Aspergillosis In Patients Research Articles

A comparison of galactomannan-ELISA and a newly developed galactomannan-LATEX test in the serologic diagnosis of invasive aspergillosis in patients with hematologic malignancies

We compared the sensitivity and specificity of galactomannan enzyme-linked immunosorbent assay (GM-ELISA) with that of a newly developed version of the commercially available latex agglutination test (GM-LATEX) in our patient population. Serum samples were collected from 144 healthy adult donors (controls); another 17 consecutive hematologic malignancy (HM) patients with probable or proven invasive aspergillosis (IA) were tested. Clinical, microbiological, and pathological data were obtained. The sensitivity of the GM-LATEX test was 53% per patient and 66% per sample and that of the GM-ELISA test was 41% per patient and 21% per sample. Both tests demonstrated a specificity of 99%. The GM-LATEX test demonstrated a superior sensitivity in terms of detecting galactomannan and thus may be useful in the diagnosis of IA in patients with HM.

Identification of novel allergens of Aspergillus fumigatus using immunoproteomics approach

Approximately 20% of the world's asthmatics are suffering from Aspergillus fumigatus (Afu)-induced allergies. The characterization of specific IgE-inducing allergens in allergic aspergillosis patients is fundamental for clinical diagnosis and for immunotherapy. Immunoproteomics combined with mass spectrometric analysis was used to identify proteins of third-week culture filtrate (3wcf) potentially responsible for Afu-specific IgE immunoreactivity, using pooled sera from Afu-sensitized asthmatics. Their allergenic potential was also tested against patients with allergic bronchopulmonary aspergillosis (ABPA), by two-dimensional (2-D) gel electrophoresis immunoblotting of 3wcf proteins with individual sera from such patients. This helped us to establish a set of candidate allergens, which could be explored further for diagnostic application in allergic aspergillosis asthmatics including ABPA. Peptide mass fingerprint using matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) and/or de novo sequencing by MS/MS analysis of the protein spots from 2-D gels led to the identification of a total of 16 allergens of Afu. Eleven of them are being reported as allergens for the first time and five had been reported earlier. Putative isoforms of the proteins Asp f 13 and chitosanase have been observed for the first time. When studied for reactivity of these proteins among patients with ABPA using their individual sera, these patients exhibited sensitization although the pattern was varying. Taken together, these proteins could thus be considered as potential allergens even among patients with ABPA. Three of these proteins viz. the hypothetical protein (# spot no. 5), extracellular arabinase (# spot no. 6) and chitosanase (# spot no. 11) could be major allergens with specific IgE immunoreactivity with six out of eight patients' sera. The immunoproteomic approach applied to the analysis of culture filtrate proteins resulted in the identification of several candidate allergens, many of them novel, contributing to the catalogue of Afu allergenic proteins, which would facilitate improved serodiagnosis for allergic aspergillosis. In addition, the immunoreactivity of these proteins observed among the patients with ABPA may be potentially useful for its serodiagnosis and opens up further opportunities for the development of personalized immunotherapeutics for patients with ABPA.

Invasive Aspergillosis in Patients with Acute Leukemia: Update on Morbidity and Mortality--SEIFEM-C Report

Invasive Aspergillosis in Patients with Acute Leukemia: Update on Morbidity and Mortality--SEIFEM-C Report

Pulmonary aspergillosis: a clinical update

Aspergillus spp may cause a variety of pulmonary diseases, depending on immune status and the presence of underlying lung disease. These manifestations range from invasive pulmonary aspergillosis in severely immunocompromised patients, to chronic necrotizing aspergillosis in patients with chronic lung disease and/or mildly compromised immune systems. Aspergilloma is mainly seen in patients with cavitary lung disease, while allergic bronchopulmonary aspergillosis is described in patients with hypersensitivity to Aspergillus antigens. Recent major advances in the diagnosis and management of pulmonary aspergillosis include the introduction of non-invasive tests, and the development of new antifungal agents, such as azoles and echinocandins, that significantly affect the management and outcome of patients with pulmonary aspergillosis. This review provides a clinical update on the epidemiology, risk factors, clinical presentation, diagnosis and management of the major syndromes associated with pulmonary aspergillosis.

