Infection In Acute Leukemia Patients Research Articles

Research Progress in Diagnosis and Treatment of Acute Leukemia Complicated with Pulmonary Infection--Review

Acute leukaemia is a group of aggressive malignancies with a high mortality rate. The reduction in functional immune cells due to the disease itself and radiotherapy/chemotherapy makes the patients susceptible to co-infections, of which pulmonary infection is a major cause of death. Early accurate diagnosis and appropriate treatment may prevent the spread of infection in patients with acute leukaemia complicated with pulmonary infection, thus reduce serious complications such as sepsis, respiratory failure and multi-organ failure. However, there are still clinical difficulties in the diagnosis and treatment of pulmonary infections in acute leukemia patients. Therefore, the current research advances in the diagnosis and treatment of bacterial, fungal and viral infections in the lungs of patients with acute leukemia were briefly summarized in this review.

Analysis of Risk Factors for Pulmonary Infection in Patients with Acute Leukemia after Chemotherapy

To investigate the risk factors of pulmonary infection in patients with acute leukemia (AL) after chemotherapy. A total of 294 patients with AL were collected and divided into infection group (n=93) and control group (n=201) according to whether the pulmonary infection occurred after chemotherapy. Analyze the correlation between sociodemographic data (sex, age, BMI), clinical data (disease type, ECOG score, invasive procedure, underlying disease, hormone therapy, empirical use of antibiotics, prognosis stratification, chemotherapy intensity, primitive cell count, white blood cell count, neutrophil count, duration of granulocyte deficiency, platelet count, hemoglobin, and albumin and pulmonary infection after chemotherapy. COX regression method was used to analyze the risk factors of pulmonary infection in AL patients after chemotherapy. Among 294 patients with AL, 11 died within 30 days after pulmonary infection. There were statistically significant differences in age, smoking history, ECOG score, invasive procedure, hormone therapy, empirical use of antibiotics, prognosis stratification, chemotherapy intensity, primitive cell count, neutrophil count, duration of granulocyte deficiency, platelet count, hemoglobin, albumin and fasting blood glucose between the 2 groups (P <0.05). COX regression analysis showed that smoking history, invasive procedure, unexperienced use of antibiotics, poor prognosis, long duration of granulocytopenia, low platelet level and low albumin were high risk factors for pulmonary infection in AL patients after chemotherapy (P <0.05). Smoking, invasive procedures, unexperienced use of antibiotics, poor prognosis, long duration of granulodeficiency, low platelet levels and low albumin are risk factors for pulmonary infection in AL patients after chemotherapy.

Blood plasma metagenomic next-generation sequencing for identifying pathogens of febrile neutropenia in acute leukemia patients

To investigate the value of metagenomic next-generation sequencing (mNGS) in acute leukemia (AL) patients with febrile neutropenia (FN). We retrospectively reviewed 37 AL patients with FN and compared the results of mNGS with blood culture (BC) and the clinical features of the mNGS-positive group and the mNGS-negative group. A total of 14 detected pathogens were the final clinical diagnosis, of which 9 strains were detected only by mNGS and 5 strains were detected by both mNGS and BC. The top pathogens were Klebsiella pneumoniae, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. A total of 67.57% (25/37) were bacterial infections, and 2.7% (1/37) were fungal or viral infections. The diagnostic positivity rate of mNGS (25/37, 67.6%) was significantly higher than that of BC (7/37, 18.9%), and the difference was statistically significant (p < 0.05). Then, we explored the clinical distinction between the mNGS-positive group and the mNGS-negative group, and 3 features were filtered, including lymphocyte count (LY), creatinine levels (Cr), and white blood cell count (WBC). Our study demonstrated that early implementation of mNGS can effectively improve the efficacy of pathogen detection in AL patients with FN. The higher diagnostic positivity rate and the ability to detect additional pathogens compared to BC made mNGS a valuable tool in the management of infectious complications in this patient population. Furthermore, the identified clinical features associated with mNGS results provided additional insights for the clinical indication of infection in AL patients with FN.

