Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

A Secure Occupational Therapy Framework for Monitoring Cancer Patients' Quality of Life.

Once diagnosed with cancer, a patient goes through a series of diagnosis and tests, which are referred to as "after cancer treatment". Due to the nature of the treatment and side effects, maintaining quality of life (QoL) in the home environment is a challenging task. Sometimes, a cancer patient's situation changes abruptly as the functionality of certain organs deteriorates, which affects their QoL. One way of knowing the physiological functional status of a cancer patient is to design an occupational therapy. In this paper, we propose a blockchain and off-chain-based framework, which will allow multiple medical and ambient intelligent Internet of Things sensors to capture the QoL information from one's home environment and securely share it with their community of interest. Using our proposed framework, both transactional records and multimedia big data can be shared with an oncologist or palliative care unit for real-time decision support. We have also developed blockchain-based data analytics, which will allow a clinician to visualize the immutable history of the patient's data available from an in-home secure monitoring system for a better understanding of a patient's current or historical states. Finally, we will present our current implementation status, which provides significant encouragement for further development.

Chronic pulmonary aspergillosis: an update on diagnosis and treatment.

Chronic pulmonary aspergillosis (CPA) affects individuals with non-systemic or mildly systemic immunodepression or altered pulmonary integrity due to underlying disease. It has been reported with a variety of clinical and radiological patterns. The condition should be distinguished from simple aspergilloma and allergic bronchopulmonary aspergillosis as well as invasive aspergillosis in severely immunocompromised patients. CPA generally requires long-term antifungal treatment and surgery may be considered. Life-threatening haemoptysis may be prevented by bronchial arteriography with embolisation. However, currently there are no documented treatment recommendations for CPA. This review provides an up-to-date practical overview of this condition, including a comprehensive update on diagnosis and management.

CT Imaging Assessment of Response to Treatment in Allergic Bronchopulmonary Aspergillosis in Adults With Bronchial Asthma.

BACKGROUND: One of the major challenges in managing allergic bronchopulmonary aspergillosis remains consistent and reproducible assessment of response to treatment. RESEARCH QUESTION: What are the most relevant changes in CT scan parameters over time for assessing response to treatment? STUDY DESIGN AND METHODS: In this ancillary study of a randomized clinical trial (NebuLamB), patients with asthma with available CT scan and without exacerbation during a 4-month allergic bronchopulmonary aspergillosis exacerbation treatment period (corticosteroids and itraconazole) were included. Changed CT scan parameters were assessed by systematic analyses of CT scan findings at initiation and end of treatment. CT scans were assessed by two radiologists anonymized to the clinical data. Radiologic parameters were determined by selecting those showing significant changes over time. Improvement of at least one, without worsening of the others, defined the radiologic response. Agreement between radiologic changes and clinical and immunologic responses was likewise investigated. RESULTS: Among the 139 originally randomized patients, 132 were included. We identified five CT scan parameters showing significant changes at end of treatment: mucoid impaction extent, mucoid impaction density, centrilobular micronodules, consolidation/ground-glass opacities, and bronchial wall thickening (P < .05). These changes were only weakly associated with one another, except for mucoid impaction extent and density. No agreement was observed between clinical, immunologic, and radiologic responses, assessed as an overall response, or considering each of the parameters (Cohen κ, -0.01 to 0.24). INTERPRETATION: Changes in extent and density of mucoid impaction, centrilobular micronodules, consolidation/ground-glass opacities, and thickening of the bronchial walls were found to be the most relevant CT scan parameters to assess radiologic response to treatment. A clinical, immunologic, and radiologic multidimensional approach should be adopted to assess outcomes, probably with a composite definition of response to treatment. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02273661; URL: www. CLINICALTRIALS: gov).

In vivo biofilm composition of Aspergillus fumigatus.

The in vivo composition of the mycelial extracellular matrix (ECM) of Aspergillus fumigatus during host invasion is reported here for the first time. A new galactosaminogalactan and the galactomannan were the major polysaccharides of the in vivo ECM. The composition of the ECM in vivo varied with the aspergillosis pathologies.

