Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

Effect of antifibrotic agents on postoperative complications after lung transplantation for idiopathic pulmonary fibrosis.

BACKGROUND: Antifibrotic agents (AFAs) are now standard-of-care for idiopathic pulmonary fibrosis (IPF). Concerns have arisen about the safety of these drugs in patients undergoing lung transplantation (LTx). METHODS: We performed a multi-centre, nationwide, retrospective, observational study of French IPF patients undergoing LTx between 2011 and 2018 to determine whether maintaining AFAs in the peri-operative period leads to increased bronchial anastomoses issues, delay in skin healing and haemorrhagic complications. We compared the incidence of post-operative complications and the survival of patients according to AFA exposure. RESULTS: Among 205 patients who underwent LTx for IPF during the study period, 58 (28%) had received AFAs within 4 weeks before LTx (AFA group): pirfenidone in 37 (18.0%) and nintedanib in 21 (10.2%). The median duration of AFA treatment before LTx was 13.8 (5.6-24) months. The AFA and control groups did not significantly differ in airway, bleeding or skin healing complications (p = 0.91, p = 0.12 and p = 0.70, respectively). Primary graft dysfunction was less frequent in the AFA than control group (26% vs. 43%, p = 0.02), and the 90-day mortality was lower (7% vs. 18%, p = 0.046). CONCLUSIONS: AFA therapy did not increase airway, bleeding or wound post-operative complications after LTx and could be associated with reduced rates of primary graft dysfunction and 90-day mortality.

Risk of Bronchial Complications After Lung Transplantation With Respiratory Corynebacteria. Results From a Monocenter Retrospective Cohort Study.

Corynebacterium spp. are associated with respiratory infections in immunocompromised hosts. A link with bronchial complications after lung transplantation (LTx) has been suggested. We aimed to assess the link between respiratory sampling of Corynebacterium spp. and significant bronchial complication (SBC) after LTx. We performed a single center retrospective study. Inclusion of LTx recipients with at least one respiratory Corynebacterium spp. sample (July 2014 to December 2018). Subjects were matched to unexposed LTx recipients. Primary outcome was SBC occurrence after Corynebacterium spp. isolation. Secondary outcomes were Corynebacterium spp. persistent sampling, chronic lung allograft dysfunction (CLAD) onset and all-cause mortality. Fifty-nine patients with Corynebacterium spp. sampling with 59 without isolation were included. Corynebacterium spp. identification was not associated with SBC occurrence (32.4% vs. 21.6%, p = 0.342). Previous SBC was associated with further isolation of Corynebacterium spp. (OR 3.94, 95% CI [1.72-9.05]). Previous SBC and corticosteroids pulses in the last 3 months were the only factors associated with increased risk of Corynebacterium spp. isolation in multivariate analysis. Corynebacterium spp. sampling was significantly associated with CLAD onset (27.1% vs. 6.9%, p = 0.021). Corynebacterium spp. isolation was not associated with SBC but with higher risk of CLAD. Whether CLAD evolution is affected by Corynebacterium spp. eradication remains to be investigated.

Low HDL-Cholesterol Concentrations in Lung Transplant Candidates are Strongly Associated With One-Year Mortality After Lung Transplantation.

High-density lipoproteins (HDLs), whose main role is the reverse transport of cholesterol, also have pleiotropic anti-inflammatory, antioxidant, anti-apoptotic and anti-infectious properties. During sepsis, HDL cholesterol (HDL-C) concentration is low, HDL particle functionality is altered, and these modifications are correlated with poor outcomes. Based on the protective effects of HDL, we hypothesized that HDL-C levels could be associated with lung transplantation (LT) outcome. We thus looked for an association between basal HDL-C concentration and one-year mortality after LT. In this single-center prospective study including consecutive LTs from 2015 to 2020, 215 patients were included, essentially pulmonary fibrosis (47%) and chronic obstructive pulmonary disease (COPD) (38%) patients. Mortality rate at one-year was 23%. Basal HDL-C concentration stratified nonsurvivors to survivors at one-year (HDL-C = 1.26 [1.12-1.62] mmol/L vs. HDL-C = 1.55 [1.22-1.97] mmol/L, p = 0.006). Multivariate analysis confirmed that HDL-C concentration during the pretransplant assessment period was the only variable inversely associated with mortality. Moreover, mortality at one-year in patients with HDL-C concentrations ≤1.45 mmol/L was significantly higher (log-rank test, p = 0.00085). In conclusion, low basal HDL-C concentrations in candidates for LT are strongly associated with mortality after LT. To better understand this association, further studies in this field are essential and, in particular, a better characterization of HDL particles seems necessary.

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.

Chronic pulmonary aspergillosis: prevalence, favouring pulmonary diseases and prognosis.

