Gut microbiota diversity after autologous fecal microbiota transfer in acute myeloid leukemia patients.

Acute myeloid leukemia (AML) intensive chemotherapy combined with broad-spectrum antibiotics, leads to gut microbiota dysbiosis promoting pathological conditions and an increased incidence of complications. Here we report findings from a phase II single-arm, multicenter study evaluating autologous fecal microbiota transfer (AFMT) in 25 AML patients treated with intensive chemotherapy and antibiotics (ClinicalTrials.gov number: NCT02928523). The co-primary outcomes of the study are to evaluate the efficacy of AFMT in dysbiosis correction and multidrug-resistant bacteria eradication. The main secondary outcomes are to define a dysbiosis biosignature, to evaluate the effect of dysbiosis correction on patient clinical status, to assess the short and mid-term safety of AFMT in this immunocompromised population, and to evaluate the feasibility of the AFMT procedure and acceptability by the patient. Intensive induction chemotherapy induces a dramatic decrease of α-diversity indices, and a microbial dysbiosis with a significant shift of the microbial communities and domination of pro-inflammatory families. After AFMT treatment, α-diversity indices return to their initial mean levels and the similarity index shows the restoration of microbial communities. The trial meets pre-specified endpoints. AFMT appears to be safe and may be effective for gut microbiota restoration in AML patients receiving intensive chemotherapy and antibiotics, with an excellent gut microbiota reconstruction based on both richness and diversity indices at the species level.

Metagenomic analysis of bloodstream infections in patients with acute leukemia and therapy-induced neutropenia.

Leukemic patients are often immunocompromised due to underlying conditions, comorbidities and the effects of chemotherapy, and thus at risk for developing systemic infections. Bloodstream infection (BSI) is a severe complication in neutropenic patients, and is associated with increased mortality. BSI is routinely diagnosed with blood culture, which only detects culturable pathogens. We analyzed 27 blood samples from 9 patients with acute leukemia and suspected BSI at different time points of their antimicrobial treatment using shotgun metagenomics sequencing in order to detect unculturable and non-bacterial pathogens. Our findings confirm the presence of bacterial, fungal and viral pathogens alongside antimicrobial resistance genes. Decreased white blood cell (WBC) counts were associated with the presence of microbial DNA, and was inversely proportional to the number of sequencing reads. This study could indicate the use of high-throughput sequencing for personalized antimicrobial treatments in BSIs.

Two cases of bacteremia caused by Leptotrichia trevisanii in patients with febrile neutropenia.

We present two cases of bacteremia caused by Leptotrichia trevisanii: a 12-year-old girl with recurrent myeloid leukemia of the mandible and a 66-year-old man with esophageal carcinoma. As this filamentous bacillus showed indefinite Gram staining and the identification based on biochemical enzymatic reactions was not definitive, identification required 16s rRNA analysis. For this organism, drug sensitivity testing showed susceptiblity to each ß-lactam antibiotics and clindamycin, but resistance to fluoroquinolone and erythromycin. This filamentous bacillus needs careful identification and appropriate antibiotic treatment.

Chronic meningitis by histoplasmosis: report of a child with acute myeloid leukemia

Meningitis is a common evolution in progressive disseminated histoplasmosis in children, and is asymptomatic in many cases. In leukemia, the impaired of the T cells function can predispose to the disseminated form. The attributed mortality rate in this case is 20 percent-40 percent and the relapse rate is as high as 50 percent; therefore, prolonged treatment may be emphasized. We have described a child with acute myeloid leukemia (AML), that developed skin lesions and asymptomatic chronic meningitis, with a good evolution after prolonged treatment with amphotericin B deoxycholate followed by fluconazole.

A case of Cunninghamella bertholettiae rhino-cerebral infection in a leukaemic patient and review of recent published studies.

Cunninghamella bertholletiae infection occurs most frequently in neutropenic patients affected by haematological malignancies, is associated with an unfavourable outcome. We report a case of rhino-mastoidal fungal infection in a leukaemic patient. Bioptical tissue cultures yield the isolation of a mould with typical properties of Cunninghamella species. Liposomal amphotericin B (L-Amb) therapy combined with surgical intervention brought the lesion to recovery. Nevertheless, the patient died 14 days after bone marrow transplantation (BMT) from bacterial sepsis. Mastoiditis was documented at CT-scan. The conditioning regimen probably caused the reactivation of the Cunninghamella infection that led to the patient's fatal outcome; fungal hyphae were detected after autopsy of brain and lung tissue.

