Cause Of Infection-related Mortality Research Articles

Oral Voriconazole Versus Intravenous Low Dose Amphotericin B for Primary Antifungal Prophylaxis in Pediatric Acute Leukemia Induction

Invasive fungal infections (IFI) are a major cause of infection-related mortality during induction chemotherapy of acute leukemia (AL) patients. Data on antifungal prophylaxis (AFP) in children are limited by retrospective design, small sample size, and variability of chemotherapy phases having different risk of IFI. There are no data comparing voriconazole versus amphotericin B (AmB) as AFP in either adult/pediatric AL. The objectives of this study were to compare efficacy and toxicity of AmB and voriconazole as AFP in pediatric AL patients. As a pilot study, total 100 children (≤15 y) with denovo acute myeloid leukemia and acute lymphoblastic leukemia were randomized to either oral voriconazole or low dose intravenous AmB as AFP during induction chemotherapy. Failure of prophylaxis occurred in 14/50 patients in voriconazole arm (1 proven mucormycosis, 1 possible IFI, 11 empirical antifungal therapy, and 1 withdrawal owing to hepatotoxicity) and 17/50 patients in AmB arm (3 possible IFI, 13 empirical antifungal therapy, and 1 withdrawal owing to difficult venous access) (P=0.66). Of the 29 patients who had failure of prophylaxis unrelated to drug toxicity, computed tomography of the chest showed infiltrates in 10 patients with 3/12 in voriconazole arm and 7/16 in AmB arm (P=0.43). Drug-related serious adverse events were 6% versus 30% in voriconazole and AmB arms, respectively (P<0.01). Further, total number of toxicities per patient in AmB arm were significantly higher as compared with voriconazole arm (P<0.0001). This is the first randomized study comparing voriconazole with AmB in pediatric AL patients as AFP during induction chemotherapy; our results showed that oral voriconazole seems to be comparable with AmB with less toxicity and more convenience. (ClinicalTrials.gov identifier: NCT00624143).

Risk factors for invasive mold infections following allogeneic hematopoietic stem cell transplantation: A single center study of 190 recipients

Invasive mold infection (IMI) is a major cause of infection-related mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed 190 allo-HSCT recipients at Changhai Hospital between the y 2000 and 2007. The survival rate was evaluated with Kaplan-Meier curves. Logistic and Cox regression models were used for multivariate analyses. The 1(st) y cumulative incidence rate of IMI was 12.8%, and invasive aspergillosis was the most commonly observed IMI (85%). Multivariate logistic regression analyses showed that significant predictors of IMI were corticosteroid therapy (odds ratio (OR) 1.656, 95% confidence interval (CI) 1.047-2.621, p = 0.031), positive cytomegalovirus antigenemia (OR 5.301, 95% CI 1.902-14.772, p = 0.001), and secondary neutropenia (OR 5.250, 95% CI 1.741-15.834, p = 0.003). The mortality rate of IMI at 12 weeks after diagnosis was 60%. In Cox regression models, IMI-related mortality was related to the dose of corticosteroid (2 mg/kg/day or more) administered at the time of IMI diagnosis (hazards ratio (HR) 20.841, 95% CI 2.151-201.944, p = 0.009) and neutropenia (HR 7.043, 95% CI 1.186-41.827, p = 0.032). These data confirm previous findings that the incidence and mortality of IMI are mostly associated with immunodeficiency caused by immunosuppressive therapy or virus infection.

Invasive Candida infections in solid organ transplant recipient children

Solid organ transplantation (SOT) is now an accepted therapy for many end-stage organ disorders and fungal infections are the principal cause of infection-related mortality in SOT recipients. Among invasive fungal infections, Candida species are the most common pathogens identified, associated with high mortality rates. The epidemiology and clinical manifestations of Candida infections vary with the type of organ transplantation. This article reviews invasive Candida infections in pediatric SOT recipients.