Role of Micafungin in the Antifungal Armamentarium

Serious infections caused by opportunistic molds remain a major problem for public health. Immune deficiency following organ transplantation and aggressive cancer treatment has greatly increased the incidence of systemic mycoses, and invasive aspergillosis in patients with AIDS is associated with significant morbidity and mortality. Amphotericin B is the first-line therapy for systemic infection because of its broad-spectrum and fungicidal activity. However, considerable side effects limit its clinical utility. The echinocandins are large lipopeptide molecules that inhibit the synthesis of 1,3-beta-D-glucan, a key component of the fungal cell wall. Three echinocandins have reached the market, and some others are in early clinical development. Caspofungin was the first echinocandin to be licensed for clinical use in most countries. Micafungin is licensed for clinical use in Japan, China, Taiwan, Jordan, Korea, Hong-Kong and the US, and anidulafungin is currently licensed in the US. The novel class of echinocandins represents a milestone in antifungal drug research that has further expanded our therapeutic options. Studies to date have shown that micafungin exhibits extremely potent antifungal activity against clinically important fungi, including Aspergillus and azole-resistant strains of Candida. In animal studies, micafungin is as efficacious as amphotericin B with respect to improvement of survival rate. Micafungin is also characterized by a linear pharmacokinetic profile and substantially fewer toxic effects. Micafungin is a poor substrate for the cytochrome P450 enzymes, and compared to azoles, fewer drug interactions are described. No dose adjustments of the drug are required in the presence of mycophenolate mofetil, cyclosporin, tacrolimus, prednisolone, or sirolimus. Strategies using this new echinocandin agent will benefit a large number of patients with severe immune dysfunction.

Advances in the serological diagnosis of invasive Aspergillus infections in patients with haematological disorders

A reliable diagnosis of invasive aspergillosis in patients with haematological malignancies is seldom achieved antemortem. Conventional laboratory diagnostic methods are insensitive and time-consuming, resulting in late diagnosis and treatment and contributing to unacceptably high mortality. As a result, routine antifungal prophylaxis and early empirical treatment have been recommended. However, overtreatment associated with these strategies results in increased toxicity and cost. The use of sensitive and rapid non-culture-based diagnostic assays, such as detection of Aspergillus antigens (galactomannan, beta-D-glucan) or detection of genomic DNA sequences may allow a shift in emphasis from empirical to pre-emptive therapy, especially when substantiated by suggestive radiological findings. These new tools may be used to confirm a presumed diagnosis of invasive aspergillosis, or, when used to screen high-risk patients, may identify an infection at the early stage of disease. The excellent negative predictive value of these assays should convince clinicians to withhold antifungal therapy in persistently febrile neutropenic patients with no other signs of fungal infection. On the other hand, consecutive positive results in a high-risk population should at least trigger a complete diagnostic work-up. This review will focus on the diagnostic utility as well as on the pitfalls of serial screening for the presence of circulating fungal antigens in haematology patients.

Caspofungin as salvage monotherapy for invasive aspergillosis in patients with haematological malignancies or following allogeneic stem cell transplantation: efficacy and concomitant cyclosporin A