Chronic meningitis by histoplasmosis: report of a child with acute myeloid leukemia.

Meningitis is a common evolution in progressive disseminated histoplasmosis in children, and is asymptomatic in many cases. In leukemia, the impaired of the T cells function can predispose to the disseminated form. The attributed mortality rate in this case is 20%-40% and the relapse rate is as high as 50%; therefore, prolonged treatment may be emphasized. We have described a child with acute myeloid leukemia (AML), that developed skin lesions and asymptomatic chronic meningitis, with a good evolution after prolonged treatment with amphotericin B deoxycholate followed by fluconazole.

Imaging findings of pulmonary infection caused by Scedosporium prolificans in a deep immunocompromised patient.

Scedosporium prolificans is an emerging fungus that causes rapid progressive and disseminated infections in immunodepressed patients. We present a case of a 34-year-old woman with chronic myelogenous leukemia who received a bone marrow transplantation and suffered a sudden respiratory failure in +67 day. Chest radiographies showed growing bilateral patchy condensations. Computed Tomography depicted bilateral nodular condensation of alveolar space. S. prolificans was detected from sputum, but the patient died 72 h later. Imaging findings of lung scedosporiosis are nonspecific, but CT may provide a prompter diagnosis and allow to add newer antifungal treatments. This report presents the first imaging report of lung scedosporiosis.

Infección fúngica invasiva en una paciente inmunocomprometida / Invasive fungal infections in immunocompromised patients

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Immunological characterization and antibacterial function of persisting granulocytes in leukemic patients receiving pulse cytosine arabinoside-consolidation chemotherapy on days 1, 3, and 5.

High-dose cytosine arabinoside (HiDAC) and intermediate-dose cytosine arabinoside (IDAC) have been introduced as effective and safe consolidation chemotherapy in acute myeloid leukemia, with relatively low rates of life-threatening infections despite the high total dose of the cytostatic drug. To explore the biological background of low toxicity, we examined the numbers, immunophenotype, and functional properties of granulocytes in patients with acute myeloid leukemia receiving HiDAC or IDAC. Interestingly, the absolute numbers of neutrophils remained >500/microl until day 10 in 92 of 125 (74%) HiDAC cycles and in 106 of 113 (94%) IDAC cycles. As assessed by electron microscopy, these day-10 granulocytes surviving chemotherapy were found to be mature cells containing secondary granules and phagolysosomes. They also expressed opsonization- and phagocytosis-linked surface Ags (C3biR, CR1, C1qR, C5aR, FcgammaRI, FcgammaRII, FcgammaRIII, and G-CSF and GM-CSF receptors) like neutrophils in healthy controls. Moreover, these day-10 neutrophils exhibited oxidative burst activity and took up and digested bacteria in the same way as neutrophils in healthy controls. There was a negative correlation between absolute neutrophil counts and severe infections in HiDAC- and IDAC-treated patients with a later onset of infections in IDAC patients (median: IDAC, day 18; HiDAC, day 16). Together, functionally mature neutrophils are detectable at least until day 10 in patients treated with HiDAC or IDAC, and may explain the relatively low hematologic toxicity of these consolidation protocols. IDAC is a superior protocol in this regard and may therefore be most suitable for elderly patients and those at high risk for severe infections.

Candidemia in patients with acute leukemia.

PURPOSE: To present the clinical course and laboratory results of leukemic patients with candidemia and to comment on the incidence and clinical findings of mycoses in this particular patient population. PATIENTS AND METHODS: From 2002 to 2005 in the Department of Hematology of our institution 53 leukemic patients with clinical signs of infection and severe neutropenia after intensive chemotherapy presented 127 febrile episodes during which blood cultures were taken, both from central venous catheters and from peripheral veins with a sterile method as described elsewhere. RESULTS: 4/53 (7.5%) of neutropenic patients presented disseminated candidiasis with positive blood cultures with different species of Candida (C) according to the EORTC criteria. Two patients had strains susceptible to all or most antifungal agents, 1 had dose-dependent sensitivity and 1 had C. krusei resistant to all agents. Two patients died probably because of disseminated candidiasis, 1 survived and 1 died of unrelated cause. CONCLUSION: Fungal infections are not uncommon in patients with hematological malignancies, but they are rarely microbiologically documented. A fast and reliable means of diagnosis of invasive fungal infections is urgently needed.

