Invasive fungal infections in allogeneic and autologous stem cell transplant recipients: a single-center study of 166 transplanted patients

OBJECTIVES: Invasive fungal infections (IFIs) remain a major cause of infection-related morbidity and mortality following hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: We retrospectively analyzed the incidence of IFIs in 166 patients undergoing either allogeneic or autologous HSCT at our institution between January 2000 and December 2003. RESULTS: Incidence of invasive aspergillosis (IA) and invasive candidiasis among allogeneic HSCT recipients was 23% (16-32%, 95% confidence interval [CI]) and 3% (1-9%, 95% CI), respectively. Duration of neutropenia and reduced-intensity conditioning were the only risk factors for IA in the multivariate model. Patients with IA had significantly reduced overall survival (8% versus 56%, P=0.01) due to higher transplant-related mortality (63% versus 31%, P=0.03). Following autologous HSCT, incidence of IA and invasive candidiasis was 8% (4-19%, 95% CI) and 2% (0.2-11%, 95% CI), respectively. Duration of neutropenia was the only risk factor for the development of IA following autologous HSCT. Overall survival of autologous HSCT recipients with IA was similar to that of patients without IA. Seventeen percent of autologous HSCT recipients were colonized with Candida species. Compared with non-colonized patients these patients had significantly reduced overall survival (72% versus 23%, P=0.004), due to increased treatment-related mortality (23% versus 9%, P=0.02). CONCLUSION: Diagnosis of IA following allogeneic HSCT and Candida colonization in the setting of autologous HSCT defines patient populations with poor outcome but primarily not as a result of the fungal pathogen. Regarding the incidence of IA, duration of neutropenia is the main risk factor, and dose-reduced conditioning is an additional risk factor for the development of IA following allogeneic HSCT, probably owing to increased recipient age in this patient cohort, requiring further studies in this transplantation setting.     

Early treatment-related mortality in adult autologous stem cell transplant recipients: a nation-wide survey of 1482 transplanted patients

OBJECTIVES: To evaluate early (<100 d) treatment-related mortality (TRM) in autologous stem cell transplant (ASCT) recipients. PATIENTS: Altogether 1482 adult patients received ASCT in six Finnish centres 1990-2003. The most common diagnoses were non-Hodgkin's lymphoma (NHL) (n = 542), multiple myeloma (MM) (n = 528), breast cancer (BC) (n = 132), Hodgkin's lymphoma (n = 86) and chronic lymphocytic leukaemia (CLL) (n = 63). RESULTS: Forty-two patients (2.8%) died from treatment-related reasons <100 d from ASCT. The median time to death was 38 d from ASCT (0-99). The risk of TRM varied according to the diagnoses. The highest risk was observed in patients with AL amyloidosis (24%) followed by NHL (4.4%) and MM (1.9%). No early TRM was observed in patients transplanted for BC or CLL. Infections were the cause of death in 16 patients (fungal 7, bacterial 6, viral 3). Organ toxicity was responsible for early death in 26 patients (heart 9, lungs 7, other 10). CONCLUSIONS: This nation-wide survey indicated a low early TRM in ASCT recipients in general, but higher risks in patients with AL amyloidosis or NHL. In addition to patient selection, also optimization of transplant procedure may be needed in these patient groups to reduce early TRM.     

Late non-relapse mortality among adult autologous stem cell transplant recipients: a nation-wide analysis of 1,482 patients transplanted in 1990-2003