Positive Results of Serum Galactomannan Assays and Pulmonary Computed Tomography Predict the Higher Response Rate of Empirical Antifungal Therapy in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Invasive fungal disease (IFD) is a leading cause of infection-related mortality among patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the mortality of IFD has been decreased with empirical antifungal therapy in this population, overtreatment remains a problem, for the persistent or recurrent fever is nonspecific for an IFD. Hence, we explored retrospectively the value of incorporating serum galactomannan (GM) test and pulmonary high-resolution computed tomography (HRCT) as predictors for higher response rate of empirical treatment. In our study, all of 124 patients after allo-HSCT received empirical antifungal therapy when the persistent or recurrent fever developed after receiving broad-spectrum antibiotics. Meanwhile, the levels of serum GM were monitored twice weekly and pulmonary HRCT was performed serially. It showed that the response rate of empirical antifungal therapy was higher in patients with positive results of serum GM tests and/or chest CT scan than that in all patients (66.1% versus 44.6%, P = .008). Moreover, only 10 of 55 patients with both negative GM tests and pulmonary HRCT responded to empirical treatment, and 7 of these 10 patients did not take antifungal agents for prophylaxis. It suggested that these 2 diagnostic tools could not predict patients without adequate Candida prophylaxis well. Thus, we concluded that serum GM assays and pulmonary CT scan could find out patients who really need empirical antifungal therapy, which resulted in improving the efficiency of the treatment.

Gastrointestinal Aspergillosis After Autologous Stem Cell Transplantation

Purpose: Introduction: Aspergillus spores are ubiquitous and once aerosolized they may colonize the airways. Invasive aspergillosis (IA) is a leading cause of infection-related mortality among immunocompromised (IC) persons, especially among recipients of hematopoietic stem cell transplants (HSCT). We present a case of IA diagnosed on upper endoscopic biopsy of the gastroesophageal (GE) junction. Case: A 75 year old woman with multiple myeloma (MM) diagnosed in 2003 with relapse in 2006 was treated with high dose chemotherapy followed by autologous stem cell transplant. After HSCT, patient was neutropenic for two weeks during which she became dyspneic with mild to moderate epigastric pain along with dyspepsia symptoms. Computer-tomography (CT) scan of her chest and abdomen demonstrated patchy airspace disease in right lung with a new pleural effusion, as well as thickening of the distal esophageal wall. Thoracentesis was performed which did not show any microbiological evidence of infection. An upper endoscopic biopsy obtained from GE junction confirmed significant inflammation with abundant fungal hyphae which was consistent with aspergillus infection. Patient was treated with voriconazole 6 mg/kg IV twice a day along with sargramostim administered daily. She showed clinical improvement over 2-3 weeks and was discharged. Discussion: Review of the medical literature reveals a large series of 4621 HSCT patients from March 2001 to December 2002 who were followed up and the incidence of IA after HSCT was 0.5% to 3.9%. IA carries a very high mortality rate of 53% to 84% after HSCT. Although IA is considered primarily a pulmonary infection, our pulmonary work-up was negative and the diagnosis of IA was exclusively made on upper endoscopic biopsy. Only a few cases of IA of gastrointestinal (GI) tract have been described in the literature. The incidence of IA of GI system was higher in the autopsy findings (17%) as compared to the prospective or retrospective studies (2%) showing likely under-diagnosis. Conclusion: Although the incidence of IA is low after HSCT, it still poses a large challenge given the high mortality rates. In IC patients IA of the GI tract must be considered in persons presenting with epigastric pain or dyspeptic symptoms as early diagnosis and treatment can prevent morbidity and mortality.Figure

Invasive mould infections in the setting of hematopoietic cell transplantation: current trends and new challenges

Invasive mould infections remain major causes of infection-related mortality following hematopoietic stem cell transplantation (HSCT). In this review, we summarize the recent advances in the diagnosis, prevention, and management of invasive mould infections in HSCT recipients. The evolving epidemiologic characteristics of post-HSCT invasive mould infections, specifically the rising incidence of Aspergillus and non-Aspergillus mould infections in the postengraftment period, necessitate the development of preventive strategies. The efficacy of prophylactic broad-spectrum triazoles against invasive mould infections in HSCT recipients has now been demonstrated in two large prospective studies. However, concerns over drug absorption, interactions, and costs may shift attention from universal prophylaxis to risk stratification and preemptive strategies. In this regard, recent studies have highlighted the potential of genetic polymorphism analysis to identify HSCT recipients at risk for invasive aspergillosis, and efforts are underway to improve the predictive values of antigen and nucleic acid detection assays. Emerging data on risk factors for invasive aspergillosis relapse after HSCT, antifungal drug monitoring, and the use of galactomannan testing to monitor treatment response may help inform therapeutic decisions for HSCT recipients. Evidence-driven management of invasive mould infections in HSCT recipients is becoming increasingly individualized, integrating host factors and pharmacologic and epidemiologic considerations. However, the optimal approach to invasive mould infection prevention in HSCT recipients remains to be resolved by prospective clinical studies.