Investigating the effect of sodium chloride on the prevention of mucormycosis fungal infection in children with acute lymphocytic leukemia during treatment

Background: Given that no comprehensive study was conducted regarding the effect of sodium chloride on the prevention of mucormycosis fungal infection in acute leukemia patients during treatment, this study aimed the investigating the effect of sodium chloride on the prevention of mucormycosis fungal infection in acute lymphocytic leukemia patients during treatment.&#x0D; Materials and Methods: This retrospective study was conducted on children with ALL who were undergoing chemotherapy in the induction phase and were susceptible to fungal and infectious diseases. Then 84 patients were randomly divided into the two groups. One group (n=46) received nasal drop containing sodium chloride (NORMONIX, 0.65%, three times a day) as the intervention group during treatment and another group did not receive sodium chloride (control group)(n=38). If the symptoms of mucormycosis was observed and detected (positive test), the injection of amphotrypsin B was started.&#x0D; Results: In the current study, 84 patients entered the study. The mean age of patients in the control group and the intervention group was 7.84±3.45, and 6.45±3.4 years, respectively (P&gt;0.05). Positive mucormycosis was seen in 24 (63.2%) patients in the control group and 16 (34.78%) patients in the intervention group (P=0.01).&#x0D; Conclusion: According to the findings of this study, the frequency of patients with positive mucormycosis in the NaCl group was significantly lower than the control group. Therefore, it seems that NaCl drop can be effective regarding reducing the incidence of mucormycosis fungal infection and can decrease the need to amphotrypsin B, but further studies should be conducted in this regard.

Successful diagnosis and treatment of fusariosis in patient with acute leukemia

Introduction. The development of febrile neutropenia complicates the course of the post-chemotherapeutic period in many patients with acute leukemia. Febrile neutropenia — the most common complication of the post-chemotherapeutic period in patients with acute leukemia (AL), and the concomitant infectious complications can cause life-threatening conditions. Invasive fungal infections in AL patients during neutropenia can be extremely severe.Aim — to present a clinical observation and successful diagnosis and treatment of the rare fungal infection induced by fungi of the genus Fusarium in an immunocompromised patient.Main findings. A clinical observation, diagnosis and treatment of a rare fungal infection caused by the fungi of the Fusarium genus is presented. The taxonomic variety of Fusarium is given, and the morphological and molecular methods of diagnostics are highlighted. Special attention is given to the choice of appropriate antifungal therapy of fusariosis.

A Predicted Model for Refractory/Recurrent Cytomegalovirus Infection in Acute Leukemia Patients After Haploidentical Hematopoietic Stem Cell Transplantation.

ObjectiveWe aimed to establish a model that can predict refractory/recurrent cytomegalovirus (CMV) infection after haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT).MethodsConsecutive acute leukemia patients receiving HID HSCT were enrolled (n = 289). We randomly selected 60% of the entire population (n = 170) as the training cohort, and the remaining 40% comprised the validation cohort (n = 119). Patients were treated according to the protocol registered at https://clinicaltrials.gov (NCT03756675).ResultsThe model was as follows: Y = 0.0322 × (age) – 0.0696 × (gender) + 0.5492 × (underlying disease) + 0.0963 × (the cumulative dose of prednisone during pre-engraftment phase) – 0.0771 × (CD34+ cell counts in graft) – 1.2926. The threshold of probability was 0.5243, which helped to separate patients into high- and low-risk groups. In the low- and high-risk groups, the 100-day cumulative incidence of refractory/recurrent CMV was 42.0% [95% confidence interval (CI), 34.7%–49.4%] vs. 63.7% (95% CI, 54.8%–72.6%) (P < 0.001) for total patients and was 50.5% (95% confidence interval (CI), 40.9%–60.1%) vs. 71.0% (95% CI, 59.5%–82.4%) (P = 0.024) for those with acute graft-versus-host disease. It could also predict posttransplant mortality and survival.ConclusionWe established a comprehensive model that could predict the refractory/recurrent CMV infection after HID HSCT.Clinical Trial Registration https://clinicaltrials.gov, identifier NCT03756675.

Clinical Characteristics and Risk Factors of Invasive Fungal Infections in Acute Leukemia Patients in Tropical Regions

To analyze the clinical characteristics and risk factors of invasive fungal infection (IFI) occurenced in patients with acute leukemia (AL) during treatment in tropical regions. The clinical data of 68 AL patients admitted to the Hainan Hospital of PLA General Hospital from April 2012 to April 2019 was retrospectively analyzed. Logistic regression analysis was used to analyze the factors affecting the occurrence of IFI in AL patients. Among the 68 patients, 44 were acute myeloid leukemia, 24 were acute lymphoblastic leukemia, 39 were male, 29 were female and the median age was 41(13-75) years old. The 68 patients received 242 times of chemotherapy or hematopoietic stem cell transplantation(HSCT), including 73 times of initial chemotherapy or inducting chemotherapy after recurrence, 14 times of HSCT, 155 times of consolidating chemotherapy. Patients received 152 times of anti-fungal prophylaxis, including 77 times of primary anti-fungal prophylaxis and 75 times of secondary anti-fungal prophylaxis. Finally, the incidence of IFI was 31 times, including 24 times of probable diagnosis, 7 times of proven diagnosis, and the total incidence of IFI was 12.8%(31/242), the incidence of IFI in inducting chemotherapy was 24.66%(18/73), the incidence of IFI in HSCT patients was 28.57% (4/14), the incidence of IFI in consolidating chemotherapy was 5.80% (9/155). Multivariate analysis showed that inducting chemotherapy or HSCT, the time of agranulocytosis ≥7 days, risk stratification of high risk were the independent risk factors for IFI in AL patients during treatment in tropical regions. The incidence of IFI in patients with AL in the tropics regions is significantly higher than that in other regions at homeland and abroad. Anti-fungal prophylaxis should be given to the patients with AL who have the high risk factors of inducting chemotherapy or HSCT, time of agranulocytosis ≥7 days and risk stratification of high risk.

