Epidemiology and outcomes of invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients in the era of antifungal prophylaxis: a single‐centre study with focus on emerging pathogens

With increased use of expanded‐spectrum triazoles for antifungal prophylaxis, the epidemiology of invasive fungal infections (IFIs) after allogeneic haematopoietic stem cell transplantation (HSCT) continues to evolve. To define the contemporary epidemiology of IFIs in this population, we reviewed all European Organization for Research and Treatment of Cancer‐Mycoses Study Group proven and probable IFIs in adults transplanted from 2002 to 2011 and determined the incidence and risk factors for IFI and post‐IFI mortality. All patients received antifungal prophylaxis. Fifty‐three (14%) of 378 allogeneic HSCT recipients developed an IFI. There were 62 IFI episodes, of which aspergillosis (n = 31; 50%) and candidaemia (n = 15; 24%) were most common. Sixteen episodes (26%) were caused by other fungi, including Mucorales (n = 6; 10%) and the following uncommon pathogens: Trichosporon asahii, Arthrographis sp., Cladosporium sp., Geosmithia argillacea and Hormographiella aspergillata. Independent IFI risk factors were hospitalisation in an intensive care unit [ICU; odds ratio (OR) = 6.0], graft‐versus‐host disease (OR = 5.3), central venous catheter use (OR = 5.2) and hypoalbuminaemia (OR = 0.3 g^?1 dl^?1 increase in albumin). The 90‐day mortality rate after IFI was 57%. Non‐cytomegalovirus systemic viral co‐infection (OR = 3.5) and stay in an ICU (OR = 2.9) were independent risk factors for death. Despite antifungal prophylaxis, IFIs remain common after allogeneic HSCT and previously uncommon pathogens are emerging.     

Pre-transplant depression as risk factor for survival of patients undergoing allogeneic haematopoietic stem cell transplantation

Introduction: Depression is discussed as a possible risk factor for survival in cancer patients. We explored this relationship for patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT). Patients and methods: The depression subscale of the Hospital Anxiety and Depression Scale (HADS) served as a measure for depression. One hundred and thirty‐eight patients (mean age 41 years; different diagnoses) participating in a psycho‐oncology study filled in the HADS after admission for allogeneic HSCT. They were followed‐up for at least two years; 72 patients died during follow‐up. Results: Depression scores were not correlated with medical and psychosocial objective factors with the exception of having under‐aged children. Controlling for medical factors that showed up as predictors for survival in our sample (patient's age at HSCT, having had a transplant before, risk for treatment failure) the HADS depression score (range 0–21) emerged as an independent predictor (Cox regression): hazard ratio = 1.087, 95% CI = 1.018–1.161. Conclusion: Depression is probably not a simple indicator of a worse health status. Further research is needed to decide if depression must be considered as an independent risk factor for survival when diagnosed in the pre‐transplant period. Copyright © 2007 John Wiley & Sons, Ltd.     

Risk factors for early invasive fungal infections in paediatric liver transplant recipients

Invasive fungal infections (IFIs) postliver transplantation are a frequent cause of morbidity and mortality; however, studies reporting on these infections in the paediatric population are scarce. To investigate the incidence and risk factors of IFIs in paediatric liver transplant recipients during the early posttransplantation period (≤3 months). Data were collected for all paediatric liver transplant recipients registered in a national transplantation center from 2004 to 2014. Using a stepwise logistic regression to identify independent risk factors for IFIs, a predictive model was formulated. Ten IFIs were identified in 81 liver transplant recipients (12.3%) all occurring during the first month posttransplantation. Candida species were responsible for nine cases (90%), of which four were non‐albicans Candida (44%). Significant risk factors were identified; recipient of multiple blood product transfusions during transplantation, prolonged use of indwelling intravenous catheter, prolonged IV antibiotic treatment, surgical complications, pulse steroid treatment and living donor liver transplantation. The predictive model used two clinical parameters to define high‐risk patients: a living donor transplantation and duration of IV antibiotic treatment (area under the ROC curve 0.918). IFIs are a significant complication occurring in the first month posttransplantation. Future studies are required to assess efficacy of targeted antifungal prophylaxis in high risk patients.     