Broad-Spectrum Antifungal Prophylaxis in Patients With Cancer at High Risk for Invasive Mold Infections: Point

Invasive fungal infections (IFIs) are a leading cause of infection-related mortality in patients with acute leukemia and prolonged neutropenia and in allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD). Although invasive candidiasis was the principal IFI predating fluconazole prophylaxis, invasive aspergillosis and other mold infections now cause most deaths from fungal infection in this patient population. The availability of broad-spectrum antifungal agents that can be safely administered over prolonged periods has stimulated interest in using mold-active prophylactic agents early as prophylaxis rather than later as therapy for suspected or documented IFIs. Two recent, prospective, randomized trials have shown a clear benefit of posaconazole prophylaxis in patients with myelodysplastic syndrome and acute mye-logenous leukemia with prolonged neutropenia and in allogeneic HSCT recipients with severe GVHD. In contrast, the peer-reviewed published database on the strategy of preemptive antifungal therapy, in which yeast-active prophylaxis (fluconazole) or no antifungal prophylaxis is used initially and modifications are triggered by a combination of laboratory markers and chest CT scans, is currently limited to an open-label feasibility study. Does sufficient evidence currently exist that the net benefit of the preemptive approach is at least on a par with posaconazole prophylaxis in the specific patient groups that were studied? The authors believe not and that more research is needed before the preemptive strategy can be recommended.

Diagnosis of invasive aspergillosis by tracking Aspergillus-specific T cells in hematologic patients with pulmonary infiltrates

Invasive aspergillosis (IA) is a leading cause of infection-related mortality in hematologic patients, with death rate ranging from 50 to 90%.1 The reason for this extremely poor outcome is because of the difficulties in a timely and undoubted diagnosis, which still relies on a very high degree of suspicion. The current diagnostic tools are limited by invasiveness, slowness, relative insensitiveness, lack of standardization and unpredictable kinetics.2 The most widely studied test, Galctomannan antigenemia (GM), has been demonstrated to be highly variable in performance, with sensitivity ranging between 29 and 100%, and is affected by several factors related either to the fungus or to the host.2 Furthermore, the detection of Aspergillus DNA through polymerase chain reaction (PCR) is still hampered by the difficulties in understanding the fungal DNA release and kinetics other than by technical barriers.2 For all these reasons, establishing an early diagnosis of IA remains a challenge.1, 2

Invasive Aspergillosis following Hematopoietic Cell Transplantation: Outcomes and Prognostic Factors Associated with Mortality

Invasive aspergillosis (IA) is a leading cause of infection-related mortality following hematopoietic cell transplantation (HCT). The aim of this study was to determine the probability of survival and prognostic factors associated with outcomes over a long period of time. Cases of proven and probable IA diagnosed in HCT recipients at the Fred Hutchinson Cancer Research Center from 1 January 1990 through 31 December 2004 were included. Patient data were collected from a prospectively maintained database and by retrospective clinical chart review. Survival was estimated using Kaplan-Meier curves, and Cox regression models were used for multivariable analyses. Four hundred five cases were identified. The probability of survival at 90 days after diagnosis was higher for patients identified as having IA between 2002 and 2004 than for patients whose IA was diagnosed in preceding years (45% vs. 22%; P<.001). Risk factors independently associated with all-cause mortality include impairment in pulmonary function before HCT, receipt of human leukocyte antigen-mismatched stem cells, neutropenia, elevated bilirubin and creatinine levels, receipt of corticosteroids at > or =2 mg/kg per day, disseminated and proven IA, and IA occurring >40 days after HCT. Factors associated with a decreased risk of all-cause mortality included receipt of nonmyeloablative conditioning and peripheral blood stem cells. In a subanalysis of attributable mortality restricted to patients receiving antifungal therapy, receipt of voriconazole was independently associated with protection from IA-related death. There has been a significant decrease in mortality in patients with a diagnosis of IA following HCT in recent years, coinciding with multiple changes in transplantation practices, including use of nonmyeloablative conditioning regimens, receipt of peripheral blood stem cells, more prompt diagnosis of IA, and use of voriconazole.