Idarubicin and Ara-C Treatment Associated with Fungal Infection in Acute Leukemia Patients with Febrile Neutropenia

Background: Pateints with acute leukemia along with febrile neutropenia is at risk for fungal as well as bacterial infections. Fungal infection is a more serious and common infection in this setting, leading to a high mortality rate. There is limited data on clinical factors predictive of fungal infection in acute leukemia with febrile neutropenia. Objective: This study aimed to evaluate clinical predictive factors of fungal infection in acute leukemia patients with FN. Methods: This was a retrospective analytical study and included adult patients diagnosed with acute leukemia, who developed FN, and had positive culture with either bacterial or fungal infection. Predictors for fungal infection were calculated by using logistic regression analysis. A subgroup analysis in patients with acute myeloid leukemia (AML) was also performed. Results: There were 94 patients who met the study criteria. Of those, 29 patients had positive culture for fungus (30.82%), categorized as Aspergillus (19 patients; 65.51%) and Candida (10 patients; 34.49%). The mortality rate was significantly higher in the fungal infection group than the bacterial infection group (24.14% vs. 6.15%; p 0.031). There were six factors in the final model predictive of fungal infection with one independent predictor: treatment regimen of Idarubicin plus Ara-C with an adjusted odds ratio of 5.188 (95% CI of 1.386, 19.419). A subgroup analysis for fungal infection in patients with AML showed that only the treatment regimen of Idarubicin plus Ara- C was a significant factor. Its adjusted odds ratio was 5.138 (95% CI of 1.156, 24.467). Conclusion: Treatment with idarubicin and Ara-C may increase the risk of fungal infection in acute leukemia patients with FN.

The role of procalcitonin and presepsin in the septic febrile neutropenia in acute leukemia patients.

BackgroundThe source of bacterial infection in neutropenic acute leukemia patients is detected in about 20–30% of cases. Bacterial cultures may require a long incubation period and risk false-positive and false- negative results. Therefore, biomarkers distinguishing septic febrile neutropenia from other etiologies in acute leukemia patients play the important role in patient assessment and treatment planning. This study aims to determine the role of procalcitonin (PCT) and presepsin (PSPN) in infectious complication in comparison to C-reactive protein (CRP) on the first and third day at the onset of febrile neutropenia in patients with acute leukemia.MethodsBetween June 2018 and February 2019, 60 acute leukemia patients with febrile neutropenia receiving chemotherapy. The 41 acute myeloid leukemia patients and 19 acute lymphoblastic leukemia patients were recruited in this study. Their ages ranged from 14 to 65 years. PCT and PSPN were measured and were compared to CRP at the onset of febrile neutropenia and after 48 hours. 20 patients had a fever of unknown origin (FUO) and 40 patients had a bacterial infection.FindingsOur results showed that the values of these markers were higher in patients with infection than patients without. The area under the curve (AUC) of PCT were 0.931 and 0.813 on day one and three respectively, which was the best in determination of infection. The cut-off values of PCT were 1.27 and 1.23 ng/mL and the cut off values of PSPN were 1.75 and 2.9 μg/L in the successive days, their clinical sensitivities were high. PCT and PSPN were capable of distinguishing the cause of febrile neutropenia from the onset of infection and predicting its complications (p<0.05). The PSPN level couldn’t differentiate gram-positive or gram-negative bacterial infection. Significant differences were found between the mean values of the PSPN during the successive days in all patients and patients with bacteremia. This study illustrated a weak positive correlation between PCT and Sequential Organ Failure Assessment (SOFA) score, the negligible correlation between CRP and SOFA score and no significant correlation between PSPN and SOFA score.InterpretationPCT is an accurate biomarker in identifying infection in acute leukemia patients, its concentration is associated with the severity of bacterial sepsis. PSPN is superior to PCT for follow-up of patients.