Telemetric monitoring of pulmonary function after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Late-onset noninfectious pulmonary complications (LONIPC) are both frequent and severe after allogeneic hematopoietic stem cell transplantation (HSCT). The high mortality rate (40-80%) may be related to delayed diagnosis. We assessed the use of telemetric home surveillance of pulmonary function for early diagnosis of LONIPC in transplant recipients. METHODS: This prospective study monitored pulmonary function in 37 allogeneic HSCT recipients. About 3 months after HSCT, they received a portable spirometer that measured forced vital capacity, forced expiratory volume per second, and midexpiratory flow 25-75 (MEF25-75). Data were transmitted twice weekly by telephone. Conventional plethysmography confirmed any significant deterioration (>20%). RESULTS: Thirteen episodes of spirometric deterioration were detected by telemetry in 11 patients during a median 17-month (4-41) follow-up period after transplantation. In these cases, examinations including spirometry, high-resolution thoracic computed tomography and bronchoalveolar lavage diagnosed LONIPC in eight episodes in seven patients (cumulative incidence 23.4%, SE 0.08, at month 24 after transplant): bronchiolitis obliterans (BO, n=3), interstitial pneumonia (IP, n=4), or both BO and IP (n=1). Five episodes improved and three were stabilized with increased immunosuppressive therapy. At the last follow-up, of the seven patients with LONIPC, one successfully stopped immunosuppressive therapy, two were receiving low-dose mycophenolate mofetil, and four were receiving low-dose corticosteroid therapy. There were no cases of respiratory failure and no patient died from LONIPC. CONCLUSION: Telemetric home monitoring of pulmonary function is a useful procedure for early diagnosis of LONIPC before clinical pulmonary symptoms and may improve outcome after allogeneic HSCT.

Treatment of chronic pulmonary aspergillosis by voriconazole in nonimmunocompromised patients.

BACKGROUND: There is no recognized medical treatment for chronic pulmonary aspergillosis (CPA) apart from surgery in patients with simple aspergilloma. To evaluate the efficacy of voriconazole in this setting, we conducted a retrospective multicenter study over a 3-year period. METHODS: For inclusion in the study, patients had to have received voriconazole for treatment of confirmed or probable CPA with a follow-up of at least 6 months. Clinical, radiologic, and mycologic data were collected at baseline, every 2 to 3 months, and at the end of treatment or at the date point. RESULTS: Twenty-four patients were included in the study, among which 9 patients presented with chronic cavitary pulmonary aspergillosis and 15 presented with chronic necrotizing pulmonary aspergillosis (CNPA). Voriconazole was given as a first-line treatment to 13 patients. The median duration of treatment and follow-up were 6.5 and 10 months, respectively. Three patients had to stop treatment with voriconazole because of toxicity. Symptoms and imagery findings were improved in 16 of 24 patients and 17 of 24 patients, respectively, at the end of follow-up. Mycology, which was positive at baseline in 21 of 23 patients, was negative in 18 of 19 patients at the end of follow-up; serologic test results were also negative in 6 of 19 evaluable patients, all of whom had CNPA. Improved radioclinical findings and mycologic eradication were observed at the end of follow-up in 11 of 19 patients (58%). Patients in whom the disease was controlled had a significantly longer median duration of treatment than patients in whom it was uncontrolled (9 vs 6 months, respectively; p = 0.04). CONCLUSION: Voriconazole provides effective treatment of CPA with an acceptable level of toxicity.

CT Imaging Assessment of Response to Treatment in Chronic Pulmonary Aspergillosis.