Frequent and long‐term follow‐up of health‐related quality of life following allogeneic haematopoietic stem cell transplantation

Health‐related quality of life (HRQL) was evaluated in 94 patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) after myeloablative (MAC, n = 18) or reduced intensity conditioning (RIC, n = 76). HRQL was assessed with the EORTC QLQ C‐30 during the inpatient period as well as during the following 3 years, i.e. at baseline and 12 times thereafter. Functional status and global quality of life decreased from baseline to weeks 2 and 3, especially role and social functions. Symptoms increased significantly during the first 3 weeks, particularly appetite loss, nausea and vomiting, diarrhoea and fatigue. It took at least 1 year for HRQL to return to the baseline level. The only function that improved significantly 3 years after HSCT was role function. Patients treated with MAC experienced significantly worse HRQL at baseline than patients treated with RIC, as well as more pain, sleep disturbance and appetite loss in weeks 3 and 4. Patients with extensive chronic graft‐versus‐host disease experienced reduced HRQL. These results provide a clinically useful overview of patients’ HRQL during and after HSCT and indicate when they require increased support. The results demonstrate the importance of close follow‐ups during the first year after HSCT to improve preventive or supportive interventions.     

Performance of serum (1,3)‐ß‐d‐glucan screening for the diagnosis of invasive aspergillosis in neutropenic patients with haematological malignancies

We report our experience with the use of (1,3)‐ß‐d ‐glucan (BDG) screening for the diagnosis of invasive aspergillosis (IA) in neutropenic patients with haematological malignancies. The performance of BDG screening was assessed retrospectively in per patient and per sample analyses. Overall, 20 among 167 patients developed IA (12%). In the per patient analysis, BDG showed 60% sensitivity and 78% specificity when the criterion for positivity was the presence of at least one BDG value ≥80 pg/mL. For 2 consecutive positive results, sensitivity decreased to 40%, while specificity increased to 93% and was similar to that of a positive galactomannan (GM; 90%). The highest specificity (97%) was observed for combined positivity of at least one BDG and at least one GM. In the per sample analysis, the specificity of BDG was 100% in the best scenario, 96% in the median scenario and 89% in the worst scenario. BDG became positive before GM in 33% of IA patients with both markers positive (n = 12). Despite good specificity for 2 consecutive positive results, the BDG test offered unsatisfactory performance for the diagnosis of IA due to low sensitivity. The combination of BDG and GM showed the potential for increasing specificity.     

高剂量化疗联合自体造血干细胞移植治疗男性生殖细胞肿瘤

生殖细胞肿瘤是15～35岁男性最常见的恶性肿瘤.大多数患者可以治愈,但仍有少数患者死于该病.多项临床研究应用高剂量化疗联合自体外周血干细胞移植治疗复发或预后不良的男性生殖细胞肿瘤,以期提高疗效.本文综述高剂量化疗联合自体外周血干细胞移植治疗男性生殖细胞肿瘤的治疗、安全性及病例选择等方面的问题.     

Post‐influenzal triazole‐resistant aspergillosis following allogeneic stem cell transplantation

Influenza virus infection is now recognised as a risk factor for invasive pulmonary aspergillosis (IPA). Delays in diagnosis contribute to delayed commencement of antifungal therapy. In addition, the emergence of resistance to first‐line triazole antifungal agents puts emphasis on early detection to prevent adverse outcomes. We present 2 allogeneic stem cell transplant patients who developed IPA due to triazole‐resistant Aspergillus fumigatus following influenza infection. We underline the challenges faced in the management of these cases, the importance of early diagnosis and need for surveillance given the emergence of triazole resistance.     

Efficacy of caspofungin in prophylaxis and treatment of an adult leukemic patient with invasive pulmonary aspergillosis in allogeneic stem cell transplantation

Summary Invasive aspergillosis is a major problem in the management of immunocompromised patients, its prevalence is rising and it is still a major cause of death in this group. The clinical success rate with classical drugs is far away from expectations. New drugs are needed in the treatment of this complication. Belonging to the new class of echinocandins, caspofungin is a newly introduced and promising drug in this fatal situation. We report a patient with acute myeloid leukemia who had invasive pulmonary aspergillosis during induction therapy being treated with amphotericin B in first step and afterwards with caspofungin. The patient received consolidation therapy and allogeneic stem cell transplantation while using caspofungin, and did not experience any adverse effect related to drug. Many side effects, e.g. derangements in liver and kidney functions, hypokalemia, infusion-related side effects and especially thrombocytopenia, which are common with amphotericin B treatment are no longer problem with caspofungin. The efficacy of caspofungin in terms of regression of pulmonary lesions and control of fever is quite successful. The optimal therapies for opportunistic fungal infections are still debated, and further evaluation is needed.     