Diagnostic Performance of Serum (1,3) β-D Glucan to Detect Fungal Infection in Acute Leukemia Patients with Chemotherapy

Chemotherapy is a predisposing factor for infection in patients with malignancy, while culture, as the gold standard,limits the diagnosis of fungal infections. (1,3) β-D glucans, the most abundant polysaccharide component of the fungal wall,are increased in patients with Invasive Fungal Infections (IFI). This research was an analytical observational study with across-sectional approach involving 60 acute leukemia patients who received chemotherapy with suspicion of fungalinfection at the General Hospital of Dr. Moewardi, Surakarta, from September to October 2019. Fungal blood cultures andserum (1,3) β-D glucan levels by the enzyme-linked immunoassay method were examined. Diagnostic tests were performedto determine sensitivity, specificity, Positive Predict Value (PPV), Negative Predict Value (NPV), Positive Likehood Ratio (PLR),Negative Likehood Ratio (NLR), and the serum's accuracy value (1,3) β-D glucan levels to fungal culture. Most (88.3%) ofpatients were diagnosed with Acute Lymphocytic Leukemia (ALL), maintenance chemotherapy phase (51.3%), risk factorsfor neutropenia (50%), and intravenous (IV) line use (56.7%). Serum (1,3) β-D glucan levels in patients with positive fungalcultures (4) in blood samples had a median of 482.87 (476.13-640.56) pg/mL, while patients with negative fungal cultures(56) had a mean±SD 298,68±114,39 pg/mL. Diagnostic test with a cut-off of 471,717 pg/mL showed sensitivity of 100.0%,specificity of 96.4%, NPV of 100%, PLR of 28.00, and NLR of 0.00 with an Area Under Curve (AUC) value of 0.982 andCoefficient Interval (CI) 95% (0.950-1.014). The measurement of serum (1,3) β-D glucan at a cut-off value of 471,717 pg/mLshowed good performance as a biomarker for diagnosing and screening IFIs.

Incidence of Invasive Fungal Infections in Acute Leukemia Patients Utilizing Micafungin Prophylaxis Compared to Second-Generation Azole Prophylaxis

Introduction/Background: Standard therapy for both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) is myelosuppressive, and patients are expected to be neutropenic for a prolonged period. Due to the high risk of infection, antimicrobial prophylaxis is warranted and should be continued throughout neutropenia. The incidence of documented invasive fungal infections ranges from 12 to 24% in patients with AML and approximately 6.5% in patients with ALL. Guidelines currently include posaconazole as a category 1 recommendation for antifungal prophylaxis, with echinocandins and other azole antifungals as category 2B. However, posaconazole can be subject to drug-drug interactions and can increase the risk of hepatotoxicity, both of which can be problematic in acute leukemia patients undergoing chemotherapy. For patients unable to receive posaconazole or another second-generation azole antifungal, micafungin is utilized. To our knowledge, there are no studies comparing second-generation azole antifungals to micafungin as prophylaxis in both AML and ALL during initial or relapsed/refractory induction therapy. The aim of this retrospective study is to compare the incidence of invasive fungal infections in patients with acute leukemia in the setting of micafungin or second-generation azole antifungal prophylaxis during initial and/or relapsed/refractory induction therapy at an academic medical center. Methods: Retrospective, single-center study from June 22, 2013 to June 22, 2018. Detailed chart reviews were performed by hand. Results: The incidence of invasive fungal infections within 100 days of chemotherapy was 11.2% in patients who received a second-generation azole and 2.7% in patients who received micafungin (P=0.7618). The incidence of invasive fungal infections within 100 days in patients who received a high intensity AML regimen was 11.2%, low intensity AML regimen 0.9%, and ALL regimen 1.8% (P=0.5378). The incidence of invasive fungal infections within 30 days of chemotherapy was 4.5% in patients who received a second-generation azole and 2.2% in patients who received micafungin (P=0.2447). The most common reason for micafungin prophylaxis was drug-drug interactions with standard ALL regimens that utilize vincristine. Of those with a documented fungal infection, 14 patients (6.3%) had a proven invasive fungal infection, and 17 patients (7.6%) had a probable/possible invasive fungal infection. The most common site of infection was in the chest (9.8%), followed by fungemia (2.2%). Other sites of infection include the brain, sinuses, liver/spleen, and skin. Beta-D-glucan was collected in 17 patients, and galactomannan antigen was collected in 26 patients. Three patients had a positive beta-D-glucan, and 1 patient had an indeterminate beta-D-glucan. Two patients had a positive galactomannan antigen. Fusarium species accounted for 4 positive cultures in patients. For those patients who did experience an invasive fungal infection, 23 out of the 31 patients (74.2%) were on posaconazole, 6 patients on micafungin (19.4%), and 2 on voriconazole (6.5%). Ten out of the 14 proven fungal infections (71.4%) occurred while on posaconazole prophylaxis, and 3 of these patients had posaconazole levels &lt;0.7 mcg/mL. Twenty-one patients (67.7%) with documented infections had a neutrophil nadir &lt; 0.1x109/L. The majority (93.5%) of those with breakthrough infections while on antifungal prophylaxis were switched to another antifungal. Conclusions: Micafungin is a reasonable alternative therapy for use in patients who are unable to receive second-generation azoles as antifungal prophylaxis during induction therapy for acute leukemia. Some invasive fungal infections occurred while patients had sub-therapeutic posaconazole levels, however others had breakthrough fungal infections with therapeutic levels. Our conclusions are limited by the small sample size and non-randomized, retrospective nature of this analysis. Disclosures Erba: Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding; Celgene, Incyte, Novartis: Speakers Bureau; Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy. LeBlanc:Seattle Genetics: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NINR/NIH: Research Funding; Jazz Pharmaceuticals: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; CareVive: Consultancy; American Cancer Society: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy; Medtronic: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Consultancy; Heron: Membership on an entity's Board of Directors or advisory committees; Duke University: Research Funding; Celgene: Honoraria; Flatiron: Consultancy. Rizzieri:AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding; Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board.