Data on the incidence and causes of late (>100 d) non-relapse mortality (NRM) in autologous stem cell transplant (ASCT) recipients is limited. We have analysed NRM in a cohort of 1,482 adult patients who received ASCT in 1990-2003 in six Finnish transplant centres. The most common diagnoses included non-Hodgkin's lymphoma (NHL) (n = 542), multiple myeloma (MM) (n = 528), breast cancer (n = 132); Hodgkin's lymphoma (HL) (n = 86) and chronic lymphocytic leukaemia (CLL) (n = 63). Until September 2005, 646 patients (44%) have died. Late NRM was observed in 68 patients (4.6% of ASCT recipients; 11% of all deaths). There were 38 males and 30 females with a median age of 58 yr (20-69) at the time of ASCT. The median time to NRM was 27 months from ASCT (3-112). The risk of NRM was highest in patients with CLL (9.5%) and those with HL (8.1%) followed by MM and NHL (4.9% and 4.8%, respectively). The risk of late NRM was comparable in patients who received total body irradiation (TBI) and those who received chemotherapy-only regimens (6.7% vs. 4.3%). Another malignancy was the most common cause of late NRM (24 patients, 35% of late NRM). Twelve patients (0.8% of ASCT recipients) have died due to secondary haematological malignancy. Altogether 22 patients (32% of late NRM) died from infectious causes. Malignancies and late infections are important causes of NRM after ASCT. These facts point out the importance of prolonged follow-up in ASCT recipients.     

Invasive fungal infections after allogeneic peripheral blood stem cell transplantation: incidence and risk factors in 395 patients

We have analysed the incidence and risk factors for the occurrence of invasive fungal infections (IFI) among 395 recipients of an allogeneic peripheral blood stem cell transplantation (PBSCT) from a human leucocyte antigen (HLA)-identical sibling. IFI (n = 50) occurred in 46 patients, giving an overall probability of 14%. There were 12 cases of invasive candidiasis (3%), with only one death. Non-Candida IFI occurred in 37 patients (12% probability), mostly invasive aspergillosis (n = 32). In multivariate analysis the only two significant variables associated with a higher risk of developing a non-Candida IFI were the development of moderate-to-severe graft-versus-host disease (GvHD, P < 0.0001; OR 4.6) and having received steroid prophylaxis for GvHD (P = 0.04; OR 2.1). In multivariate analysis the variables associated with a lower overall survival after PBSCT were development of a non-Candida IFI (P < 0.0001; OR 5.6), non-early disease phase (P = 0.0001; OR 1.9), steroid prophylaxis (P = 0.02; OR 1.4), moderate-to-severe GvHD (P = 0.01; OR 1.6) and cytomegalovirus infection post transplant (P = 0.001; OR 1.8). Our results show that non-Candida IFI (in particular aspergillosis) was an important cause of infectious morbidity and mortality after an HLA-identical sibling PBSCT, while invasive candidiasis was rare. Use of steroid prophylaxis and, in particular, the development of moderate-to-severe GvHD post transplant were risk factors for non-Candida IFI. Prophylactic strategies for these infections should thus take into account these risk factors.     

Risk factors and prognosis of invasive fungal infections in allogeneic stem cell transplantation recipients: a single‐institution experience

P. Zhang, E.‐L. Jiang, D.‐L. Yang, Z.‐S. Yan, Y. Huang, J.‐L. Wei, M. Wang, Q.‐L. Ma, Q.‐G. Liu, D.‐H. Zou, Y. He, L.‐G. Qiu, S.‐Z. Feng, M.‐Z. Han. Risk factors and prognosis of invasive fungal infections in allogeneic stem cell transplantation recipients: a single‐institution experience. Transpl Infect Dis 2010: 12: 316–321. All rights reserved Objective. Invasive fungal infections (IFI) are frequent complications of allogeneic hematopoietic stem cell transplantation (SCT) and major causes of a poor prognosis. Analysis of risk factors and prognosis of IFI are important for the control of IFI. Patients and methods. We retrospectively reviewed the medical records of all allogeneic SCT recipients from January 2000 to December 2007. For the homogeneity of analysis, only 286 patients with no history of IFI were included. Results. Fifty‐five cases of IFI were identified, corresponding to cumulative incidence of 19.8%. Different overall survival rates were recorded in patients with or without IFI (20.3% vs. 55.3%, P=0.004). Multivariate analysis identified 2 risk factors of IFI: use of high‐dose steroid and cytomegalovirus infections, and risk stratification can classify the patients into 3 subgroups with different incidences of IFI (9.2%, 25.4%, and 34.1%, P=0.0007). Further analysis confirmed use of steroid as a risk factor of inferior prognosis in IFI cases (0 vs. 57.1%, P<0.0001), which was due to higher rates of IFI‐related mortality (64.7% vs. 23.9%, P=0.018). Conclusion. Post‐transplant IFI was an unfavorable prognostic factor of the SCT recipients, and risk stratification can identify patients with high risk of IFI. Use of steroid played an important role in the pathogenesis as well as prognosis of IFI.     