Chronic pulmonary aspergillosis (CPA) is an emerging disease in patients with common chronic pulmonary diseases (CPDs). While its prevalence is linked to tuberculosis (TB) in endemic countries, epidemiological and prognostic data are lacking in low TB incidence countries. The aim of this study was to describe these features in CPA patients hospitalised in France between 2009 and 2018.We estimated the prevalence and mortality of hospitalised CPA patients using the French nationwide administrative hospital database. We also assessed the association with CPD, thoracic interventions and malnutrition.From 2009 to 2018, 17 290 patients were hospitalised in France for CPA, with an increasing prevalence during this period. Most patients were male (63.5%) with a median age of 65 years at CPA diagnosis, living in farming regions and large cities. The proportion of underlying chronic obstructive pulmonary disease (COPD) and emphysema during the previous 5 years was 44% and 22%, respectively, whereas it was only 3% for both TB and non-TB mycobacterial (NTM) infections. The mortality rates during the first hospitalisation, at 1 year and at 5 years were 17%, 32% and 45%, respectively. In multivariate analysis, mortality rates were increased in patients aged >65 years, male patients and patients with malnutrition, diabetes or lung cancer history. The risk of mortality in patients with COPD or emphysema was higher than in those with previous mycobacterial lung infection.In France, CPA is an emerging infection commonly associated with non-mycobacterial CPD. This shift in the distribution profile of underlying CPD will likely worsen CPA mortality.

Management of patients with pulmonary mycobacteriosis in France: a multicenter retrospective cohort study.

BACKGROUND: Recent studies report very low adherence of practitioners to ATS/IDSA recommendations for the treatment of nontuberculous mycobacteria pulmonary disease (NTM-PD), as well as a great variability of practices. Type of management could impact prognosis. METHODS: To evaluate management and prognosis of patients with NTM-PD cases with respect to ATS recommendations, we conducted a multicenter retrospective cohort study (18 sentinel sites distributed throughout France), over a period of six years. We collected clinical, radiological, microbiological characteristics, management and outcome of the patients (especially death or not). RESULTS: 477 patients with NTM-PD were included. Respiratory comorbidities were found in 68% of cases, tuberculosis sequelae in 31.4% of patients, and immunosuppression in 16.8% of cases. The three most common NTM species were Mycobacterium avium complex (60%), M. xenopi (20%) and M. kansasii (5.7%). Smear-positive was found in one third of NTM-PD. Nodulobronchiectatic forms were observed in 54.3% of cases, and cavitary forms in 19.1% of patients. Sixty-three percent of patients were treated, 72.4% of patients with smear-positive samples, and 57.5% of patients with smear-negative samples. Treatment was in adequacy with ATS guidelines in 73.5%. The 2-year mortality was 14.4%. In the Cox regression, treatment (HR = 0.51), age (HR = 1.02), and M. abscessus (3.19) appeared as the 3 significant independent prognostic factors. CONCLUSION: These findings highlight the adequacy between French practices and the ATS/IDSA guidelines. Treatment was associated with a better survival.

A CPAnet consensus statement on research priorities for chronic pulmonary aspergillosis: a neglected fungal infection that requires attention.

Chronic pulmonary aspergillosis (CPA) is a severe fungal infection with a high morbidity and mortality, and is usually seen in immunocompetent patients with respiratory disorders. Clinical presentation is nonspecific and often overlaps with the symptoms and the radiological pattern caused by the underlying disease. Clinical management of CPA is further hampered by limited information about the epidemiology, disease dynamics, sensitivity and specificity of different mycological tests, mechanisms of antifungal resistance, efficient treatment and management strategies. In order to contribute to a better understanding and to improve CPA patient management and outcome, we established the Chronic Pulmonary Aspergillosis Network (CPAnet), a self-organized multinational research collaboration. Key research priorities, defined by using a modified Delphi process, include the establishment of a multinational web-based registry, the validation of different diagnostic tests, the establishment of a culture collection from samples of patients with proven CPA and the establishment of a consensus on a treatment outcome definition.

Treatment of Chronic Pulmonary Aspergillosis: Current Standards and Future Perspectives.

Chronic pulmonary aspergillosis (CPA) complicates conditions including tuberculosis, chronic obstructive pulmonary disease and sarcoidosis, and is associated with high morbidity and mortality. Surgical cure should be considered where feasible; however, many patients are unsuitable for surgery due to extensive disease or poor respiratory function. Azoles are the only oral drug with anti-Aspergillus activity and itraconazole and voriconazole are considered as first-line drugs. A randomized controlled trial demonstrated improvement or stability in three-quarters of patients given 6 months of itraconazole, but a quarter relapsed on stopping therapy. Long-term treatment may therefore be required in some cases. Itraconazole, voriconazole and posaconazole require therapeutic drug monitoring. No published data are yet available for isavuconazole. Adverse drug effects of azoles are common, including peripheral neuropathy, heart failure, elevated liver enzymes, QTc prolongation and sun sensitivity. Many serious drug-drug interactions occur, including major interactions with rifamycins, simvastatin, warfarin, clopidogrel, immunosuppressant drugs like sirolimus. Furthermore, drug resistance occurs, including cross-resistance to all azoles, but the true prevalence is not yet determined. Intravenous therapy is possible with echinocandins or amphotericin B, but long-term use is challenging. Hemoptysis complicates CPA and can be fatal. Tranexamic acid should be given acutely to reduce bleeding. Bronchial artery embolization can stop acute bleeds. In some circumstances, emergency surgery may be necessary to resect the source of the bleed. Current CPA treatments can be beneficial but have many drawbacks. New oral anti-Aspergillus agents are needed, along with optimization of currently available treatments.