Values of Procalcitonin for Predicting Outcome of Infection in Acute Leukemia Patients with Bacterial Bloodstream Infection

To investigate the effects of serum procalcitonin(PCT) levels for predicting the outcome of bacteria bloodstream infection in acute leukemia patients. Clinical data from 236 patients with acute leukemia accompanied by bacterial bloodstream infection during July 2014 to November 2017 were retrospectively analyzed, 236 patients were divided into 5 groups (<0.05 ng/ml, 0.05- <0.5 ng/ml, 0.5- <2.0 ng/ml, 2.0- <10.0 ng/ml and >10.0 ng/ml) according to PCT concentrations. The median age of patients was 40(13-73) years old. The male 123 cases(52.1%) and female 113 cases(47.9%) in 236 patients. The incidence of infection-related dealth in 5 groups was 0%, 1.4%, 13.8%, 25.0% and 33.3%, respectively; the incidence of septic shock and other serious complications in 5 groups was 0%, 2.1%, 13.8%, 25.0%, 33.3% and 6.4%, 7.0%, 24.1%, 41.7%, 50.0%, respectively, showing the concentration dependent manner and statistically significant difference (u=2127, P=0.000; u=2234, P=0.000; u=4102, P=0.000). Further analysis showed that with the increase of PCT concentration, the cumulative incidence of septic shock, infection-related death and other serious complications was gradually increased with statistically significance (HR=2.887, P=0.000, 95%CI:1.960-4.260; HR=3.158, P=0.000, 95%CI: 2.100-4.740; HR=2.158, P=0.000, 95%CI:1.550-3.000) respectively. Increased procalcitonin level is an independent risk factor for septic shock and infection-related death (HR=2.517, P=0.000, 95%CI: 1.520-4.168; HR=2.881, P=0.000, 95%CI: 1.692-4.904)respectively. Serum procalcitonin level positively correlates with the incidence of serious bacteria bloodstream infection complications in the patients with acute leukemia. Increased procalcitonin level is an independent risk factor for septic shock and infection-related death, indicating that procalcitonin may be an important prognostic factor for infection outcome in acute leukemia patients with bacteremia.

Pre-engraftment bloodstream infections in acute leukemia patients undergoing unrelated cord blood transplantation following intensified myeloablative conditioning without ATG.

The aim of this study is to investigate the impact of pre-engraftment bloodstream infections (BSIs) on the outcomes in acute leukemia patients undergoing myeloablative cord blood transplantation (CBT). A total of 226 acute leukemia patients who received unrelated CBT were enrolled in this study, and all these patients received an intensified myeloablative conditioning without ATG. Pre-engraftment BSIs occurred in 72 patients (31.9%), and the median time of onset was 4.5days after cord blood infusion, BSIs of gram-negative bacilli, and gram-positive cocci comprised of 63.8 and 36.2%, respectively. The cumulative incidences of neutrophil and platelet engraftment, acute or chronic graft versus host disease (GVHD) were comparable among the non-BSI, gram-negative bacilli BSI, and gram-positive cocci BSI groups. The cumulative incidence of transplant-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DFS) was similar between the non-BSI and the BSI groups. For subgroups analysis, TRM was lower in gram-positive cocci BSI patients compared with that of gram-negative bacilli BSI patients (8.3 vs 39.3%) (p = 0.01) (HR = 0.39, p = 0.034), and the 5-year OS was higher in gram-positive cocci BSI cohort (79.1 vs 44.2%) (p = 0.01) (HR = 0.36, p = 0.046). Our study demonstrated that, for acute leukemia patients who received CBT after myeloablative conditioning that omitted ATG, pre-engraftment BSI had no impact on engraftment, GVHD, TRM, relapse, and long-term survival. Due to the fact that gram-negative bacilli BSI was associated with poor outcomes compared with gram-positive cocci BSI, appropriate early empirical antimicrobial management strategies and better supportive care are required to decrease the gram-negative bacilli BSI-related mortality.

