Serum Galactomannan Research Articles

Nonspecific elevation of serum Aspergillus galactomannan antigen levels in patients with rheumatoid arthritis.

Infections are an important cause of morbidity and mortality in patients with rheumatoid arthritis. Patients receiving immunosuppressive or anti-tumor necrosis factor (TNF) agents are vulnerable to fungal infections, including those derived from Aspergillus species. Detection of the Aspergillus galactomannan antigen in serum is useful for the early diagnosis of invasive aspergillosis in patients with hematological malignancies. However, its usefulness for detecting early invasive aspergillosis in rheumatoid arthritis patients remains unestablished. Galactomannan antigen levels were measured in 340 patients (311 female patients). For patients who exhibited galactomannan antigen levels ≥0.5 during the initial examination, a second examination was performed 3-6 months later. Conventional blood tests and chest radiography were also performed. Elevated galactomannan antigen levels (≥0.5) were observed in 62 (18.2%) of 340 patients during the initial examination. A second examination was performed in 56 of 62 patients, 50 of whom exhibited elevated antigen levels. Elevated antigen levels were not associated with the use of any drug including anti-TNF agents. Serum galactomannan antigen levels were correlated with the albumin/globulin ratio (r=-0.19, p<0.001), γ-globulin (%; r=0.17, p=0.001), and hemoglobin concentration (r=-0.15, p=0.005). No patient was clinically diagnosed with invasive aspergillosis during the study period. Serum galactomannan antigen levels are frequently elevated in a nonspecific manner in patients with rheumatoid arthritis.

Autologous Stem Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma: A Single-Center Experience

patients were male and 21 female. The mean age was 43 years (2775). Central venous catheter was used in 45 (78.9%) HSCTs. FNEs was detected in 54 (94.7%) HSCT. All the patients received antiviral and antifungal prophylaxis and antibacterial prophylaxis was used in 26 (46.7%) HSCT. In FNEs, 10.5% efficient pathogen microorganism was isolated from blood cultures. 66.7% of pathogens were gram-positive, 33.3% were gram-negative bacterias. 3.5% efficient pathogen microorganism was isolated from urine cultures, all of them were gram-negative bacterias. 14.0% efficient pathogen microorganism was isolated from catheter cultures, all of them were gram-positive bacterias. A pathogen was isolated in 8.8% of stem cell products. Serum galactomannan antigen (SGA) was detected positive in only one (1.7%) episodes and false positivity of SGA was not detected. CMV-DNA was positive in 8.8% episodes. Thirty HRCT was performed in FNEs. Pneumonia was detected 8.8% in all episodes. 40% of pneumonia that detected in HRCTs was fungal and no viral pneumonia was detected. Conclusion: It can supply useful additive for a better FEN management process if the medical centers follow their infection agents closely, perform CMV and SGA assays and modify their empiric antibiotic treatment policies in especially HSCT groups.

Diagnosis of Invasive Aspergillosis: Use of the Galactomannan Assay

Invasive aspergillosis is the cause of severe morbidity and mortality in immunocompromised patients. Given the challenges of fungal cultures, non-culture surrogates are crucial to the timely diagnosis of invasive aspergillosis (IA) to initiate expedited treatment. The Platelia™ Aspergillus EIA (Bio-Rad, Hercules, California) is a double-sandwich ELISA that detects the galactomannan (GM) of the fungal cell wall and was cleared by the FDA for use in serum and bronchoalveolar fluid (BAL) in 2003 and 2011, respectively. The population in which GM has been studied the most and has shown the greatest accuracy is that of hematologic malignancy. The optimal optical density index (ODI) cutoff to define test positivity in the serum is still a matter of debate because this value influences test performance. Using a lower ODI threshold (≥0.5 vs. ≥1 vs. ≥1.5) optimizes sensitivity at the expense of specificity and vice versa using a higher ODI threshold. One must be alert to the potential for false-positive results, particularly if a ODI cutoff of 0.5 is used in the serum. False positives can occur due to medications, i.e., piperacillin/tazobactam, though there is increasing evidence that newer formulations are less cross-reactive with GM, and false-positive results occur in the presence of other molds that cross-react with GM. As the use of mold-active antifungal prophylaxis increases, one must be aware that GM may not perform as well due to lower pre-test probability of IA and lower test sensitivity. Emerging evidence indicates that use of GM in combination with other tests, e.g., Aspergillus PCR or lateral flow device (LFD), may enhance diagnostic accuracy beyond GM alone; however, further validation of these diagnostics in combination are required before routine implementation can be recommended. BAL GM performs better than serum as it is significantly more sensitive, though the optimal ODI cutoff is also debated (≥0.5 vs. ≥1).False-positive results can be due to use of medications, as with serum GM. False negatives can occur with the use of certain agents which decrease the viscosity of the BAL fluid, and use of such agents need to be considered by the clinician when evaluating a test result. Again, BAL GM, in conjunction with other tests, e.g., PCR and LFD, are promising, but further studies are needed. GM in other fluids, i.e., CSF, urine, and tissue, may be useful, but the studies are very limited. In summary, when employed in the right clinical context and interpreted appropriately, serum and BAL GM can facilitate the diagnosis and early treatment of IA. While there are significant limitations and the landscape is evolving, the test has an important role in clinical practice today.