Outcome of progressive disease after autologous stem cell transplantation in patients with non-Hodgkin's lymphoma: a nation-wide survey

OBJECTIVES: To analyse outcome and prognostic factors in non-Hodgkin's lymphoma (NHL) patients who progress after autologous stem cell transplantation (ASCT). PATIENTS: Altogether 115 consecutive NHL patients transplanted in 1991-2000 were studied. Histology included diffuse large B cell (n = 52), follicular (n = 26), mantle cell (n = 15), T cell (n = 16) and other subtypes (n = 6). The median time from ASCT to the progression was 7 months. Ninety-six patients (83%) received salvage treatment. RESULTS: Twenty-four patients (25%) achieved complete remission and 30 (31%) partial remission. The median overall survival was 8 months (range 0-98+) and the projected 4-year survival 21%. In multivariate analysis factors predicting treatment response after the progression included the use of rituximab (P = 0.036), histology other than diffuse large B cell (P = 0.001) and International Prognostic Index < or =2 at progression (P < 0.001). Normal lactate dehydrogenase (LDH) at progression (P = 0.002), response to salvage treatment (P < 0.001) and time from ASCT to progression > or =7 months (P = 0.022) were predictors for overall survival. CONCLUSIONS: Although the prognosis of patients who progress after ASCT is generally poor, many patients will respond to current therapies, and some may experience prolonged survival. Normal LDH at time of disease progression and longer time to progression after ASCT were the most powerful predictors for a promising outcome.     

Incidence of chronic renal injury in patients undergoing autologous stem cell transplant therapy

Background

Haemopoietic stem cell transplant (HSCT) is a well-established treatment option for many haematologic immunologic and oncologic diseases, allowing the safe administration of high-dose chemotherapy. Increased risk of acute renal injury is associated with HSCT; however, the risk of chronic kidney injury in autologous HSCT remains unclear.

Aims

This cohort study investigates the incidence of chronic renal injury and its predisposing factors in a single-centre population of 139 patients who underwent autologous HSCT.

Methods

Estimated glomerular filtration rate (eGFR) was measured at baseline and at 3, 6, 12 and 24 months following autologous stem cell reinfusion and used as a marker of renal dysfunction.

Results

A significant reduction in mean eGFR of patients was observed from baseline (80.62 ± 2.97 mL/min) to 24 months (71.54 ± 4.14 mL/min), independent of primary diagnosis (P = 0.0019). At baseline, 12% of the cohort had stage 3 or worse chronic renal injury and this increased to 38% by 24 months. By univariate analysis, age at baseline greater than the mean of 58 years and the occurrence of acute kidney injury during the peritransplant period emerged as predictive factors for the development of chronic kidney disease at 24 months.

Conclusions

The current results indicate there is an increased incidence of chronic renal injury in patients who have undergone autologous peripheral blood haemopoietic stem cell transplantation therapy and this injury is potentiated by the autologous stem cell transplant procedure.     