Common genetic variants in the interleukin-6 and chitotriosidase genes are associated with the risk for serious infection in children undergoing therapy for acute myeloid leukemia.

Infectious complications represent a substantial cause of morbidity and mortality in children undergoing therapy for acute myeloid leukemia (AML). Since it has been shown that alterations in innate immune pathways contribute to the risk for serious infections, we analyzed well-characterized variants in innate immune genes (TNF, IL6, IL8, MPO, CHIT, FCGR2A, TLR2, and TLR4) to determine their possible contribution to infectious complications during therapy for pediatric AML. The study population consisted of 168 North European Caucasian children enrolled on the clinical trial AML-BFM 93. We found an association between Gram-negative bacterial infection and common, functional variants in two genes, IL6 and CHIT. The risk for infection was significantly higher in children with the G allele in the IL6 promoter at -174 bp (P=0.026) and in patients with the H allele of CHIT (P=0.033). The promoter variant in IL6 has been shown to increase expression while the H allele disrupts both function and circulating levels. Our data suggest that variant alleles of both IL6 and CHIT could influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML. Follow-up studies, namely replication association studies and in vitro investigation of these common polymorphisms, are warranted to confirm these observations.

Lethal pulmonary hemorrhage caused by a fulminant Stenotrophomonas maltophilia respiratory infection in an acute myeloid leukemia patient.

Stenotrophomonas maltophilia (Sm) pneumonia in immunocompromized hosts is an increasingly common nosocomial infection. Even though resistant to multiple antimicrobials, this gram-negative bacteria usually does not present with a fulminant course leading to a fatal hemorrhagic respiratory infection in neutropenic patients. We report here the case of a 63-year-old woman treated by intensive chemotherapy for acute myeloid leukemia (AML) who presented while severely neutropenic and thrombocytopenic a Sm pulmonary infection with hemoptysis leading to death in 48 h. The bronchoalveolar lavage (BAL) performed shortly before death was highly hemorrhagic and contained a striking amount of extra- and intra-cellular pathogens. Blood and BAL cultures grew S. maltophilia. Post-mortem examination revealed bilateral extensive intra-alveolar hemorrhage (IAH) associated with a great amount of microorganisms and severe bone marrow aplasia was observed without evidence of leukemia residual disease. Sm pneumonia usually does not evolve into such a devastating clinical picture although infections due to the bacteria are known to be associated with high morbidity and mortality. So far, the present observation is the fourth similar case reported in the literature. Even though an early diagnosis and an adequate antibiotic prescription may improve Sm infection prognosis, S. maltophilia proves difficult to eradicate due to a high resistance rate in part intrinsic but also in part acquired.

[Generalized cryptococcosis in HIV infection]. / Generalizovannyi kriptokokkoz pri VICh-infektsii.

Two cases of generalized cryptococcosis in patients who died of HIV infection are described. The course of the disease was masked by other diseases and final diagnosis was established after necropsy. Leukemia was a clinical "mask" in one case and generalized tuberculosis in the other. Numerous cryptococci were found in different organs histologically with positive Shiff-reaction. Ultrastructurally, cryptococci were of variable forms this probably reflecting different stages of interaction between microorganisms and the host.

Spontaneous remission in adult acute myeloid leukemia in association with systemic bacterial infection-case report and review of the literature.

Spontaneous remission of acute myeloid leukemia in the adult is a rare event. We report on a 31-year-old male patient suffering from acute myeloid leukemia (AML) M5a according to the French-American-British (FAB) classification with biphenotypic features in flow cytometric examination and severe bacterial infection with group G streptococci at the time of diagnosis. Because of sepsis and stable clinical conditions, chemotherapy was delayed and antibiotics were administered intravenously. Within 6 weeks a spontaneous remission of AML occurred. Remission lasted for about 2 months. At the time of relapse, a change in phenotype of the leukemic blasts with a loss of B-lymphoid markers could be demonstrated by flow cytometry. The patient was treated with an induction therapy according to the multicentric German AMLCG 2000 schedule. To our knowledge, this is the first report of a spontaneous remission in an AML FAB M5a associated with coexpression of myeloid- and lymphoid-associated antigens on the leukemic blasts. Possible mechanisms of this phenomenon are discussed with a review of the literature.