Effects of host response and antifungal therapy on serum and BAL levels of galactomannan and (1→3)-β-D-glucan in experimental invasive pulmonary aspergillosis.

Galactomannan and (1→3)-β-D-glucan are useful biomarkers of invasive pulmonary aspergillosis (IPA). However, the effects of immunosuppression on levels of galactomannan or (1→3)-β-D-glucan in IPA are not well understood or quantified. We therefore studied the simultaneous levels of galactomannan and (1→3)-β-D-glucan in two rabbit models of experimental IPA: (1) AraC-induced neutropenia in untreated (UC-AraC) and liposomal amphotericin B-treated (LAMB-AraC) rabbits; and (2) nonneutropenic cyclosporine-methylprednisolone immunosuppression in untreated (UC-CsA+M) and LAMB-treated (LAMB-CsA+M) rabbits. Simultaneous levels of galactomannan and (1→3)-β-D-glucan were determined in bronchoalveolar lavage (BAL) fluid and serial serum specimens and correlated with pulmonary host response. Serum galactomannan index (GMI) and (1→3)-β-D-glucan concentration-time-curves were higher in UC-AraC vs. UC-CsA+M (Mann-Whitney U-test, P < .05). Serum galactomannan and (1→3)-β-D-glucan in treatment groups demonstrated therapeutic responses with similarly lower levels in comparison to UC (P < .01) in both models. Host differences did not affect BAL fluid GMI or (1→3)-β-D-glucan but did affect galactomannan and (1→3)-β-D-glucan levels in serum. The higher serum GMI and (1→3)-β-D-glucan concentration-time-curves in UC-AraC correlated with extensive pulmonary infiltration by angioinvasive hyphae and minimal inflammation, while the lower concentration-time-curves in UC-CsA+M were associated with shorter and fewer hyphae in lung tissue and an intensive neutrophil response to Aspergillus hyphae. Thus, serum levels of galactomannan and (1→3)-β-D-glucan in IPA depended upon immunosuppression, which also affected severity of infection and hyphal morphology, while BAL fluid galactomannan and (1→3)-β-D-glucan were sensitive biomarkers not affected by host response.

Correlation between Circulating Fungal Biomarkers and Clinical Outcome in Invasive Aspergillosis.