Caspofungin (CAS) has shown efficacy as salvage monotherapy for invasive aspergillosis (IA) in two open label non-comparative trials. The association between hepatotoxicity and concomitant use of CAS and cyclosporin A (CsA) has not been fully elucidated. We report results on CAS efficacy in the first cohort from outside Europe and USA and the interaction between CAS and CsA. We retrospectively reviewed the charts of all patients with haematological malignancies or postallogeneic haematopoietic stem cell transplant (HSCT) who received >/=1 dose of CAS as salvage monotherapy for IA as part of the Australian Special Access Scheme (4/2001-8/2002). Outcomes were assessed at the end of CAS therapy. Favourable response (FR) was defined as >50% clinical and radiological improvement. Risk factors for elevation of liver transaminases (LTs) were examined using multivariate models. 54 patients were included in the analysis with 47 neutropenic at study entry. Proven or probable IA occurred in 11 and refractory IA in 28. An FR occurred in 26 (48.1%) and predictors for a poor response to CAS were allogeneic HSCT, graft vs. host disease and treatment with CAS for <14 days. Concomitant CAS and CsA for >7 days was an independent risk factor for laboratory hepatoxicity. The CAS efficacy results from the Australian cohort confirm those of previous studies. Close monitoring of LTs is necessary on concomitant CAS and CsA but clinically relevant hepatotoxicity is rare.

Galactomannan Antigen Enzyme-Linked Immunosorbent Assay for Diagnosis of Invasive Aspergillosis after Hematopoietic Stem Cell Transplantation

Invasive aspergillosis is difficult to diagnose in patients undergoing hematopoietic stem cell transplantation (HSCT). In 2003, a serum enzyme-linked immunosorbent assay (ELISA) test for the detection of galactomannan (a glycoprotein found on the Aspergillus cell wall) became available in the United States. In 2004, patients undergoing HSCT were screened biweekly with the galactomannan ELISA at our institution. We performed a retrospective chart review of 121 SCT patients who underwent galactomannan testing. Thirteen of the patients (10.7%) had at least 1 positive galactomannan ELISA, and 4 had multiple positive tests. When calculated in reference to a proved or probable diagnosis of aspergillosis, the galactomannan ELISA had a sensitivity of 0.50 and a specificity of 0.94. The positive predictive value was 0.46, and the negative predictive value was 0.94. Galactomannan ELISA had fewer false-positive and false-negative results in pediatric patients than in adult patients. In 4 of the 12 cases of invasive aspergillosis, the galactomannan ELISA was positive before other microbiologic evidence of aspergillosis was available. In these cases, a positive ELISA predated culture and cytologic evidence of invasive aspergillosis by a mean of 5 days (range, 1-8 days). Our findings indicate that a biweekly serum galactomannan ELISA is a highly specific diagnostic tool for detecting invasive aspergillosis in patients undergoing HSCT. When used regularly, the ELISA may allow for earlier diagnosis of invasive aspergillosis in some patients. The test is troubled by a low sensitivity and high frequency of false-negative tests.

Invasive pulmonary aspergillosis in patients with decompensated cirrhosis: case series

BackgroundOpportunistic invasive fungal infections are increasingly frequent in intensive care patients. Their clinical spectrum goes beyond the patients with malignancies, and for example invasive pulmonary aspergillosis has recently been described in critically ill patients without such condition. Liver failure has been suspected to be a risk factor for aspergillosis.Case presentationWe describe three cases of adult respiratory distress syndrome with sepsis, shock and multiple organ failure in patients with severe liver failure among whom two had positive Aspergillus antigenemia and one had a positive Aspergillus serology. In all cases bronchoalveolar lavage fluid was positive for Aspergillus fumigatus. Outcome was fatal in all cases despite treatment with voriconazole and agressive symptomatic treatment.ConclusionInvasive aspergillosis should be among rapidly raised hypothesis in cirrhotic patients developing acute respiratory symptoms and alveolar opacities.

Economic Evaluation of Voriconazole versus Caspofungin for the Treatment of Invasive Aspergillosis in Spain