Prevention and Early Treatment of Invasive Fungal Infection in Patients with Cancer and Neutropenia and in Stem Cell Transplant Recipients in the Era of Newer Broad-Spectrum Antifungal Agents and Diagnostic Adjuncts

Invasive fungal infection (IFI) is a leading cause of infection-related mortality among patients with cancer and prolonged neutropenia and among allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease. Invasive candidiasis was the principal IFI in the period predating fluconazole prophylaxis, whereas today, invasive aspergillosis and other mold infections cause the majority of deaths from fungal infection in this patient population. The changing epidemiology of IFI, in addition to advances made in antifungal therapeutics and early diagnosis of IFI, warrant a reevaluation of earlier strategies aimed at prevention and early treatment of IFI that were developed several years ago. Here, we propose that persistent neutropenic fever is nonspecific for an IFI and should not be used as the sole criterion for empirical modification in the antifungal regimen in a patient receiving mold-active prophylaxis. We explore the potential benefits and gaps in knowledge associated with employing chest CT scans and laboratory markers as diagnostic adjuncts for IFI. Finally, we discuss the implications of newer antifungal agents and diagnostic adjuncts in the design of future clinical trials to evaluate prophylaxis and early prevention strategies.

Invasive aspergillosis following HSCT: Outcomes and prognostic factors associated with mortality

Invasive aspergillosis (IA) is a common cause of infection-related mortality in hematopoietic stem cell transplant (HSCT) recipients, despite appropriate therapy. Factors influencing outcomes have not been fully elucidated. To determine prognostic factors associated with mortality we retrospectively reviewed all cases of proven and probable IA diagnosed in HSCT recipients at the Fred Hutchinson Cancer Research Center (FHCRC) from 1st Jan 1990 to 31st Dec 2004. All-cause and attributable mortality were recorded.

Spectrum of Pulmonary Infections in Renal Transplant Recipients in the Tropics: A Single Center Study

Pulmonary infections have been implicated as the most common cause of infection related mortality in renal transplant recipients. An appropriate empirical treatment of post transplant pulmonary infections requires knowledge of the spectrum of the microorganisms involved in causing these infections. Besides this knowledge, an aggressive diagnostic approach including the use of invasive tests is often essential to make an early diagnosis for instituting timely and appropriate therapy. We carried out a prospective cohort study to analyze the spectrum of pulmonary infections in these patients and study the utility of bronchoalveolar lavage (BAL) in the diagnosis of the same. From September 2001 to December 2002, 428 patients were under follow up with the department. In all, 40 renal transplant recipients reported with 44 episodes of pulmonary infection during this study period. All patients underwent detailed and appropriate investigations including specific laboratory tests, sputum analysis, X-ray chest, CT and BAL. The spectrum of the causative organisms and the utility of BAL as compared to the other methods of diagnosis were studied and compared. Out of the 44 episodes of pulmonary infection evaluated, single causative organism could be found in only 24 (54.5%) episodes and multiple etiologies were found in 15 (34.1%) episodes. No definitive cause could be found in 5 episodes. Out of 57 organisms isolated in the 44 episodes, 20 (45.4 %) were bacteria, 16 (36.3 %) each were M. tuberculosis and fungus, 3 were CMV infection and 2 were nocardia. BAL gave a diagnostic yield of 75.8% (25 out of 33 cases). Nine of forty patients died (mortality rate 22.5%) of which 6 deaths could be attributed directly to pulmonary infection. Out of these 9 patients who died, cause of pulmonary infection was bacterial in 5, fungal in 2 and CMV disease in 1. In one patient, organism could not be isolated. Our study has shown that more than 1/3rd of pulmonary infections in renal transplant recipients can be attributed to multiple organisms. Bacterial infections were the commonest cause of post transplant pulmonary infection. Tuberculosis is common cause of pulmonary infection in these patients in our set up. Because of its high diagnostic yield, BAL should be considered in all patients with suspected pulmonary infections in the post transplant period.