Objective means are needed to predict and assess clinical response in patients treated for invasive aspergillosis (IA). We examined whether early changes in serum galactomannan (GM) and/or β-D-glucan (BDG) can predict clinical outcomes. Patients with proven or probable IA were prospectively enrolled, and serial GM and BDG levels and GM optical density indices (GMI) were calculated twice weekly for 6 weeks following initiation of standard-of-care antifungal therapy. Changes in these biomarkers during the first 2 and 6 weeks of treatment were analyzed for associations with clinical response and survival at weeks 6 and 12. Among 47 patients with IA, 53.2% (25/47) and 65.9% (27/41) had clinical response by weeks 6 and 12, respectively. Changes in biomarkers during the first 2 weeks were associated with clinical response at 6 weeks (GMI, P = 0.03) and 12 weeks (GM+BDG composite, P = 0.05; GM, P = 0.04; GMI, P = 0.02). Changes in biomarkers during the first 6 weeks were also associated with clinical response at 6 weeks (GM, P = 0.05; GMI, P = 0.03) and 12 weeks (BDG+GM, P = 0.02; GM, P = 0.02; GMI, P = 0.01). Overall survival rates at 6 weeks and 12 weeks were 87.2% (41/47) and 79.1% (34/43), respectively. Decreasing biomarkers in the first 2 weeks were associated with survival at 6 weeks (BDG+GM, P = 0.03; BDG, P = 0.01; GM, P = 0.03) and at 12 weeks (BDG+GM, P = 0.01; BDG, P = 0.03; GM, P = 0.01; GMI, P = 0.007). Similar correlations occurred for biomarkers measured over 6 weeks. Patients with negative baseline GMI and/or persistently negative GMI during the first 2 weeks were more likely to have CR and survival. These results suggest that changes of biomarkers may be informative to predict and/or assess response to therapy and survival in patients treated for IA.

A Clinical Study of Acquired Immunodeficiency Syndrome Associated Penicillium Marneffei Infection from a Non-Endemic Area in China.

ObjectiveTo investigate the clinical characteristics, diagnosis, treatment and prognosis of penicilliosis among the patients with acquired immunodeficiency syndrome (AIDS) in non-endemic areas of China, and then to discuss its incubation period and the diagnostic performance of serum galactomannan test for penicilliosis.MethodsMedical records and travel histories of penicilliosis patients in Zhongnan hospital from January 2006 to December 2013, and the interval from when the patients left the endemic area to the onset of the disease was analyzed. Serum galactomannan levels of penicilliosis patients and AIDS patients with fever were measured by the Platelia Aspergillus Enzyme Immunoassay Kit.ResultsA total of 47 AIDS-associated penicilliosis were confirmed by fungal culture, which accounted for 4.8% of 981 AIDS-related admissions. The sensitivity and specificity of serum galactomannan test for penicilliosis were 95.8% (23/24) and 90.9% (30/33), respectively, (cutoff index = 1.0). Two independent predictors for early mortality (death within 12 weeks) of the patients (21.3%, 10/47) were a delayed diagnosis and no treatment with antifungal therapy. Among 14 patients who became ill after leaving endemic areas, ten patients presented with the onset symptoms within 12 months (from 11 days to 360 days). We found a patient living with asymptomatic P. marneffei fungemia who had not received any antifungal therapy until 18 months’ follow up.ConclusionsThe co-infection of P. marneffei and HIV was not uncommon in the non-endemic areas of penicilliosis in China. There exists a latent form of infection for P. marneffei. The incubation period of penicilliosis may be quite different from one patient to another. In AIDS patients, the serum galactomannan test has utility for the diagnosis of penicilliosis. When patients with penicilliosis/AIDS were diagnosed early and treated with standardized antifungal therapy and combined antiretroviral therapy, their prognosis improved.

PIN55 - Economic Analysis of Empiric Versus Diagnostic-Driven Strategies for Immunocompromised Patients With Suspected Aspergillus Invasive Fungal Infections In China