Invasive fungal infections are becoming increasingly prevalent and are more frequently the aetiological agents responsible for nosocomial infections. Since mid-2002, two new antifungal drugs - voriconazole, a third-generation azole, and caspofungin, a member of a new class of drugs called echinocandins - have been marketed in Spain. Both drugs have proven [corrected] efficacy in the treatment of aspergillosis, are better tolerated than amphotericin B and are cheaper [corrected] than liposomal amphotericin B. The objective of this study was to conduct an economic evaluation of voriconazole versus caspofungin for the treatment of invasive aspergillosis in Spain. This was a cost-minimisation analysis (2006 costs) from the hospital perspective. Duration of treatment and bodyweight of patients were obtained from the Fungcost study and the incidence of adverse events was obtained from different published sources. Only direct costs were considered. Mean expected cost and incremental cost were calculated, and univariate and bivariate (bodyweight/treatment duration) sensitivity analyses were conducted. The mean expected cost per episode was 6041.93 euro (intravenous treatment acquisition cost 5524.75 euro) for voriconazole and 7174.05 euro (intravenous treatment acquisition cost 6672.80 euro) for caspofungin in invasive aspergillosis; the incremental cost was 1132.18 euro. Results were robust for any treatment duration and sensitive to bodyweights <103.42 kg. Voriconazole is a more cost-effective option than caspofungin in invasive aspergillosis in patients with a bodyweight <103.42 kg.

Validation of Serum Aspergillus Galactomannan Index as a Surrogate Endpoint for Outcome of Invasive Aspergillosis: Clinical and Research Implications.

Background: Assessing clinical outcome of aspergillosis with conventional clinical and laboratory criteria is difficult. A composite “global outcome response” (clinical, radiologic, pathologic and microbiologic criteria) is frequently used but suffers from poor sensitivity and specificity, and has not been standardized or validated. A reliable, quantitative, non-invasive, and easy to measure laboratory test than can substitute for this composite endpoint, i.e. serve as a surrogate endpoint for aspergillosis outcome is highly desirable. Galactomannan (GM) is an Aspergillus-specific polysaccharide released during aspergillosis and detected by the serum GM test. The test which is reported as an index of optical density (OD) is an accepted diagnostic marker for aspergillosis and preliminary data suggest a correlation between GM index (GMI) and outcome.Purpose: To evaluate serum GMI as a surrogate endpoint for outcome of invasive aspergillosis in patients with hematological cancer.Patients and Methods: patients at risk for aspergillosis (11/03-2/06) underwent GMI screening during periods at risk. The clinical and laboratory findings of patients with ≥ 2 (+) GMI (OD ≥ 0.5) were reviewed. To validate GMI as a surrogate endpoint for aspergillosis, a k correlation concordance coefficient test between GMI and an objective clinical outcome of aspergillosis (death) was applied. The correlation is considered perfect when k is 1.0; excellent when ≥ 0.75.Results: 30 patients had GMI (+) aspergillosis of the respiratory tract [myeloma 92%; median age: 59 years (27–75); 15 males]. Aspergillosis developed following stem cell transplantation [autologous (11), allogeneic (1)], or after conventional chemotherapy (18). Among 25 neutropenic patients (<1000/ml), persistent GMI elevation was associated with death (5/5 patients) while return to negative values predicted survival (20/20 patients). Among 5 non-neutropenic patients, 1 with persistently elevated GMI died compared to no death among the remaining 4 whose GMI became negative. Overall, the GMI correlated with clinical outcome in all 30 patients with a perfect 1.0 k correlation concordance coefficient.Conclusion: we have validated GMI as an excellent surrogate endpoint for the outcome of invasive aspergillosis among patients with hematological cancer. This FDA-approved test is reproducible, quantitative, non-invasive, easy to measure and widely available. These findings have important implications for patient care and for the design of clinical trials of mould-active antifungal agents.

Aspergilloses au cours de maladies systémiques traitées par corticoïdes et/ou immunosuppresseurs : analyse de neuf cas et revue de la littérature