Nebulized Liposomal Amphotericin B for Treatment of Pulmonary Infection Caused by Hormographiella aspergillata: Case Report and Literature Review.

Invasive fungal infection is a serious complication following allogeneic hematopoietic stem cell transplantation. Pulmonary infection due to Hormographiella aspergillata is an uncommon condition associated with a high mortality rate. The susceptibility of H. aspergillata to available antifungal agents is not well established. We report for the first time a case of H. aspergillata lung infection that responded poorly to conventional treatment with liposomal amphotericin B (LAmB; 3 mg kg-1 of body weight per day) with renal damage at higher posology (5 mg kg-1 of body weight per day), but improved rapidly after addition of nebulized LAmB to intravenous LAmB (3 mg kg-1 of body weight per day). Successful treatment of our patient using nebulized LAmB would be worth evaluating in cases refractory to standard treatment or when the reference treatment may not be extended due to interaction or side effects.

Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation.

RATIONALE: Systemic steroids are the standard treatment for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) despite their poor efficacy and disabling side effects. OBJECTIVES: To evaluate the effectiveness and tolerance of budesonide/formoterol as an alternative treatment for BOS after HSCT. METHODS: In this randomized, double-blind, placebo-controlled study, we randomly assigned 32 HSCT recipients with mild/severe BOS to receive budesonide/formoterol or placebo for 6 months. The primary outcome was the change in the FEV1 after 1 month of treatment (M1) compared with the baseline value. Patients were unblinded at M1 if there was no improvement in the FEV1. Those who had initially received placebo were switched to budesonide/formoterol. Intention-to-treat analysis was performed to assess the primary outcome. Additional analyses took scheduled treatment contamination into account. MEASUREMENTS AND MAIN RESULTS: At M1, the median FEV1 increased by 260 ml in the budesonide/formoterol arm compared with 5 ml in the placebo arm (P = 0.012). The median increases in the FEV1 at M1 relative to the baseline value for the treated and placebo groups were 13 and 0%, respectively (P = 0.019). Twenty-five patients received budesonide/formoterol during the study. The median difference in the FEV1 between the baseline and after 1 month of treatment for these patients was +240 ml (P = 0.0001). The effect of budesonide/formoterol on the FEV1 was maintained in the 13 patients who completed 6 months of treatment. CONCLUSIONS: Budesonide/formoterol administration led to a significant improvement in the FEV1 in patients with mild/severe BOS after allogeneic HSCT. Clinical trial registered with www.clinicaltrials.gov (NCT00624754).

Nebulised liposomal amphotericin B for Aspergillus lung diseases: case series and literature review.

Over the past 10 years the incidence of Aspergillus spp. has significantly increased, and it is now the most widespread air transmission fungal pathogen in developed countries. Whatever the clinical expression of the pulmonary disease and despite recent progress in antifungal drug therapy, morbidity and mortality related to aspergillosis lung disease still constitute a serious threat for immunosuppressed or mildly immunocompromised patients. Moreover, the treatments currently used have many limitations due to adverse effects and drug interactions. Finally, subjects exposed to azoles present an increased risk of Aspergillus-resistant strain emergence. We have reported five cases with aspergillosis lung diseases that were either difficult to control or in which patients had a contra-indication to triazole therapy, but which showed durable improvement following the administration of nebulised liposomal amphotericin B. Our alternative strategy could be of interest for patients with aspergillosis lung disease who otherwise cannot be conventionally treated by triazoles.

Pneumocystis jirovecii pneumonia in HIV-negative patients: a prospective study with focus on immunosuppressive drugs and markers of immune impairment.

Pneumocystis jirovecii pneumonia (PCP) is emerging in HIV-negative patients, for whom the prognosis is significantly worse than in HIV-infected patients and risk factors are poorly characterized. We performed an observational, multi-centre, prospective study of 56 consecutive cases of documented PCP in HIV-negative patients, and found that: (1) the main underlying conditions were haematological malignancies (43%), solid tumours (25%), inflammatory diseases (20%), and solid organ transplantation (7%); (2) most patients (80%) had received prolonged corticosteroids, with a mean daily dose of 47.3 ± 32.8 mg equivalent prednisone when PCP was diagnosed, and a mean cumulative dose of 5807 ± 5048 mg over the last 12 months; and (3) the median CD4 cell count was 0.12 × 109/l (range 0.0-1.42), with a median CD4/CD8 ratio of 1.32 (0.0-6.4). These findings may be used to better target PCP prophylaxis according to the level of risk and contribute to decrease the burden of PCP in HIV-negative patients.

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.