BACKGROUND: Long-term antifungal therapy is usually the only treatment option for chronic pulmonary aspergillosis. However, response rates are difficult to compare because the reported clinical, mycologic, or radiologic criteria are not standardized. Objective parameters are therefore needed. To define the most relevant CT imaging variables in assessment of response to treatment, we investigated changes over time in CT imaging variables. METHODS: Changes in CT imaging variables were assessed by systematic analysis of the CT scan findings of 36 patients at diagnosis and 6 months after initiation of treatment. The relevant radiologic variables were determined by selecting those showing significant changes over time. Two experienced thoracic radiologists, blinded for clinical and serologic response, independently performed CT scan analyses. Interreader agreement and concordance between radiologic and clinical response were evaluated. RESULTS: Of the 36 patients, seven experienced clinical deterioration while undergoing therapy. Significantly evolving radiologic variables included cavity and pleural wall thickening (P < .05), which were associated with clinical improvement. There was a strong association between fungus ball disappearance and cavity/pleural wall thickening reduction and clinical improvement (P = .04). There was poor agreement between size changes of cavities or nodules, and clinical evolution (Cohen's κ, -0.13 to -0.24). CONCLUSIONS: Variations in cavity and pleural wall thickness may be the most relevant CT imaging variables for assessing response to treatment. Loss of fungus ball is strongly associated with clinical and radiologic improvement, but cavity size changes are unrelated to chronic pulmonary aspergillosis evolution. All these CT imaging variables may be applied in future clinical trials to assess treatment outcome.

Diagnosis and management of idiopathic pulmonary fibrosis: French practical guidelines.

Idiopathic pulmonary fibrosis (IPF) is the most frequent chronic idiopathic interstitial pneumonia in adults. The management of rare diseases in France has been organised by a national plan for rare diseases, which endorsed a network of expert centres for rare diseases throughout France. This article is an overview of the executive summary of the French guidelines for the management of IPF, an initiative that emanated from the French National Reference Centre and the Network of Regional Competence Centres for Rare Lung Diseases. This review aims at providing pulmonologists with a document that: 1) combines the current available evidence; 2) reviews practical modalities of diagnosis and management of IPF; and 3) is adapted to everyday medical practice. The French practical guidelines result from the combined efforts of a coordination committee, a writing committee and a multidisciplinary review panel, following recommendations from the Haute Autorité de Santé. All recommendations included in this article received at least 90% agreement by the reviewing panel. Herein, we summarise the main conclusions and practical recommendations of the French guidelines.

Expression of calcineurin activity after lung transplantation: a 2-year follow-up.

The objective of this pharmacodynamic study was to longitudinally assess the activity of calcineurin during the first 2 years after lung transplantation. From March 2004 to October 2008, 107 patients were prospectively enrolled and their follow-up was performed until 2009. Calcineurin activity was measured in peripheral blood mononuclear cells. We report that calcineurin activity was linked to both acute and chronic rejection. An optimal activity for calcineurin with two thresholds was defined, and we found that the risk of rejection was higher when the enzyme activity was above the upper threshold of 102 pmol/mg/min or below the lower threshold of 12 pmol/mg/min. In addition, we report that the occurrence of malignancies and viral infections was significantly higher in patients displaying very low levels of calcineurin activity. Taken together, these findings suggest that the measurement of calcineurin activity may provide useful information for the management of the prevention therapy of patients receiving lung transplantation.

Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome.

BACKGROUND: Clinical characteristics, risks, and outcomes in solid organ transplant (SOT) recipients with zygomycosis in the era of modern immunosuppressive and newer antifungal agent use have not been defined. METHODS: In a matched case-controlled study, SOT recipients with zygomycosis were prospectively studied. The primary outcome measure was success (complete or partial response) at 90 days. RESULTS: Renal failure (odds ratio [OR], 3.17; P = .010), diabetes mellitus (OR, 8.11; P < .001), and prior voriconazole and/or caspofungin use (OR, 4.41; P = .033) were associated with a higher risk of zygomycosis, whereas tacrolimus (OR, 0.23; P = .002) was associated with a lower risk of zygomycosis. Liver transplant recipients were more likely to have disseminated disease (OR, 5.48; P = .021) and developed zygomycosis earlier after transplantation than did other SOT recipients (median, 0.8 vs 5.7 months; P < .001). Overall the treatment success rate was 60%. Renal failure (OR, 11.3; P = .023) and disseminated disease (OR, 14.6; P = .027) were independently predictive of treatment failure, whereas surgical resection was associated with treatment success (OR, 33.3; P = .003). The success rate with liposomal amphotericin B was 4-fold higher even when controlling for the aforementioned variables. CONCLUSIONS: The risks identified for zygomycosis and for disseminated disease, including those that were previously unrecognized, have implications for further elucidating the biologic basis and for optimizing outcomes in SOT recipients with zygomycosis.