Isolation from blood culture of a Leclercia adecarboxylata strain producing an SHV-12 extended-spectrum beta-lactamase.

We report on the first isolation of an extended-spectrum beta-lactamase-producing Leclercia adecarboxylata strain from the bloodstream in a 58-year-old man with acute myeloid leukemia. The strain, resistant to ceftazidime, cefotaxime, and aztreonam, produces the SHV-12 beta-lactamase, one of the most common variants found in Italian nosocomial isolates of Enterobacteriaceae.

[Paecilomyces lilacinus systemic infection in an immunocompromised child]. / Infección sistémica por Paecilomyces lilacinus en un paciente inmunodeprimido pediátrico.

The incidence of systemic fungal infections increased during the last two decades. Rare fungi, such as Mucor, Fusarium and Paecilomyces, are emerging as causes of systemic fungal infections in immunocompromised hosts. There are reports of cutaneous infections, endophthalmitis, keratitis, sinusitis, neuropathy and fungemia in immunocompromised and immunocompetent adult patients. We report a 5 years old neutropenic patient with acute myeloid leukemia treated with multiple courses of chemotherapy, with a fungemia caused by Paecilomyces lilacinus (PL). His initial clinical course was characterized by fever, skin lesions, respiratory distress and shock. Blood and bone marrow cultures were positive. The patient was treated with amphotericin B and itraconazole with a good clinical response.

Prior invasive pulmonary and cerebellar mucormycosis is not a primary contraindication to perform an autologous stem cell transplatation in leukemia.

Mucormycosis infections, caused by fungi of the families Rhizopus, Mucor or Absidia, are typically rapidly progressive and often fatal. We report a 27-year-old male with acute myeloid leukemia (AML) developing an invasive pulmonary-CNS mucormycosis during the neutropenic period after salvage induction chemotherapy; the infection was successfully controlled with surgery and antifungal therapy. The patient received two courses of consolidation chemotherapy and underwent autologous stem cells transplantation (ASCT) while receiving secondary antifungal systemic prophylaxis with liposomal Amphotericin B (L-AMB, Ambisome). There was no clinical, radiological or microbiological evidence of mycotic reactivation during the bone marrow transplantation (BMT) procedure.

Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years' experience of infection in GIMEMA centres.

A retrospective survey was conducted over a 10-year period (1990-99) among 52 haematology divisions in order to evaluate the clinical and laboratory characteristics and outcome of patients with proven Pneumocystis carinii pneumonia (PCP) complicating haematological diseases. The study included 55 patients (18 with non-Hodgkin's lymphoma, 10 with acute lymphoblastic leukaemia, eight with acute myeloid leukaemia, five with chronic myeloid leukaemia, four with chronic lymphocytic leukaemia, four with multiple myeloma, three with myelodysplastic syndrome, two with myelofibrosis and one with thalassemia) who developed PCP. Among these, 18 (33%) underwent stem cell transplantation; only two received an oral prophylaxis with trimethroprim/sulphamethoxazole. Twelve patients (22%) developed PCP despite protective isolation in a laminar airflow room. The most frequent symptoms were: fever (86%), dyspnoea (78%), non-productive cough (71%), thoracic pain (14%) and chills (5%); a severe hypoxaemia was present in 39 patients (71%). Chest radiography or computerized tomography showed interstitial infiltrates in 34 patients (62%), alveolar infiltrates in 12 patients (22%), and alveolar-interstitial infiltrates in nine patients (16%). Bronchoalveolar lavage was diagnostic in 47/48 patients, induced sputum in 9/18 patients and lung biopsy in 3/8 patients. The diagnosis was made in two patients at autopsy. All patients except one started a specific treatment (52 patients trimethroprim/sulphamethoxazole, one pentamidine and one dapsone). Sixteen patients (29%) died of PCP within 30 d of diagnosis. Multivariate analysis showed that prolonged steroid treatment (P < 0.006) and a radiological picture of diffuse lung involvement (P < 0.003) were negative diagnostic factors.