Invasive fungal disease in allogeneic hematopoietic stem cell transplant recipients: an autopsy-driven survey

Abstract: Invasive mycoses are pre-eminent causes of morbidity and mortality in the allogeneic stem cell transplant setting. In spite of novel diagnostic modalities, the timely and specific identification of invasive mycoses still remains challenging. We analyzed the case history of 97 consecutive patients receiving 103 allogeneic stem cell transplants between January 2003 and October 2006 performed by a single team at 2 transplant centers in Budapest, Hungary. All patients with febrile neutropenia not responding to broad-spectrum antibacterial therapy received amphotericin B deoxycholate empirically. In cases of proven or probable invasive aspergillosis, intravenous voriconazole was instituted. Patients who failed to improve on initial therapy were treated with an antifungal combination, while responders were switched to oral voriconazole. A total of 38 patients died following allografting. Both centers had an autopsy rate of 100% due to central health care regulations. An infectious cause of death could be identified in 15 cases, invasive fungal disease being the most prevalent and accounting for 10 fatalities. Six patients died of invasive aspergillosis, while invasive candidiasis and mucormycosis led to a fatal outcome in 2 cases each. Despite the regular use of galactomannan antigen detections and imaging, an ante mortem diagnosis of proven/probable invasive fungal disease could only be established in 4 of 10 autopsy-verified cases (aspergillosis: 3, candidiasis: 1, mucormycosis: 0). In the remaining 6 patients, deep mycoses were missed clinically and were revealed only by postmortem histology. Present diagnostic and therapeutic strategies still seem to be suboptimal for the management of invasive fungal diseases in the high-risk allogeneic stem cell transplant population.     

Haematopoietic stem cell mobilization with plerixafor and G-CSF in patients with multiple myeloma transplanted with autologous stem cells

A proportion of patients with multiple myeloma (MM) who have already undergone autologous stem cell transplantation (autoSCT) might benefit from a further transplantation. For this, they might need to undergo another round of stem cell mobilization. We analyzed retrospectively the outcomes of stem cell mobilization with plerixafor and granulocyte colony-stimulating factor (G-CSF) in a group of 30 patients who had undergone autoSCT previously, and in 46 other patients. The previously transplanted patients were significantly different from the remaining patients with respect to the intensity and number of previous therapies. We observed that the median peripheral blood concentration of CD34+ cells after the first administration of plerixafor was lower in previously transplanted (19 cells/μL) than in other patients (30 cells/μL, P < 0.05). Despite a comparable number of apheresis sessions being performed, the median total yield of CD34+ cells was significantly lower in the previously transplanted than in the remaining patients (2.8 × 10(6) cells/kg vs. 4.2 × 10(6) cells/kg, P < 0.05). However, successful collection of at least 2.0 × 10(6) CD34+ cells/kg was achieved finally in a similar proportion of previously transplanted and other patients (70% vs. 82.6%). Our data suggest that stem cell mobilization with plerixafor and G-CSF might overcome the negative effect of prognostic factors for poor stem cell mobilization in patients with MM who have undergone autoSCT previously.     

Results of autologous stem cell transplant in multiple myeloma patients with renal failure

Data are presented on 81 multiple myeloma (MM) patients with renal failure (creatinine > 176.8 micromol/l) at the time of autologous stem cell transplantation (auto-SCT), including 38 patients on dialysis. The median age was 53 years (range: 29-69) and 26% had received more than 12 months of prior chemotherapy. CD34+ cells were mobilized with granulocyte colony-stimulating factor (G-CSF) alone (n = 51) or chemotherapy plus G-CSF (n = 27), yielding medians of 10 and 16 x 106 CD34+ cells/kg respectively (P = 0.003). Sixty patients (27 on dialysis) received melphalan 200 mg/m2 (MEL-200). Because of excessive toxicity, the subsequent 21 patients (11 on dialysis) received MEL 140 mg/m2 (MEL-140). Thirty-one patients (38%) completed tandem auto-SCT, including 11 on dialysis. Treatment-related mortality (TRM) was 6% and 13% after the first and second auto-SCT. Median times to absolute neutrophil count (ANC) > 0.5 x 109/l and to platelets > 50 x 109/l were 11 and 41 d respectively. Non-haematological toxicities included mucositis, pneumonitis, dysrhythmias and encephalopathy. At a median follow up of 31 months, 30 patients have died. Complete remission (CR) was achieved in 21 patients (26%) after first SCT and 31 patients (38%) after tandem SCT. Two patients discontinued dialysis after SCT. Median durations of complete remission (CR) and overall survival (OS) have not been reached; probabilities of event-free survival (EFS) and OS at 3 years were 48% and 55% respectively. Dialysis dependence and MEL dose did not affect EFS or OS. Sensitive disease prior to SCT, normal albumin level and younger age were independent prognostic factors for better OS. In conclusion, renal failure had no impact on the quality of stem cell collections and did not affect engraftment. MEL-140 had an acceptable toxicity and appeared equally effective as MEL-200. In the setting of renal failure, the role of auto-SCT early in the disease course and benefits of tandem SCT require further evaluation.     