Safety and feasibility of physical therapy in cytopenic patients during allogeneic haematopoietic stem cell transplantation

This study aimed to investigate the safety and feasibility of physical therapy in cytopenic patients undergoing allogeneic haematopoietic stem cell transplantation (allo‐HSCT), and to investigate the effect of physical therapy on physiological functions and quality of life (QOL) in allo‐HSCT patients. The study cohort included 321 patients who underwent allo‐HSCT. To investigate the safety and feasibility of physical therapy during cytopenia, patients were assigned to the physical therapy group (n = 227) or the control group (n = 94). To determine the effects of physical therapy, patients were divided according to the frequency with which they underwent physical therapy (n = 51 per group). Handgrip strength, knee extensor strength and a 6‐min walk test were used as measures of physiological function. Short‐Form 36 was used to assess QOL. The physical therapy group had higher rate of achieving engraftment and lower death rate than the control group (P < 0.05). After HSCT, the high‐frequency physical therapy group showed significantly less decline than the low‐frequency physical therapy group with respect to physical functioning of QOL (P < 0.01). Physical therapy is quite beneficial and can be performed safely and feasibly in cytopenic patients during allo‐HSCT.     

Factors associated with changes in quality of life in patients undergoing allogeneic haematopoietic stem cell transplantation

KISCH A., LENHOFF S., ZDRAVKOVIC S. & BOLMSJÖ I. (2012) European Journal of Cancer Care Factors associated with changes in quality of life in patients undergoing allogeneic haematopoietic stem cell transplantation It is well known that patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) experience changes in quality of life. We investigated factors associated with quality of life changes in adult HSCT patients. The Functional Assessment of Cancer Therapy – Bone Marrow Transplantation (FACT‐BMT) scale, supplemented with the Functional Assessment of Chronic Illness Therapy – Spiritual Well‐being (FACIT‐Sp) subscale, was administered on three occasions, immediately before transplantation, 100 days and 12 months after transplantation. Analyses of nine selected factors were made where changes in quality of life were found. Seventy‐five patients were included and 40 of these completed the study. Emotional well‐being was found to improve between the baseline and 100 days, while all other dimensions deteriorated, including overall quality of life. Physical and social/family well‐being deteriorated between the baseline and the 12‐month follow‐up, while emotional well‐being improved. The main factors associated with deteriorating quality of life over time were found to be significant infections, female gender and transplantation with stem cells from a sibling donor. In our further studies we aim to focus on the relationships between patients and sibling donors in order to improve the care. Careful attention must be paid to continuous adequate information during the transplantation procedure.     

Fludarabine and melphalan conditioning with tacrolimus as GVHD prophylaxis for allogeneic stem cell transplant recipients is an effective reduced-intensity combination regimen compared to the conventional regimen

Background  As a reduced-intensity stem-cell transplantation (RIST) regimen, the combination of fludarabine and melphalan (FM) with an appropriate immunosuppressant reduces nonrelapse mortality (NRM). Methods  We retrospectively compared the efficacy of a RIST regimen with FM with that of a conventional stem cell transplantation (CST) regimen. Eighty-two consecutive hematological patients who underwent allogeneic stem-cell transplantation (SCT) at our hospital were enrolled. Preparation for RIST consisted of 25 mg/m² fludarabine and melphalan 70 mg/m². The conventional regimen employed high-dose cyclophosphamide and total-body irradiation (12 Gy) or busulfan and high-dose cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxis for RIST consisted of tacrolimus alone or in conjunction with short-term methotrexate for unrelated donors. Results  Of the 82 patients, 42 received the conventional CST regimen (median age, 35 years) and 40 received the RIST regimen (median age, 51 years). The probability of NRM was 17% (7/42) in the CST group and 8% (3/40) in the RIST group. Grade II to IV GVHD occurred in significantly more CST patients (38%) than RIST patients (28%). However, the overall survival was the same in the two groups (43%). Conclusion  The RIST regimen with FM incorporating tacrolimus and methotrexate demonstrated low TRM incidence and moderate control of GVHD and had efficacy comparable to that of the CST regimen, despite the advanced age of the RIST patient group.     

Prospective evaluation of the SeptiFAST multiplex real‐time PCR assay for surveillance and diagnosis of infections in haematological patients after allogeneic stem cell transplantation compared to routine microbiological assays and an in‐house real‐time PCR method