This is a multicentric retrospective study of aspergillosis in patients treated by corticosteroids and/or immunosuppressive drugs for systemic diseases and a review of the literature. Nine patients, 5 men and 4 women, mean age of 62.8 years old were included among which Horton's diseases (3 cases), systemic lupus erythematosus (2), polymyositis (1), microscopic polyangiitis (1), idiopathic thrombocytopenic purpura (1), rheumatoid polyarthritis (1). Aspergillosis occurred in average 28.4 month after the diagnosis of systemic disease, and 28 months after the beginning of its treatment: corticosteroids in all cases, at a dose of 50.8 mg/day (equivalent prednisone) in average, cyclophosphamide (2 cases), methotrexate (1), intravenous immunoglobulins (1), leflunomide (1). All cases were invasive or chronic pulmonary aspergillosis located in the lungs (6 cases), or in the brain (3). Revealing symptoms were mild and non specific. Lymphopenia was severe in most cases, in average 472 lymphocytes/mm 3 and 283 CD4+/mm 3. The diagnosis was confirmed 20.75 days after the first symptoms in invasive aspergillosis, and 18.5 months in the chronic pulmonary cases, by cultures in 7 cases (broncho-alveolar lavage: 4; cerebral biopsy: 3), and direct microscopy examination of broncho-alveolar lavage in 2 cases. Specific serology was positive in 4 cases. Patients were treated by voriconazole (4 cases), itraconazole (2), amphotericin B (1), association of caspofungin and voriconazole (1), successive voriconazole and itraconazole (1). Six patients recovered from aspergillosis with 10.8 months of following time, 3 patients died a few days after confirmation of the diagnosis. Fifty-four cases of the literature are analysed.

Cytokine profiling of pulmonary aspergillosis

Aspergillus fumigatus is ubiquitous and yet causes invasive, chronic and allergic disease of the lung. Chronic cavitary pulmonary aspergillosis (CCPA) is a slowly destructive form of pulmonary aspergillosis, without immunocompromise. We hypothesized that CCPA cytokine gene polymorphisms would differ from patients with allergic bronchopulmonary aspergillosis (ABPA) and uninfected controls. We have profiled functional cytokine gene polymorphisms for interleukin (IL)-10, IL-15, transforming growth factors (TGF)-beta1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma in patients with CCPA (n = 24) who were compared with other forms of aspergillosis (mostly ABPA) (n = 15) and with ethnically matched controls (n = 65-330). Results are described with reference to the high-producing genotype in each case. Susceptibility to aspergillosis (all patients compared with normal controls) was associated with higher frequency of the IL-15 +13689*A allele (OR = 2.37, P = 0.0028) and A/A genotype (chi(2) = 10.31, P < 0.001), with a lower frequency of the TNF-alpha-308*A/A genotype (chi(2) = 11.05, P < 0.01). Within the aspergillosis patients, CCPA is associated with lower frequency of the IL-10 -1082*G allele (OR = 0.38, P = 0.0006) and G/G genotype (chi(2) = 22.45, P < 0.001) and with a lower frequency of the TGF-beta1 +869 *T allele (OR +0.42, P < 0.0029) and T/T genotype (chi(2) = 17.82, P < 0.001) compared with non-CCPA patients and normal controls. Patients infected with Aspergillus appear to be higher producers of IL-15, a Th2-promoting cytokine, and lower producers of TNF-alpha, a cytokine central in protective responses. CCPA occurs in patients who are genetically lower producers of both IL-10 and TGF-beta1. As these cytokines are regulatory and anti-inflammatory, CCPA may be a consequence of poor inflammatory response control in the lung.

Efficacy of environmental measures to decrease the risk of hospital-acquired aspergillosis in patients hospitalised in haematology wards

This study evaluated a multidisciplinary strategy to decrease the rate of invasive pulmonary aspergillosis (IPA) among adult patients hospitalised in two haematology wards in a single 560-bed building at the University Hospital of Saint-Etienne. Upgrading of the air filtration system and construction of an air-lock chamber at the entrance to the unit were completed during 1994. In 1995, specific hygienic measures were introduced during hospital building work, including the use of plastic barriers, watering during demolition work, reduction of pedestrian traffic in construction areas, and the wearing of high-efficiency filtration masks by immunosuppressed patients when outside the protected unit. This strategy was evaluated by a prospective survey of IPA cases between 1993 and 2001, coupled with environmental surveillance. The number and risk-level of hospital renovation projects increased between 1995 and 2001 (p < 0.01). In parallel, the rate of IPA decreased globally in the haematology unit from 0.85% (1.19/1,000 patients) in 1993 to 0.28% (0.21/1,000 patients) in 2001. The incidence of IPA decreased significantly between 1993-1996 and 1997-2001 (p 0.02, Mann-Whitney test). These results show that a multidisciplinary approach involving engineers, infection control practitioners, mycologists and clinicians enables IPA rates among patients hospitalised in haematology wards to be significantly decreased.