造血干细胞移植后患者侵袭性真菌感染发生及危险因素分析

目的 了解造血干细胞移植（HSCT）后患者侵袭性真菌感染（ZVI）的发病率及危险因素。方法 选择2003年6月至2004年9月于我所进行HSCT的患者148例,按照我国IFI的诊断标准及临床疗效进行回顾性分析。结果 诊断IFI的患者共52例,其中确诊者35例,拟诊者17例。其发生时间为移植后2—400d,中位时间为62d。确诊IFI在移植后3、6个月及1年的累积发病率分别为15．6％、42．5％、48．9％。根据多因素分析,早期IFI的危险因素为：Ⅲ～Ⅳ度的急性移植物抗宿主病（GVHD）、广谱抗生素的长期应用及巨细胞病毒感染;晚期IFI的危险因素为：广泛型慢性GVHD和激素的长期应用。结论 具有较多危险因素的HSCT受者更易发生IFI,而避免或减少上述危险因素是预防IFI的有效方法。     

Changing landscape of invasive aspergillosis in allogeneic stem cell transplant recipients

Abstract: Invasive aspergillosis (IA) is an important infectious complication in allogeneic stem cell transplant (SCT) recipients. Diagnosis of IA has been difficult and often delayed and treatment outcome has been poor, with mortality rates up to 80%. This review summarizes recent developments in this field. There are indications that the incidence of IA may be decreasing due to multiple factors including better understanding of pathogenesis of IA, earlier diagnosis, and various prophylactic and preventive strategies. Recently posaconazole has shown to be effective in reducing the risk of IA in patients treated for graft-versus-host disease (GVHD). Early use of high-resolution thoracic computed tomography assisted with complimentary methods including bronchoalveolar lavage and serum galactomannan determinations are useful in early diagnosis. Our treatment armamentarium against IA has broadened significantly during the last years and there are some indications of improved outcome more recently. On the other hand, increasing use of blood progenitor grafts instead of marrow with higher risk of chronic GVHD, increasing age of SCT recipients, and wide use of donor lymphocyte infusions for treatment of minimal residual disease or relapse may affect to the opposite direction. Despite some promises and improvements, IA will continue to remain a challenge in the upcoming years.     

Invasive filamentous fungal infections associated with renal transplant tourism

S. Shoham, F. Hinestrosa, J. Moore Jr, S. O'Donnell, M. Ruiz, J. Light. Invasive filamentous fungal infections associated with renal transplant tourism.
Transpl Infect Dis 2010: 12: 371–374. All rights reserved Abstract: ‘Transplant tourism,’ the practice of traveling abroad to acquire an organ, has emerged as an issue in kidney transplantation. We treated a patient who developed invasive aspergillosis of the allograft vascular anastomosis after receiving a kidney transplant in Pakistan, prompting us to review the literature of invasive mycoses among commercial organ transplant recipients. We reviewed all published cases of infections in solid organ transplant recipients who bought their organs abroad and analyzed these reports for invasive fungal infections. Including the new case reported here, 19 cases of invasive fungal infections post commercial kidney transplant occurring in 17 patients were analyzed. Infecting organisms were Aspergillus species (12/19; 63%), Zygomycetes (5/19; 26%), and other fungi (2/19; 5%). Invasive mold infections were present at the transplanted graft in 6/17 patients (35%) with graft loss or death in 13/17 (76%) of patients and overall mortality (10/17) 59%. Invasive fungal infections, frequently originating at the graft site, have emerged as a devastating complication of commercial renal transplant and are associated with high rates of graft loss and death.     