PIN55 EcoNomIc ANAlysIs of EmPIrIc VErsus DIAgNostIc-DrIVEN strAtEgIEs for ImmuNocomPromIsED PAtIENts WIth susPEctED AsPErgIllus INVAsIVE fuNgAl INfEctIoNs IN chINA Qin L.1, Chen Y.2, Lesher B.1, Liu Q.3, Charbonneau C.4, Earnshaw S.R.5, McDade C.5, Mao N.6, Gao X.1 1Pharmerit International, Bethesda, MD, USA, 2Pfizer Investment Co. Ltd., Beijing, China, 3Southern Medical UniversityNanfang Hospital, Guangzhou, China, 4Pfizer Inc, Paris, France, 5RTI Health Solutions, Research Triangle Park, NC, USA, 6China Pharmaceutical University, Nanjing, China OBJECTIVES: To examine the clinical and economic impact of diagnostic-driven (DD) versus empiric treatment strategies in neutropenic patients with suspected Aspergillus invasive fungal infections (IFIs) in Beijing, Chengdu, and Guangzhou, China. METHODS: A decision-analytic model was used to estimate total costs and survival associated with a DD and empiric treatment strategy for managing suspected IFIs in adult patients with neutropenia due to hematological malignancy or autologous/allogeneic stem cell transplant. In the DD strategy, IFI was identified via serum galactomannan (GM) enzyme-linked immunosorbent assay (ELISA) so that early initiation of targeted treatment could be administered. IFI incidence (10.9%), portion of actual IFIs diagnosed via empiric treatment (30%), overall mortality (10.7%), and IFI-related mortality (28.6%) were obtained from the literature. Survival rates were generated based on the proportion of patients with identified and appropriately treated IFIs. Empiric and DD treatment patterns and resource use were based on clinical opinion (3-5 clinicians from top hospitals per city). Medical costs (in 2014 Chinese Yuan [¥]) included antifungal drugs, treatment-related adverse events, and other medical resource costs. Cityspecific costing sources were used wherever possible. RESULTS: Medical costs were lower for the DD versus the empiric strategy in Beijing (¥4,118 vs ¥5,245), Chengdu, (¥5,463 vs ¥6,389), and Guangzhou (¥9,762 vs ¥10,351). Fewer patients received antifungal treatment using the DD strategy (6.7% versus 11.4%), and survival rates were similar. One-way sensitivity analysis showed results were most sensitive to changes in GM test sensitivity followed by IFI incidence. Probabilistic sensitivity analysis showed that treating via a DD strategy was dominant 99% of the time. CONCLUSIONS: These results suggest that in China, a DD strategy to identify IFIs in immunocompromised patients with persistent fever in order to better target antifungal treatment compared to an empiric antifungal treatment strategy may be cost-saving, while maintaining a similar overall survival rate.

Generic piperacillin/tazobactam is not associated with galactomannan false-positivity in adult patients with cancer: a case-control study.

Recent products of piperacillin/tazobactam (PTZ) from the original manufacturer, previously considered a major cause of galactomannan (GM) false-positivity, are reported not to be related to it. However, data regarding generic PTZ are limited and controversial. To evaluate the effect of generic PTZ on GM false-positivity in Korea, we performed a case-control study in adult patients with cancer. A case-control study was designed. Electronic medical records of cancer patients who were admitted and tested for serum GM between March and June 2014 at a tertiary care university hospital were reviewed. During the study period, a single generic PTZ (C manufacturer, Korea) was used. Patients who received PTZ within 24h prior to serum GM testing were enrolled. Age- and GM test date-matched non-PTZ patients were selected as controls. A total of 110 patients received PTZ within 24h prior to serum GM testing during the study period. The GM optical density index (ODI) of the PTZ group did not vary significantly from that of the control group (p = 0.251). The percentage of false-positive patients in the PTZ group was also similar to that of the control group (p = 0.538). There was no statistical relationship between GM ODI titer and time interval from PTZ administration (p = 0.095) or cumulative PTZ dose (p = 0.416). In a case-control study that evaluated 220 patients, a generic PTZ in Korea was not related to GM false-positivity.

Invasive pulmonary aspergillosis in heart transplant recipients.

Invasive pulmonary aspergillosis is the most common invasive mycosis in heart transplant recipients. Early clinical recognition of this complication is difficult and laboratory data is not specific. Our aim was to study the characteristics of invasive pulmonary aspergillosis infections in heart transplant recipients. Between 2007 and 2013, there were 82 patients who underwent heart transplant at our institution, including 6 patients who were diagnosed with invasive pulmonary aspergillosis. Medical records of these patients were reviewed for demographic, clinical, and radiographic features, microbiology data, serum galactomannan levels, antifungal treatment, and overall outcomes. The most common species causing the infection was Aspergillus fumigatus. The infection was encountered irrespective of the duration since the transplant. Bronchoalveolar lavage with positive culture for Aspergillus species and/or abnormal serum galactomannan level was suggestive of invasive pulmonary aspergillosis. In our opinion, empiric antifungal therapy should be commenced as soon as invasive pulmonary aspergillosis is suspected in heart transplant recipients to reduce mortality. Although the duration of antifungal therapy for invasive pulmonary aspergillosis is debatable, heart transplant recipients may require long-term therapy to avoid recurrence.