We prospectively evaluated a multiplex real‐time PCR assay (SeptiFast, SF) in a cohort of patients undergoing allo‐BMT in comparison to an in‐house PCR method (IH‐PCR). Overall 847 blood samples (mean 8 samples/patient) from 104 patients with haematological malignancies were analysed. The majority of patients had acute leukaemia (62%) with a mean age of 52 years (54% female). Pathogens could be detected in 91 of 847 (11%) samples by SF compared to 38 of 205 (18.5%) samples by BC, and 57 of 847 (6.7%) samples by IH‐PCR. Coagulase‐negative staphylococci (n=41 in SF, n=29 in BC) were the most frequently detected bacteria followed by Escherichia coli (n=9 in SF, n=6 in BC). Candida albicans (n=17 in SF, n=0 in BC, n=24 in IH‐PCR) was the most frequently detected fungal pathogen. SF gave positive results in 5% of samples during surveillance vs in 26% of samples during fever episodes. Overall, the majority of blood samples gave negative results in both PCR methods resulting in 93% overall agreement resulting in a negative predictive value of 0.96 (95% CI: 0.95‐0.97), and a positive predictive value of 0.10 (95% CI: ?0.01 to 0.21). SeptiFast appeared to be superior over BC and the IH‐PCR method.     

Relationship of physical activity with physical function and health‐related quality of life in patients having undergone allogeneic haematopoietic stem‐cell transplantation

In this study, we investigated the differences in physical activity before and after transplantation, and the relationship between physical activity and physical function and health‐related quality of life (QOL) in 30 patients who underwent allogeneic haematopoietic stem cell transplantation (allo‐HSCT). Duration and intensity of physical activity were quantified using a three‐dimensional accelerometer. Physical function was quantified by handgrip and knee‐extensor strength, with the 6‐minute walk test (6MWT) used as a measure of exercise capacity. Health‐related QOL was assessed using the 36‐item Short‐Form Health Survey. The proportion of daily activities performed at an intensity >3.0 metabolic equivalents (METs) increased significantly after allo‐HSCT (p < .05). Daily activity time performed at an intensity of 1.6–2.9 METs significantly correlated only with left knee strength (p < .05). In contrast, the total number of daily steps and the proportion of activity performed at 1.6–2.9 METs and >3.0 METs were positively correlated with the 6MWT (p < .05). Additionally, physical functioning and general health subscales in health‐related QOL positively correlated with daily activities performed at >3.0 METs (p < .05). Physical activity was associated with 6MWT and health‐related QOL. These findings have implications for rehabilitation planning for patients undergoing allo‐HSCT.     

Graft-versus-tumor effect after reduced-intensity allogeneic hematopoietic stem cell transplantation in a patient with advanced colon cancer

A 27-year-old man with advanced colon cancer that was resistant to conventional chemoradiotherapies was treated with reduced-intensity allogeneic peripheral blood stem cell transplantation (PBSCT). After obtaining complete donor-type chimerism, there was an apparent graft-versus-tumor effect accompanied by severe hepatic graft-versus-host disease (GVHD) showing hyperbilirubinemia, resulting in a stable disease condition that lasted for 18 months, which had not been seen previously in his previous disease history. The antitumor effect observed in this patient was insufficient for the patient to achieve complete remission, because the disease was at an already widespread and treatment-resistant stage. He finally died of hepatic failure due to extensive liver GVHD 65 months after the diagnosis of the advanced colon cancer and 29 months after the allogeneic PBSCT. Prospective studies are necessary to achieve better clinical results in patients with advanced colon cancer.     

Risk and prognostic factors of transplantation‐associated thrombotic microangiopathy in allogeneic haematopoietic stem cell transplantation: a nested case control study

Transplantation‐associated thrombotic microangiopathy (TA‐TMA) is a significant complication of haematopoietic stem cell transplantation. However, it remains controversial which clinical or laboratory markers are of evident risk and prognostic value. From 2006 to 2013, a nested case control study was carried out in our centre to study the risk and prognostic factors of TA‐TMA. A total of 654 consecutive patients who underwent allogeneic haematopoietic stem cell transplantation were studied. Twenty‐six (4.0%) patients matched the established diagnostic criteria. Subjects with TA‐TMA had significantly higher 3‐year none relapse mortality compared with those without (65.4% vs 15.4%, P < 0.0001). Grades 2 to 4 aGVHD and cytomegalovirus viremia were independent risk factors, and serum LDH level >500U/L as well as hypertension were early signs of TA‐TMA occurrence. Liver dysfunction and significant gastric bleeding were independent risk factors for TA‐TMA related mortality. Subjects with either liver dysfunction or significant gastric bleeding had significantly higher 3 year TA‐TMA related mortality cumulative incidence than subjects without. These observations lead to the conclusion that allo‐HSCT recipients with grades 2 to 4 aGVHD or cytomegalovirus viremia should be monitored for TA‐TMA. Liver dysfunction and significant gastric bleeding are prognostic factors for TA‐TMA. Copyright © 2016 John Wiley & Sons, Ltd.