Importanţa clinică a modulării tratamentului cu Voriconazol în cazul aspergilozei pulmonare invazive pentru două cazuri de leucemie acută mieloblastică

Background. Patients with acute leukemia are at high risk to develop invasive fungal infections, and Aspergillus spp is the most common pathogen. Aim. The two cases that are presented highlight the importance of adjusting the algorithm for diagnosis and treatment of invasive fungal infections in acute leukemia patients according to the particularities of each case in order to obtain an optimal response to the antifungal therapy. Methods and results. We present two cases of acute leukemia in young patients, who develop pulmonary invasive aspergillosis during severe neutropenia following chemotherapy. The diagnosis is clinical, mycrobiological, and esspecially imagistic, the CT scan revealing images typical for pulmonary invasive aspergillosis and allowing early antifungal therapy. Conclusions. The two cases illustrate the favourable outcome of patients with acute leukemia and pulmonary invasive aspergillosis when treated early with Voriconazole and the importance of dose adjusting according to clinical evolution.

Does the Occurrence of Invasive Fungal Infection in Acute Leukemia Patients, Impact on the Chemotherapy Schedule and Event-Free Survival? a Case-Control Study

Background: In acute leukemia (AL) patients, mortality rates of the most common IFI (i.e., aspergillosis and candidiasis) are well illustrated in the literature from the IFI diagnosis, as well as the rate of fungal relapse during subsequent periods at risk, such as neutropenic phases, or transplant. However, few data are available about the impact of IFI on the subsequent chemotherapy schedule and the indirect impact of IFI on the relapse-free and overall survival. Clinicians are usually reluctant to give the full chemotherapy doses on time, due to the risk of life-threatening fungal relapse during the subsequent courses. Even with secondary prophylaxis, they often delay or decrease the doses of chemotherapy. This may impact on the leukemia outcome. The aim of this case-control study was to assess the potential impact of proven or probable IFI onset on the application of the chemotherapy schedule in AL patients, and its consequences on the leukemia outcome, by comparing patients with and without IFI in a single institution. Delays and changes in chemotherapy doses and drug choices were evaluated and compared to the planned schedule in the protocol.Methods: All consecutive AL patients with a first episode of proven or probable IFI according to the EORTC-MSG criteria between 2000–2006 were reviewed. All patients have been treated in, or according to, clinical research protocols where timing and doses of chemotherapy were predefined. Patients who were planned for allogeneic transplant were excluded as those who were at their last consolidation course when they got IFI or in a palliative phase of the leukemia. Any delay, dose decrease, or dose change were defined as any difference compared to the planned schedule. We planned to include 3 control patients for each case, selected among AL patients without IFI, and matched for age, sex, type of AL, chemotherapy protocol, and year of treatment. 27 case and 76 control patients were finally included. The event-free survival (EFS) was defined as survival without evidence of relapse or progression, or death of any cause.Results: The mean age of the 27 case patients (26 myeloid and 1 lymphoblastic AL) was 52 y (± 13), the M/F ratio was 14/13 IFI (7 candidiasis, 19 aspergillosis, 1 zygomycosis) was proven for 10 patients (37%), and probable for 17 (63%). Twenty (71%) of these IFI occurred during the first induction phase. All patients were treated for their IFI with ≥ 1 antifungal, and 4 of them had a surgical resection of the main fungal lesion(s). These 27 patients were compared to 76 controls (73 myeloid and 3 lymphoblastic AL) without IFI. A delay of the next course of chemotherapy according to the planned protocol was significantly more frequent in the IFI group (16/27, 59%) than in the control group (16/76, 21%) (p=.001). Similarly, the dose or choice of the drugs was modified more frequently in the IFI group (7/27, 26%) than in the control group (6/76, 8%) (p=.037). Only 9 (33%) patients got their next chemotherapy course without any modification in time, dose, or choice of drug, vs. 19/76 (75%) in the control group (p<.0001). The EFS of the IFI group was lower than that of the control group, although this difference was not significant.Conclusion: In this single-institution case-control study, the occurrence of IFI significantly modified the application of chemotherapy courses, both on timing of the courses, and dose and choice of the drugs when compared to patients without IFI. Although the difference was not significant, there was a tendency for a lower EFS in the IFI group when compared to the control group.−

Invasive Fungal Infection in Acute Leukemia Patients: What Is Their Impact on the Chemotherapy Schedule?.