Our 2015 approach to invasive pulmonary aspergillosis.

At the University Hospital of Cologne, in general two patient groups at high risk for invasive aspergillosis receive posaconazole prophylaxis: Acute myelogenous leukaemia patients during remission induction chemotherapy and allogeneic haematopoietic stem cell transplant recipients. Other patients at risk undergo serum galactomannan testing three times weekly. At 72-96h of persisting fever despite broad-spectrum antibiotics, or at onset of lower respiratory tract symptoms a thoracic computed tomography (CT) scan is performed. Without lung infiltrates on CT, IPA is ruled out. In lung infiltrates not suggestive for IPA mycological confirmation is pursued. In patients without posaconazole prophylaxis empiric caspofungin will be considered. CT findings typical for IPA prompt targeted treatment, and mycological confirmation. Bronchoalveolar lavage (BAL) is most important for cultural identification and susceptibility testing, and facilitates diagnosing other pathogens. BAL performance is virtually independent of platelet counts. If despite suggestive infiltrates BAL does not yield the diagnosis, CT-guided biopsy follows as soon as platelet counts allow. Surgery can also be beneficial in diagnosis and treatment of IPA. If the diagnosis of IPA is not established, mucormycosis is a valid concern. In patients with breakthrough IPA during posaconazole prophylaxis liposomal amphotericin B is the drug of choice. If no posaconazole prophylaxis was given, voriconazole is the treatment of choice for IPA.

Invasive aspergillosis after kidney transplant: case-control study.

Transplant recipients are at risk for invasive aspergillosis (IA), associated with a significant mortality rate. Renal transplant-specific risk factors have not been established. Forty-one adult kidney transplant recipients diagnosed with proven or probable IA from 1995 through 2013 were identified by search of the computerized patient files in the University Hospitals Leuven. The control population in this 1:2 case-control study consisted of the 2 patients who received a kidney transplant immediately before and after each identified patient and did not develop IA (n = 82). Leukopenia after kidney transplant increased the risk of IA among all patients (odds ratio [OR], 2.345 [95% confidence interval {CI}, 1.084-5.071]). For early-onset infection (ie, occurred during the first 3 months after transplant), a longer duration of renal replacement therapy pretransplant and the occurrence of leukopenia were risk factors (OR per year, 1.192 [95% CI, 1.006-1.413] and OR, 3.346 [95% CI, 1.063-10.527], respectively), whereas donor cytomegalovirus seropositivity increased the risk for late-onset IA (ie, occurred >3 months after transplant) (OR, 3.677 [95% CI, 1.388-9.743]). Twelve-week mortality rate was 39%. Disseminated infection, leukopenia, and the height of the serum galactomannan index were associated with an increased risk of death (hazard ratio [HR], 5.080 [95% CI, 1.740-14.830]; HR, 3.198 [95% CI, 1.183-8.649]; and HR, 1.371 [95% CI, 1.123-1.674], respectively). Prolonged renal replacement therapy before kidney transplant increases the risk of IA early after transplant. The height of the serum galactomannan index predicts mortality.

Utilidad de la prueba Aspergillus-LFD para el diagnóstico de aspergilosis: primera experiencia en Chile

The diagnosis of invasive aspergillosis remains a challenge. Detection of galactomannan in serum and bronchoalveolar lavage is a useful tool; however due to methodological and economic reasons, the test frequencies of galactomannan assays vary from daily to weekly, which constitute a risk to the patient. In this study, we aimed to evaluate and correlate the performance of the new kit Aspergillus-LFD with the GM-EIA. Aspergillus-LFD kit represents a fast, economical and simple test; showed a good performance and excellent correlation with GM-EIA kit. Given the above, the Aspergillus-LFD is emerging as an alternative to consider in the early diagnosis of invasive aspergillosis.