Generation of cytotoxic T cell responses directed to human leucocyte antigen Class I restricted epitopes from theAspergillusf16 allergen

Invasive aspergillosis (IA) is a major cause of infection-related mortality in patients with haematological malignancies, especially in recipients of haematopoietic stem cell transplants. We have prepared overlapping pentadecapeptides (11-aa overlap with previous peptide) spanning the entire 427-aa coding region of the Aspergillus allergen, Asp f16 shown previously in mice to induce Th1-type cell responses in vivo and in humans to induce proliferative and cytotoxic CD4(+) T cell responses. Mature dendritic cells (DC) pulsed with a complete pool of peptides were used to generate T cell lines. Two lines from HLA-B*3501(+) donors were found to be strongly cytotoxic to autologous Asp f16-peptide pool- and Aspergillus culture extract-pulsed targets after 4-5 weekly primings. Cytotoxic T lymphocyte (CTL) culture supernatant killed Aspergillus conidia, and cells directly killed Aspergillus hyphae. Cytotoxic activity and interferon (IFN)-gamma production were mediated exclusively by CD8(+) T cells in response to pool-pulsed targets. Interleukin (IL)-4 production was not detected. CTL activity was restricted by HLA-B*3501 and based on peptide prediction programmes was most probably directed to YFKYTAAAL (YFK), LPLCSAQTW (LPL) and GTRFPQTPM (GTR) in one donor, while only LPL was recognized by CTL from the second donor. Pool-pulsed B*3503(+) BLCL but not B*3502(+) or B*3508(+) BLCL presented peptide to donor no. 1. B*3503(+) BLCL presented YFK and to a lesser extent GTR, but not peptide LPL. Our data show that in addition to our previously identified Class II restricted peptide response, DC pulsed with a pentadecapeptide pool from Asp f16 are capable of inducing polyclonal, HLA-Class I-restricted, Aspergillus-specific T cells that may be capable of conferring immunity to IA.

Analysis of T-cell responses to Aspergillus fumigatus antigens in healthy individuals and patients with hematologic malignancies

Invasive aspergillosis has become a major cause of infection-related mortality in nonneutropenic patients after allogeneic stem cell transplantation (SCT). To assess the potential role of Aspergillus-specific T-cell responses for the successful control of invasive aspergillosis, lymphoproliferative responses to Aspergillus fumigatus antigens were studied in healthy individuals, patients with evidence of invasive aspergillosis, and patients late after allogeneic SCT. In healthy individuals, a positive lymphoproliferative response was documented to cellular extracts of A fumigatus (14 of 16), the 88-kDa dipeptidylpeptidase (4 of 16), and the 90-kDa catalase (8 of 11). A predominant release of interferon gamma (IFN-gamma) in culture supernatants on stimulation with A fumigatus antigens was demonstrated in 13 of 17 healthy individuals, indicating a T(H)1 response. In patients with clinical evidence of invasive aspergillosis, a favorable response to antifungal therapy was found to correlate with a higher IFN-gamma/interleukin 10 (IL-10) ratio in culture supernatants (n = 7; median ratio, IFN-gamma/IL-10 = 1.0; range, 0.09-24.8) compared to 10 patients with progressive or stable disease (median ratio, IFN-gamma/IL-10 = 0.1; range, 0.002-2.1; P =.04). Steroid treatment was found to suppress Aspergillus-specific lymphoproliferation (P =.037) and release of IFN-gamma in culture supernatants (P =.017). In contrast to cytomegalovirus- and tetanus toxoid-specific T-cell responses, Aspergillus-specific T-cell reconstitution late after allogeneic SCT was characterized by low stimulation indices and a low IFN-gamma/IL-10 ratio. In addition, phosphoantigen-reactive V(gamma)9/V(delta)2 T-cell clones from healthy individuals were found to produce significant amounts of tumor necrosis factor in response to A fumigatus antigens. In conclusion, these results further support the hypothesis that T cells contribute to the host defense against A fumigatus.