Invasive fungal infection (IFI) occurs in 2–12% of acute leukemia patients, with different prevalences according to centers, and phases of treatment. The mortality rates of the main IFI (i.e., aspergillosis and candidiasis) are well illustrated in the literature, as well as the risk of fungal relapse during subsequent periods at risk, such as a new neutropenic phase, or transplant. However, few data are available about the impact of IFI on the subsequent chemotherapy schedule. Clinicians are usually reluctant to give the full chemotherapy doses on time, due to the risk of life-threatening fungal relapse during the subsequent courses. Even with secondary prophylaxis which is now widely given, they usually delay or decrease the doses of chemotherapy. This may impact on the leukemia outcome.Objective: The aim of this single-institution retrospective study was to look at the impact of proven or probable IFI onset on the application of the chemotherapy schedule as planned in the initial strategy in patients with acute leukemia. Delays, and changes in chemotherapy doses and drug choices were evaluated and compared to the planned schedule in the protocole.Methods: All consecutive acute leukemia patients with a first episode of proven or probable IFI according to the EORTC-MSG criteria between 2000–2006 were reviewed. All patients have been treated in, or according to, clinical research protocols where timing and doses of chemotherapy were predefined. Patients who were planned for allogeneic transplant were excluded as those who were at their last consolidation course when they got IFI. Any delay, dose decrease or dose change were defined as any difference compared to the planned schedule.Results: 28 patients (7 candidiasis, 20 aspergillosis, 1 zygomycosis) were included (M/F: 15/13; mean age: 54y), including 27 acute myeloid leukemia and one acute lymphoblastic leukemia. Eleven (39%) were proven, 17 (61%) were probable. Twenty (71%) of these IFI occurred during the first induction phase. All patients were treated for their IFI with ≥ 1 antifungal, and 4 of them had a surgical resection of the main fungal lesion (s). Seventeen of 28 (60%) had their next course delayed (median delay: 14 days) when compared to the planned protocole. The doses of the antineoplastic drug(s) were modified in 7 (25%) patients. Only 9 (32%) patients got their next chemotherapy course without any modification in time, dose, or choice of drug. Although the number of patients in our study does not allow definite conclusions, these changes should have an impact on leukemia-free and overall survivals.Conclusion: Due to the risk of fungal relapse during a subsequent period at risk, IFI has a practical impact on the dates, doses, and choices of chemotherapy in acute leukemia in more than two thirds of the patients, due to subjective decisions of the clinicians. Effective antifungal strategies are needed to avoid the onset of IFI in acute leukemia patients.

Voriconazole Replacing Liposomal Amphotericin B as First-Line Therapy in Suspected or Proven Fungal Infection in Acute Leukemia Patients: A Retrospective Audit of Clinical and Financial Outcomes in a UK District Hospital.

Background: In most centres in the United Kingdom, systemic antifungal therapy (AFT) is used as third-line therapy for fever complicating profound, prolonged neutropenia (PPN) during the treatment of acute leukemia. Voriconazole has been recommended as first-line AFT at the Kent and Canterbury Hospital (KCH) since October 2002; liposomal amphotericin B was the previous treatment of choice. The aim of the audit was to identify numbers of episodes of PPN and the numbers of suspected fungal infections in a 2-year period following the policy change. Subsequently the clinical and financial outcomes were examined. In addition, the impact on cost of AFT following centralisation of leukemia treatment from two district hospitals onto one site was examined.Methods: A retrospective audit was conducted on data from hematology inpatients undergoing remission induction or consolidation therapy for acute leukemia at KCH between January 2003 and December 2004. The costs of voriconazole and liposomal amphotericin B treatment from 2002 to 2004, and 8 months prior and post centralisation of inpatient care (April 2004, which increased the population from 400,000 to 600,000), were examined.Results: 84 episodes of PPN were identified in 41 patients undergoing treatment for acute leukemia; mostly acute myeloid leukemia (AML). Itraconazole prophylaxis from d1 of therapy and GCSF from d+5 was used in the majority of cases. 18 cases of suspected or radiologically proven fungal infection were identified. High-resolution computed tomography of the chest was performed in 10 cases and suspicious lesions identified in three. Voriconazole was used as first-line therapy in 17/18 cases. In 7 cases, treatment was switched to liposomal amphotericin B. Reasons for switching were rising C-reactive protein (1 patient), persistent fever (2 patients), radiological progression (1 patient) and side effects (3 patients). Of the 3 patients with radiological evidence of fungal infection, two had a complete resolution (1 voriconazole, 1 voriconazole/liposomal amphotericin B) and 1 patient died of refractory leukemia. There was a fall in total antifungal spend from £263K in 2002/3 to £229K in 2003 and a further 68% fall to £73K in 2004. We suspect this was due to increasing adherence to the new antifungal protocol and to improved practices following centralisation: in the 8 months pre-centralisation the antifungal spend across all hospitals was £102K falling by 74% to £26K in the 8 months on the single site.Conclusion: Since introducing voriconazole as first-line AFT, centralising inpatient services, and adopting common policies for antimicrobial prophylaxis, there has been considerable financial benefit with no increase in morbidity and/or mortality.