Utility of Aspergillus-LFD: first experience in Chile

The diagnosis of invasive aspergillosis remains a challenge. Detection of galactomannan in serum and bronchoalveolar lavage is a useful tool; however due to methodological and economic reasons, the test frequencies of galactomannan assays vary from daily to weekly, which constitute a risk to the patient. In this study, we aimed to evaluate and correlate the performance of the new kit Aspergillus-LFD with the GM-EIA. Aspergillus-LFD kit represents a fast, economical and simple test; showed a good performance and excellent correlation with GM-EIA kit. Given the above, the Aspergillus-LFD is emerging as an alternative to consider in the early diagnosis of invasive aspergillosis.

Immune reconstitution inflammatory syndrome in neutropenic patients with invasive pulmonary aspergillosis

Clinical and radiologic deterioration is sometimes observed during neutrophil recovery in patients with invasive pulmonary aspergillosis (IPA). This deterioration can be caused by immune reconstitution inflammatory syndrome (IRIS) as well as by progression of the IPA. However, there is limited data on IRIS in neutropenic patients. Over a 6-year period, adult patients with neutropenia who met the criteria for probable or proven IPA by the revised EORTC/MSG definition were retrospectively enrolled. IRIS was defined as de novo appearance or worsening of radiologic pulmonary findings temporally related to neutrophil recovery, with evidence of a decrease of 50% in serum galactomannan level. Of 153 patients, 36 (24%, 95% CI 18%-31%) developed IRIS during neutrophil recovery. More of these patients received voriconazole than did those with non-IRIS (42% vs. 25%, P = 0.05). Thirty- and ninety-day mortalities were lower in the patients with IRIS than in those with non-IRIS (11% vs. 33%, P = 0.01, and 33% vs. 58%, P = 0.01, respectively). IRIS is relatively common among neutropenic patients with IPA, occurring in about one quarter of such patients. It is associated with voriconazole use and has a good prognosis.

Serum Galactomannan Screening for Diagnosis of Invasive Pulmonary Aspergillosis in Children After Stem Cell Transplantation or with High-Risk Leukemia

Both transplanted and leukemia patients are at high risk (HR) for invasive pulmonary aspergillosis (IPA). Methods for rapid diagnosis are crucial. Our objective was to investigate the impact of serial serum galactomannan assay (GMA) screening on IPA diagnosis in children. Between January 2010 and December 2011, all children following stem cell transplantation (SCT) or with HR leukemia were prospectively included. Serum samples for GMA were taken once-twice weekly. Results >.5 were considered positive. Patients suspected of having IPA were stratified as possible, probable, and definite. Forty-six children (median age, 8 years) were included, 38 after SCT (32 allogeneic), 8 with HR leukemia. A total of 510 samples were taken; screening period was 1–6 months for 34 patients. GMA was negative in 28 patients, all but one without suspicion of IPA. Eighteen patients had positive GMA: while four (22%) were upgraded to probable IPA, fourteen (78%) were considered as false positives (FP), some associated with piperacillin-tazobactam treatment. GMA sensitivity and specificity were 0.8 and 0.66, respectively; positive- and negative-predictive values (PPV, NPV) were 0.22 and 0.96, respectively. GMA may have a role in evaluating HR children for IPA. Both NPV and FP rates are high. The cost benefit of early detection versus over-diagnosis should be further studied.

Prophylaxis of Invasive Pulmonary Aspergillosis with Nebulized Lipid Complex Amphotericin B Is Feasible, Well Tolerated and Safe in Children with Acute Leukemia. Results of a Phase II Open Trial