Relative impact of human leukocyte antigen mismatching and graft ischemic time after lung transplantation.

BACKGROUND: Recent data strongly suggest that human leukocyte antigen (HLA) mismatching has a negative impact on development of bronchiolitis obliterans syndrome (BOS) and survival after lung transplantation (LTx). Because HLA matching is sometimes achieved by extending ischemic time in other solid-organ transplantation models and ischemic time is a risk factor per se for death after LTx, we sought to compare the theoretical benefit of HLA matching with the negative impact of lengthened ischemic time. METHODS: In this collaborative study we compared the relative impact of HLA mismatching and ischemic time on BOS and survival in 182 LTx recipients. RESULTS: Using multivariate analyses, we observed a lower incidence of BOS (hazard ratio [HR] = 1.70, 95% confidence interval [CI]: 1.1 to 2.7, p = 0.03) and enhanced survival (HR = 1.91, 95% CI: 1.24 to 2.92, p = 0.01) in patients with zero or one HLA-A mismatch compared with those having two HLA-A mismatches. This beneficial effect on survival was equivalent to a reduction of ischemic time of 168 minutes. CONCLUSIONS: We observed a reduced incidence of BOS and a better survival rate in patients well-matched at the HLA-A locus, associated with an opposite effect of an enhanced ischemic time. This suggests that graft ischemic time should be taken into account in future studies of prospective HLA matching in LTx.

Acute eosinophilic pneumonia after allogeneic hematopoietic stem cell transplantation.

A 55-year old woman with multiple myeloma was treated with hematopoietic stem cell transplantation (HSCT). She developed cutaneous and hepatic graft-vs-host disease (GVHD). Sixty-five days after HSCT, acute respiratory failure occurred. A thoracic computed tomography scan showed bilateral patchy infiltrates. Bronchoalveolar lavage revealed 40% eosinophils on differential cell count with no infectious pathogens. These findings were in favor of acute eosinophilic pneumonia. High-dose steroid treatment was started, which had a rapid and lasting favorable course. After HSCT, clinicians should be aware that acute eosinophilic pneumonia mimics infectious pneumonitis and can be associated with GVHD.

Detection of Aspergillus galactomannan antigenemia to determine biological and clinical implications of beta-lactam treatments.

Detection of Aspergillus galactomannan (GM) in serum with the Platelia Aspergillus enzyme immunoassay (EIA) is useful for diagnosing invasive aspergillosis. From May 2003 to November 2004, 65 patients who did not develop aspergillosis had at least two positive sera while receiving a beta-lactam treatment (GM index [GMI], >or=0.5). Of the 69 treatment episodes scored, 41 consisted of a beta-lactam other than piperacillin-tazobactam (n=29), namely, amoxicillin-clavulanate (n=25), amoxicillin (n=10), ampicillin (n=3), or phenoxymethylpenicillin (n=2). In all cases, antigenemia became negative 24 h to 120 h upon stopping the antibiotic. Monitoring of 35 patients, including 26 with hematological malignancies, revealed three antigenemia kinetic patterns: each was observed with any drug regimen and consisted of a persistent GMI of >2.0 (65.7%), >0.5, and

Involvement of toll-like receptor 2 in experimental invasive pulmonary aspergillosis.