Central Venous Catheter Infections in Patients with Acute Leukemia

Background: Central venous catheters (CVCs) have become an essential tool for an appropriate management of patients with acute leukemia. Infectious complications are a major concern in patients treated for acute leukemia. Although CVC-related infections are considered to be a major source of infections during neutropenia (<500/µl), data regarding the incidence of CVC-related infections are rare in acute leukemia. Patients and Methods: We analyzed nontunneled CVCs in 58 patients with acute leukemia (22 men/36 women) in 119 chemotherapy cycles from April 1996 to January 1998 in a prospective trial. Proven CVC-related infection was defined as the isolation of the same organism from peripheral blood and CVC tip. CVC infection was suspected or possible when exit site inflammation and positive blood culture or organisms typical for CVC infection were observed. Results: Mean neutropenia/cycle was 16.3 days (SD 8.0). 178 CVCs with 2,576 CVC days (mean 14.5 days, SD 7.2 days) were used in 119 cycles. Fever occurred in 87 cycles (73%). Blood stream infection was proven in 31 out of 87 febrile episodes (26.1%) with 40 isolates (8 gram-negative, 31 gram-positive, 1 Candida spp.). Colonization of the CVC tip was observed in 24 CVC lines with 28 isolates (27 gram-positive, 1 gram-negative); however, proven CVC-related infections were observed in 5 episodes only, all with coagulase-negative staphylococci. In another 6 episodes, CVC-related infection was assumed (local inflammation and gram-positive blood culture). Six further episodes had typical blood isolates (4 coagulase-negative staphylococci, 1 Candida spp.) and were considered possible CVC-related infections. In none of the remaining afebrile 32 cycles was a CVC infection observed or suspected. Conclusion: Gram-positive organisms contributed to the majority of CVC-related infections (16 out 17 CVC infections); however, the overall incidence of CVC infections in acute leukemia patients was 6.5/1,000 CVC days only (1.9 proven/2.3 suspected/2.3 possible/1,000 CVC days).

Combination of pipemidic acid, colistin sodium methanesulfonate and nystatin may be less effective than nystatin alone for prevention of infection during chemotherapy-induced granulocytopenia in acute leukemia

Pipemidic acid (PPA) and colistin sodium methanesulfonate (CLM) may selectively suppress aerobic gram-negative bacilli. Twenty-nine patients with acute leukemia were randomized after each course of consolidation chemotherapy to receive a single agent of nystatin (NYS) (34 courses) versus a combination of NYS, PPA and CLM (36 courses). The duration of fever over 39 degrees C was longer with the three drug combination (4.6 +/- 5.1 days) than with NYS alone (1.8 +/- 1.8 days) (P less than 0.01). Four cases of pneumonia occurred and four patients including one having pneumonia died of infection with the three drug combination, while no pneumonia or death occurred with NYS alone (P = 0.06 and P = 0.06, respectively). The combination of NYS, PPA and CLM may be less effective than NYS alone for the prevention of infection in acute leukemia patients with chemotherapy-associated granulocytopenia.

Selective decontamination of the digestive tract and fungal infection in acute leukemia patients.

For prevention of infection we used an SD design including antibacterial (trimethoprim 480 mg/daily, sulfamerazine 720 mg/daily, and polymyxin 0.25 mg/daily) and antifungal (4-6 million IU nystatin/daily) components. We analyzed retrospectively 138 treatment periods in 108 patients. The intensified chemotherapy resulted in severe granulocytopenia below 0.1 x 10(9)/liter over 25.2 days. In 19 patients there was suspicion of major fungal infection; therefore they were given amphotericin B and 5-fluocytosine. Fourteen of them died; major fungal infections were documented in 5 cases. In 18% of all the deceased we found major fungal infections. There was a correlation between fungal infection, the late stages of the hematological malignancy, and the lesions on the oropharyngeal mucosa. However, in terms of the serological and culture findings no correlation appeared to exist between the group with and the group without fungal infection. The SD regime is meant to suppress the Candida cell concentration in the digestive tract but has no influence on Aspergillus in the respiratory tract.