造血干细胞移植后侵袭性真菌病的临床研究

目的探讨造血干细胞移植(hematopoietic stem cell transplantation,HSCT)后侵袭性真菌病(invasive fungal disease,IFD)的发生率、发病时间、临床表现及治疗效果。方法对军事医学科学院附属医院造血干细胞移植科2000年1月至2006年12月326例行HSCT的病例进行回顾性分析。结果326例行HSCT的患者中39例发生了IFD,发生率为11.9%。确诊9例,临床诊断21例,拟诊9例。39例IFD中,念珠菌病7例,霉菌病32例。HLA相合同胞、无关相合或相关不合及自体HSCT的IFD发生率分别为11.1%(26/234),18.5%(10/54)和7.9%(3/38)。30例出现IFD患者有移植物抗宿主病(graft versus host disease,GVHD)。IFD发生的中位时间78(17~198)d,临床表现主要是发热,广谱抗生素治疗无效,部分患者出现低氧血症。39例中,存活21例,死亡18例,联合抗真菌药物治疗9例患者6例存活。结论IFD是HSCT后的主要死亡原因,无关供者和相关不合的HSCT的IFD发生率明显升高,有GVHD患者发生IFD机会明显增加,联合抗真菌治疗效果有待进一步证实。     

白血病患者并发真菌肺炎行异基因移植7例临床分析

目的观察并发曲霉菌肺炎的白血病患者行异基因外周血造血干细胞移植的疗效及安全性。方法回顾性分析7例伴曲霉菌肺炎的白血病患者成功完成异基因外周血造血干细胞移植的过程。结果入组7例患者中,男4例,女3例,中位年龄22.8（13-37）岁,随访时间均大于6个月,移植后1个月复查患者嵌合体均为100%完全供者嵌合。移植后平均抗真菌治疗时间为3个月,7例患者肺部真菌感染全部达到显效,造血干细胞100%植入,无1例发生相关死亡。结论伴发曲霉菌肺炎的白血病患者采用有效的抗真菌治疗方案仍然可以接受异基因外周血造血干细胞移植,并不会影响供者造血干细胞植入,且患者耐受性良好,值得进一步研究。     

Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

Background

Recovery of thymopoiesis after allogeneic hematopoietic stem cell transplantation is considered pivotal for full immune competence. However, it is still unclear to what extent insufficient recovery of thymopoiesis predicts for subsequent opportunistic infections and non-relapse mortality.

Design and Methods

A detailed survey of all post-engraftment infectious complications, non-relapse mortality and overall survival during long-term follow-up was performed in 83 recipients of allogeneic stem cell grafts after myeloablative conditioning. Recovery of thymopoiesis was assessed using analysis of signal joint T-cell receptor rearrangement excision circles. The impact of recovery of thymopoiesis at 2, 6, 9 and 12 months post-transplantation on clinical outcome beyond those time points was evaluated by univariate and multivariate Cox regression analyses.

Results

The cumulative incidence of severe infections at 12 months after transplantation was 66% with a median number of 1.64 severe infectious episodes per patient. Patients in whom thymopoiesis did not recover were at significantly higher risk of severe infections according to multivariable analysis. Hazard ratios indicated 3- and 9-fold increases in severe infections at 6 and 12 months, respectively. Impaired recovery of thymopoiesis also translated into a higher risk of non-relapse mortality and outweighed pre-transplant risk factors including age, donor type, and disease risk-status.

Conclusions

These results indicate that patients who fail to recover thymopoiesis after allogeneic hematopoietic stem cell transplantation are at very high risk of severe infections and adverse clinical outcome.