Usefulness of Sequential Aspergillus galactomannan Antigen Detection Combined With Early Radiologic Evaluation for Diagnosis of Invasive Pulmonary Aspergillosis in Patients Undergoing Allogeneic Stem Cell Transplantation

Background Early diagnosis of invasive pulmonary aspergillosis (IPA) is important as prompt treatment with antifungal drugs may increase patient survival. Our study investigated the efficiency of routine testing of the Aspergillus galactomannan antigen (AGA) test in combination with chest CT scans for IPA diagnosis. Patients and Methods From February 2002 to June 2004, 74 hemato-oncologic patients undergoing allogeneic stem cell transplantation were prospectively studied with serum AGA twice weekly from admission until death or discharge and weekly afterward when possible. Chest CT scans were performed when fever of unknown origin had lasted beyond 3 days of antibacterial therapy. Results Seven patients were classified with possible IPA and two patients, proven IPA. Fourteen patients showed positive results for AGA (OD index ≥ 1.0 on two subsequent sera). The sensitivity and specificity of the test were 100% and 93%, respectively; the positive and negative predictive values were 64% and 100%, respectively. All patients with possible/proven IPA showed abnormal CT signs; in four cases, imaging signs followed AGA positivity (median 5 days), whereas in five cases they preceded serologic positivity (median, 8 days). In the nine patients with IPA, antifungal therapy was promptly instituted, including lipid formulations of amphotericin B ( n = 5) or caspofungin ( n = 4). In only two of the nine patients (22%) with IPA, the primary cause of death was fungal infection. Conclusions The combination of AGA detection and early chest CT scans might be considered useful tools to detect minimal changes of IPA. Based on these findings, aggressive antifungal therapy should be initiated.

Chemokines Indicate Allergic Bronchopulmonary Aspergillosis in Patients with Cystic Fibrosis

Allergic bronchopulmonary aspergillosis (ABPA) is characterized by a Th2 immune response. Mouse models suggest a critical role for the Th2 chemokines thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in ABPA. To determine whether serum levels of TARC and MDC characterize ABPA in patients with cystic fibrosis (CF) and to examine longitudinally if levels of TARC and MDC indicate ABPA exacerbations in patients with CF. Levels of TARC and MDC and levels of Th1 (IL-12 and IFN-gamma) and Th2 (IL-4, IL-5, and IL-13) cytokines were analyzed in serum of 16 patients with CF with ABPA, six non-CF patients with asthma with ABPA, 13 patients with CF colonized with Aspergillus fumigatus, six patients with CF sensitized to A. fumigatus, 12 atopic patients with CF, and 13 non-CF atopic control subjects by ELISA. The longitudinal course of TARC, MDC, and IgE levels was assessed during ABPA episodes. Patients with ABPA had significantly higher serum levels of TARC compared with the other patient groups. Cytokine levels did not differ among the patient groups. Longitudinally, levels of TARC indicated ABPA exacerbations in patients with CF more clearly than IgE levels. In patients with CF and ABPA, levels of TARC correlated positively with specific IgE to A. fumigatus and rAsp f4. Serum levels of TARC differentiate patients with CF or patients with asthma with ABPA from patients with CF colonized with or sensitized to A. fumigatus, atopic patients with CF, and atopic control subjects. Longitudinally, levels of TARC indicate ABPA exacerbations, suggesting TARC as a marker for identification and monitoring of ABPA in patients with CF.

