology Department at Fondazione IRCCS Policlinico San Matteo of Pavia between 1 January 2011 and 31 December 2015. HSCT data and medical records were collected retrospectively. All patients and, when possible, all donors were tested before and after transplant in order to assess their immunological status with LIAISON XL Toxo-IgG II/IgM (DiaSorin, Saluggia, Italy). In all suspected cases VIDAS TOXO-IgG II and IgG AVIDITY, Toxo-ISAGA IgM (Biomerieux, Marcy l'Etoile, France), ETI-ToxoA (DiaSorin) were performed. To assess their humoral immunological status and in house Interferon Gamma Release Assay, QuantiFERON-ELISA (Cellestis Limited, Carnegie, Victoria, Australia), with Toxoplasma antigen (kindly provided by Diasorin) was also used. The commercial real-time PCR test ELITE-MGB (ELITech Group, Torino Italia) was performed on peripheral blood, and/or cerebrospinal fluid in all the suspected cases and was also used to monitor the recovery. The 187 allo-HSCTs analysed in the study included 15 second allo-HSCT (8%) and 5 patients who received a previous auto-HSCT. Mean age at transplant was 9 years. Underlying disease included malignant (66.3%) and non-malignant (33.7%) disorders. Forty-three patients with a malignant disease (23%) received allo-HSCT in advanced disease status, 81 (43.3%) in early disease status. Only 4 patients received a reduced intensity conditioning regimen. Thirty-seven (19.8%) were matched family donor (MFD), 86 (45.9%) matched unrelated donor (MUD) and 64 (34.2%) partially matched family donor. Main characteristics of the cohort analysed are summarised in Table 1. Of 187 HSCT recipients, 28.8% (54/187) were toxo-IgG positive before transplant and 71.2% (133/187) were naive for protozoan infection. Toxoplasma serology was available only for 152/187 donors: 23% were toxo-IgG positive and 77% were toxo-IgG negative. We found a high number of non-tested donors (18.7%, 35/187), wh...