▪ BACKGROUNDAcute leukemia is the most frequent cancer in childhood. The use of dose-intensive chemotherapy regimens has significantly increased the overall survival of acute leukemia during the last years. As a result of more dose-intensive myelosuppressive and immunosuppressive therapies there is a higher risk of systemic fungal infections. Invasive pulmonary aspergillosis (IPA) represents a significant source of morbidity and mortality (>50%), and therefore measures that effectively prevent IPA are needed. Prophylaxis of IPA with anti-mold azoles is effective, but has adverse systemic effects and important drug interactions with some chemotherapeutic agents (i.e. vincristine). Currently there is no optimal prophylaxis for IPA in pediatric patients so new strategies are needed. Because IPA originates from the inhalation of conidia, a prophylactic approach is the topical administration of antifungals inside the lungs. Aerosolized lipid formulations of amphotericin B could prevent IPA and avoid systemic adverse events and drug interactions. There are no published studies reporting feasibility and safety of inhaled lipidic amphotericins in the pediatric population. PATIENTS AND METHODSThe safety, feasibility and tolerance of nebulized lipid complex amphotericin B (ABCL) was evaluated in a phase II open label single arm trial on the use in pediatric patients (3 to 18 year-old) with acute leukemia during intensive chemotherapy. Nebulized therapy was administered by a PARI eFlow®rapid nebulizer system twice weekly, at 50 mg the first week and then 25 mg during intensive chemotherapy until recovery of neutropenia (3 consecutive absolute neutrophil count (ANC) ≥1x109/L or one ANC ≥1.5x109/L). Treatment was resumed during neutropenic episodes following subsequent chemotherapy cycles. Serum galactomannan assay was performed twice weekly during neutropenia. High-resolution chest computed tomography was done when there was a clinical suspicion of IPA. Fluconazole was allowed but antifungal drugs with anti-mold activity were not permitted. The trial is registered at www.clinicaltrials.gov as NCT01615809. RESULTSThirty-two patients were included, 19 were male (59.4%), median age was of 5.5 years (range 3-16). Twenty-nine patients were diagnosed with acute lymphoblastic leukemia (ALL), 3 with acute myeloid leukemia. Among the patients with ALL, 24 had a de novo ALL and 5 a relapsed ALL. A total of 389 administrations of nebulized ABCL were performed, with a median per patient of 13 (range 1-19). All patients tolerated the drug and no patient had to discontinue it due to intolerance or an adverse event. No patient presented a severe adverse event in relation to ABCL. Five patients suffered from mild adverse events (cough, eye discomfort). Nine patients were withdrawn from the study, 2 were referred to another institution to undergo bone marrow transplantation and 7 due to systemic administration of an antifungal agent with anti-mold activity. Three of these patients developed a possible or probable IPA. There were no other cases of IPA. CONCLUSIONSProphylactic nebulizations with ABCL were well tolerated, safe and feasible in children aged 3-18 years diagnosed with acute leukemia. There is a need to perform further studies with a higher number of patients to evaluate the efficacy of this approach. DisclosuresRives:Teva Pharma: Other. Off Label Use: Nebulized Amphotericin-B lipid complex is not approved for prophylaxis of invasive fungal infection in pediatric patients with acute leukemia.

Serum galactomannan versus a combination of galactomannan and polymerase chain reaction-based Aspergillus DNA detection for early therapy of invasive aspergillosis in high-risk hematological patients: a randomized controlled trial.

The benefit of the combination of serum galactomannan (GM) assay and polymerase chain reaction (PCR)-based detection of serum Aspergillus DNA for the early diagnosis and therapy of invasive aspergillosis (IA) in high-risk hematological patients remains unclear. We performed an open-label, controlled, parallel-group randomized trial in 13 Spanish centers. Adult patients with acute myeloid leukemia and myelodysplastic syndrome on induction therapy or allogeneic hematopoietic stem cell transplant recipients were randomized (1:1 ratio) to 1 of 2 arms: "GM-PCR group" (the results of serial serum GM and PCR assays were provided to treating physicians) and "GM group" (only the results of serum GM were informed). Positivity in either assay prompted thoracic computed tomography scan and initiation of antifungal therapy. No antimold prophylaxis was permitted. Overall, 219 patients underwent randomization (105 in the GM-PCR group and 114 in the GM group). The cumulative incidence of "proven" or "probable" IA (primary study outcome) was lower in the GM-PCR group (4.2% vs 13.1%; odds ratio, 0.29 [95% confidence interval, .09-.91]). The median interval from the start of monitoring to the diagnosis of IA was lower in the GM-PCR group (13 vs 20 days; P = .022), as well as the use of empirical antifungal therapy (16.7% vs 29.0%; P = .038). Patients in the GM-PCR group had higher proven or probable IA-free survival (P = .027). A combined monitoring strategy based on serum GM and Aspergillus DNA was associated with an earlier diagnosis and a lower incidence of IA in high-risk hematological patients. Clinical Trials Registration. NCT01742026.