Aspergillus fumigatus, an opportunistic fungal pathogen, causes severe and usually fatal invasive pulmonary aspergillosis in immunocompromised hosts. Interestingly, Drosophila cells lacking the Toll protein are prone to A. fumigatus infection. In the current study, we looked for the involvement of Toll-like receptor 2 (TLR2) in the recognition of A. fumigatus by analyzing the in vivo and ex vivo responses of immunocompromised TLR2(-/-) and TLR2(+/+) mice to this fungus. Upon intratracheal administration of conidia, survival and tumor necrosis factor alpha (TNF-alpha), interleukin-12, and macrophage inhibitory protein-2 alpha concentrations in the airspaces of TLR2(-/-) mice were significantly lower than those of TLR2(+/+) animals. In vitro analysis of TNF-alpha production by conidia-challenged alveolar macrophages from TLR2(-/-) revealed a significant deficiency in comparison with macrophages from TLR2(+/+) mice. Infected TLR2(-/-) mice also have a higher respiratory distress and a higher pathogen burden than TLR2(+/+) mice. These data demonstrate that TLR2 plays a significant role in the defense of the host against A. fumigatus infection.

Catalases of Aspergillus fumigatus.

Upon infection of a host, the pathogenic fungus Aspergillus fumigatus is attacked by the reactive oxygen species produced by phagocytic cells. Detoxification of hydrogen peroxide by catalases was proposed as a way to overcome this host response. A. fumigatus produces three active catalases; one is produced by conidia, and two are produced by mycelia. The mycelial catalase Cat1p was studied previously. Here we characterized the two other catalases, their genes, and the phenotypes of gene-disrupted mutants. CatAp, a spore-specific monofunctional catalase, is resistant to heat, metal ions, and detergent. This enzyme is a dimeric protein with 84.5-kDa subunits. The 749-amino-acid polypeptide exhibits high levels of similarity to the Aspergillus nidulans CatA catalase and to bacterial catalase HPII of Escherichia coli. In spite of increased sensitivity to H(2)O(2), killing of DeltacatA conidia by alveolar macrophages and virulence in animals were similar to the killing of conidia by alveolar macrophages and virulence in animals observed for the wild type. In contrast to the Cat1p and CatAp catalases, the mycelial Cat2p enzyme is a bifunctional catalase-peroxidase and is sensitive to heat, metal ions, and detergent. This enzyme, an 82-kDa monomer, is homologous to catalase-peroxidases of several fungi and bacteria. Surprisingly, mycelium of the double Deltacat1Deltacat2 mutant with no catalase activity exhibited only slightly increased sensitivity to H(2)O(2) and was as sensitive to killing by polymorphonuclear neutrophils as mycelium of the wild-type strain. However, this mutant exhibited delayed infection in the rat model of aspergillosis compared to infection by the wild-type strain. These results indicate that conidial catalase is not a virulence factor and that mycelial catalases transiently protect the fungus from the host.

Conidial hydrophobins of Aspergillus fumigatus.

The surface of Aspergillus fumigatus conidia, the first structure recognized by the host immune system, is covered by rodlets. We report that this outer cell wall layer contains two hydrophobins, RodAp and RodBp, which are found as highly insoluble complexes. The RODA gene was previously characterized, and DeltarodA conidia do not display a rodlet layer (N. Thau, M. Monod, B. Crestani, C. Rolland, G. Tronchin, J. P. Latgé, and S. Paris, Infect. Immun. 62:4380-4388, 1994). The RODB gene was cloned and disrupted. RodBp was highly homologous to RodAp and different from DewAp of A. nidulans. DeltarodB conidia had a rodlet layer similar to that of the wild-type conidia. Therefore, unlike RodAp, RodBp is not required for rodlet formation. The surface of DeltarodA conidia is granular; in contrast, an amorphous layer is present at the surface of the conidia of the DeltarodA DeltarodB double mutant. These data show that RodBp plays a role in the structure of the conidial cell wall. Moreover, rodletless mutants are more sensitive to killing by alveolar macrophages, suggesting that RodAp or the rodlet structure is involved in the resistance to host cells.