Prospective Evaluation of a Polymerase Chain Reaction–ELISA Targeted toAspergillus fumigatusandAspergillus flavusfor the Early Diagnosis of Invasive Aspergillosis in Patients with Hematological Malignancies

Current laboratory and radiological methods for diagnosis of invasive aspergillosis (IA) lack sensitivity and specificity. We prospectively evaluated the diagnostic value of twice-weekly screening for circulating Aspergillus fumigatus and A. flavus DNA with a polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA). Among the 201 adult patients with hematological malignancies who were included in the study, 55 IA cases were diagnosed. On the basis of the analysis of 1205 serum samples from 167 patients, the sensitivity, specificity, and positive and negative predictive values of the PCR-ELISA for proven and probable IA cases were 63.6%, 89.7%, 63.6%, and 89.7%, respectively, when samples with 2 consecutive positive results were used. The use of a combination of the PCR-ELISA and a galactomannan (GM) assay increased the sensitivity to 83.3%, increased the negative predictive value to 97.6%, and decreased the specificity to 69.8%. In most patients with IA, PCR-ELISA positivity anticipated or was simultaneous with the initiation of antifungal therapy, the abnormalities found by computed tomography, the mycological/histological diagnosis, and the GM positivity. Overall, 56.3% of the patients had at least 1 positive sample, and the false single-positive rate was 44.8%. In addition to serial screening for GM antigenemia and radiological surveillance, PCR-ELISA may improve the rates of early diagnosis of IA and the management of patients with hematological malignancies.

Sensitization to Aspergillus Antigens and Occurrence of Allergic Bronchopulmonary Aspergillosis in Patients With Asthma

Sensitization to Aspergillus Antigens and Occurrence of Allergic Bronchopulmonary Aspergillosis in Patients With Asthma

Effective Blood Concentration of Micafungin for Pulmonary Aspergillosis

We previously reported that a 150 mg or higher daily dose is necessary for treatment of pulmonary aspergillosis with micafungin (MCFG) alone in patients with blood diseases. Since a delay in the treatment of pulmonary aspergillosis has a major influence on patient survival, clarification of the effective blood concentration of MCFG enables rapid treatment. Establishment of an appropriate dose is also useful for reducing the risk of adverse effects, such as MCFG-induced impairment of liver function. Aiming for the rapid and safe treatment of pulmonary aspergillosis, we established new clinical diagnostic criteria of mycosis and MCFG therapeutic effect judgment criteria, and investigated the effective blood concentration of MCFG for mycosis. The blood trough level of MCFG in patients with blood diseases at each clinical improvement rating of pulmonary aspergillosis was 5.23+/-2.44 microg/ml in markedly improved cases, 4.08+/-2.63 microg/ml in improved cases, and 3.45+/-1.63 microg/ml in successfully prevented cases, showing no significant difference among the 3 groups. Based on this finding, it is advisable to target a 5 microg/ml or higher blood trough level of MCFG in establishing the dose for aspergillosis in patients with blood diseases.

Molecular typing of aspergilli: Recent developments and outcomes.

Aspergillus spp. have been the subject of numerous epidemiological studies. The most useful typing techniques are DNA based methods including the random amplified polymorphic DNA technique, microsatellite length polymorphisms, restriction fragment length polymorphism (RFLP) analysis using retrotransposon-like sequences as probes, and multilocus sequence typing. The results of typing clinical isolates indicate that most of the invasive aspergillosis (IA) patients were infected by a single strain. Genetic analysis could not discriminate between clinical and environmental isolates of Aspergillus. fumigatus, indicating that every strain present in the environment is a potential pathogen if it encounters the appropriate host. The source of infection can also be monitored by typing. Typing studies led to the discovery of a new pathogenic species, A. lentulus, and to the identification of several species not known previously to be pathogenic. Typing studies revealed the existence of two genetically isolated groups within a global A. fumigatus population. Aspergillus fumigatus was found to be the first example of a true cosmopolitan fungus. Additionally, the results obtained in several studies support the premise that recombination played an important role in A. fumigatus populations. The discovery of functional mating type genes in A. fumigatus indicates that past or recent sexual processes could be responsible for the observed recombining population structure.