Epidemiology, clinical characteristics, and outcome of invasive aspergillosis in renal transplant patients.

Invasive aspergillosis (IA) has been considered an infrequent complication after renal transplantation. We aimed to evaluate the differences in clinical and epidemiologic characteristics of IA between renal and other types of transplantation. We reviewed all cases of solid organ transplant (SOT) recipients from Hospital Clinic at Barcelona, who had proven and probable IA, according to the EORTC/MSG criteria, between June 2003 and December 2010. A total of 1762 transplants were performed. From this cohort, 27 cases of IA were diagnosed (1.5%): in 56% (15/27) liver, 33% (9/27) kidney, and 11% (3/27) combined transplant. The median onset time from renal and non-renal transplants to IA was 217 and 10 days, respectively (P < 0.001). There were 6 cases (22%) of late IA (>6 months), all in kidney recipients (P < 0.001). Renal transplant patients with IA more frequently had chronic lung disease (44% vs. 6%) and chronic heart failure (33% vs. 6%); they also had none of the classical risk factors for IA defined for liver transplantation (0% vs. 33%, P = 0.001), and therefore they did not receive antifungal prophylaxis (0% vs. 72%, P = 0.001). In 14/24 patients, serum galactomannan antigen was positive, and this related to higher mortality. While classical risk factors described for IA in liver recipients are still valid, IA appears later in renal patients and is commonly associated with co-morbid conditions.

Impact and cost of the serum galactomannan assay at a tertiary care facility.

Invasive aspergillosis carries a high mortality with a rising prevalence in immunocompromised hosts. Diagnosis of invasive aspergillosis is challenging and delays in treatment are associated with poor outcomes. The galactomannan assay (GM), a non-culture-based surrogate marker of fungal infection, is widely used in diagnosis. It is unknown whether this assay impacts clinical decision making. We evaluated whether GM testing results in earlier initiation of antifungal therapy and is cost effective. We carried out a retrospective review of the electronic medical records of all patients undergoing GM at a 907-bed tertiary-care general hospital from July 11, 2011, to June 12, 2012. Records of patients with a positive GM were individually reviewed to determine the timing of the assay result, presence and timing of relevant culture data, whether BAL GM was performed, radiology data consistent with invasive aspergillosis, and the timing of initiation of antifungal therapy. For each case, it was determined whether GM results impacted the decision to initiate antifungal therapy. Forty-six nonduplicate GM samples were positive (>0.5) of 1419 performed. Results were considered to be false positives in 18 cases by care teams. In 21 cases, antifungal therapy was initiated before the assay result based on clinical suspicion, culture data, and/or radiology. The serum GM was performed 164 times at a cost of $21,789 for a single positive result effecting modification of patient care. Serum GM testing at a tertiary-care institution is commonly used but infrequently impacts clinical decision making with major financial burden.

Significant structural change in both O- and N-linked carbohydrate moieties of the antigenic galactomannan from Aspergillus fumigatus grown under different culture conditions.

Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Diagnosis of this infection frequently employs detection of the circulating galactomannan in the patient serum using enzyme immunoassay (EIA), a highly sensitive and specific system. Although there are many structural studies of the galactomannan of Aspergillus fumigatus, some inconsistencies are present in these results. In this study, to clarify the relationship between the growth conditions and structure of the galactomannans, we cultured A. fumigatus using two distinct yeast/fungal cultivation media, i.e. the yeast extract-peptone-dextrose (YPD) medium and yeast nitrogen base (YNB) medium. Galactomannans prepared from the resulting culture supernatants were structurally characterized by (1)H and (13)C nuclear magnetic resonance, methylation analysis, acetolysis and α-mannosidase degradation. These assays revealed that the galactomannan from the YPD cultivation had short β-1,5-linked galactofuranose (Galf) oligosaccharide chains in both the O- and N-linked carbohydrate moieties, while the galactomannan from the YNB cultivation incorporated long Galf oligosaccharide chains. The galactomannans derived from the two culture conditions significantly differed in reactivity based on the EIA diagnostic system. We also demonstrated the presence of a novel Galf-containing branched oligosaccharide in the O-linked moiety.