TY - JOUR
AU - Aliberti,, Stefano
AB - Abstract Bronchiectasis is a chronic airway infection syndrome, distinct from cystic fibrosis that is rising in prevalence and is associated with significant morbidity and mortality. It can be caused by many etiologies including post-infectious effects or be seen in common lung diseases such as chronic obstructive pulmonary disease (COPD) or severe asthma. Bronchiectasis is associated with many Aspergillus-associated syndromes: allergic bronchopulmonary aspergillosis (ABPA) may complicate asthma, thus leading to bronchiectasis as part of the diagnostic criteria of ABPA or can complicate preexisting bronchiectasis due to another etiology. Aspergilloma can develop in areas of lung damage seen in patients with bronchiectasis, whereas fungal bronchitis may lead to later bronchiectasis. Invasive aspergillosis, perhaps more commonly viewed as a consequence of significant immunosuppression, is also seen in the absence of immunosuppression in those with underlying lung diseases including bronchiectasis. The pathogenesis and treatments of these diverse Aspergillus-associated diseases in bronchiectasis are discussed. bronchiectasis, aspergillus, invasive aspergillosis, COPD, Asthma Introduction Bronchiectasis is a chronic airways sepsis syndrome usually defined in the presence of permanent airway dilatation (often demonstrated on high-resolution CT scanning) and recurrent airway symptoms of daily sputum production and episodic infective exacerbations.1,2 Bronchiectasis is therefore a descriptive term and does not represent a single primary diagnosis or etiology. Aspergillus diseases can be associated with the development of bronchiectasis such as that seen in allergic bronchopulmonary aspergillosis (ABPA), whereas other Aspergillus-related diseases can complicate patients with already established bronchiectasis and lung architectural disruption, for example, an aspergilloma in a patient with post-tuberculosis bronchiectasis. Furthermore, other primary diseases such as chronic obstructive pulmonary disease (COPD) can increase the risk of Aspergillus-related disease but also independently can be associated with bronchiectasis. Background and etiology of bronchiectasis While cystic fibrosis (CF) lung disease is characterized by bronchiectasis, this article will focus on bronchiectasis due to other causes and will not discuss Aspergillus-related diseases in cystic fibrosis. Recently, there has been a move in the nomenclature to use bronchiectasis, a syndrome defined in its own right, rather than using the term ‘noncystic fibrosis’ bronchiectasis.3 The etiology of bronchiectasis varies between countries with common defined etiologies being post-infectious (commonly post-pneumonic or post- tuberculous) (Table 1).2,4,5 Despite extensive etiological work, up to 40–50% of cases still have an idiopathic origin.2,3,–8 Bronchiectasis is also commonly seen after acute severe lung infections especially post-pneumonic or post-tuberculous bronchiectasis. It is likely that some of the post-infectious and idiopathic groups have certain subtle immunodeficiencies yet to be identified. The relevance of these to future risk of fungal disease is unclear. Bronchiectasis is seen as comorbidity in patients with more common respiratory diseases most notably in those with more severe asthma and chronic obstructive pulmonary disease (COPD).5,9,–11 The bronchiectasis COPD overlap syndrome (BCOS) is noteworthy given it is both common and was reported as one of the commonest associations by Quint et al.9 It is also noteworthy as there is a particularly poor mortality reaching twofold increase in mortality in BCOS as compared to other forms of bronchiectasis.9,10,12 In BCOS, it is unknown if bronchiectasis is a complication of COPD or the conditions arise merely be co-association. However, it is clear that rates of up to 40% bronchiectasis seen in more severe COPD patients.10 Given that COPD is an expected top three global cause of death, this association, however, suggests that BCOS patients will be an important etiological grouping in the future. Bronchiectasis has been described as a complication of rheumatoid arthritis and this has particular relevance to Aspergillus disease when significant immunosuppression used to control the arthritis may increase the risk of more invasive fungal diseases. Bronchiectasis is also recognized as a form of chronic allograft rejection/dysfunction after lung transplantation. The bronchiectasis seen in lung transplant chronic allograft rejection, can be accelerated by Aspergillus colonization.13 There is an undoubted a rise in overall prevalence of bronchiectasis, and in an aging population this aging related condition is anticipated to increase in importance due to mortality and healthcare costs.9,14,–17 Clinical features of bronchiectasis Common clinical symptoms of bronchiectasis include cough productive of sputum, fatigue, hemoptysis, and episodic infective exacerbations.1 Other important symptoms such as wheeze, chest pain, and sinusitis are common in bronchiectasis. These are diagnostically challenging as they could arise due to the bronchiectasis, the etiology leading to bronchiectasis, for example, asthma or Aspergillus-associated comorbidities (e.g., Aspergillus-associated sinusitis). Bronchiectasis can be a progressive disease that leads to hospitalizations, premature mortality, and leads to poorer quality of life.2 As a result bronchiectasis is also associated with increased healthcare utilization and cost.14,15,18 Recent data suggest an increasing mortality rate rising 3% year after year with increased mortality especially seen in the elderly.19 Major factors associated with bronchiectasis disease progression include recurrent exacerbations, extremes of age, and persistent infection with pathogens particularly Pseudomonas aeruginosa.11,12,20,–22 The presence of P. aeruginosa in bronchiectasis patients clearly defines a specific clinical phenotype and leads to worse clinical outcomes including not only exacerbations but also quality of life and mortality.11,23,24 Recurrent exacerbations irrespective of Pseudomonas appear to drive progression.22 Because up to 40% of bronchiectasis patients suffer from two or more exacerbations per year, a large proportion of patients are therefore at risk of disease progression.11,20 Recently, stratification by a number of demographic and clinical features has defined bronchiectasis as mild, moderate, or severe.20 Notably in the bronchiectasis severity index (BSI), persistent Pseudomonas infection (and to a lesser degree persistent infection with other pathogens) was associated with a poorer outcome including premature mortality and risk of death.20 A recent seven-center study of over 1,200 bronchiectasis patients with no known cystic fibrosis has shown ABPA to be more common in the higher BSI severity groups, although this was reported as a trend after failing to reaching statistical significance (ABPA rates ranging from 3.3% in low BSI to 5.6% in, high severity BSI, P = .313).5 Bronchiectasis prevalence It had been widely believed that the prevalence of bronchiectasis would fall with the advent of childhood immunizations (particularly against pertussis and measles), better access to antibiotics (reducing the rates/severity of pneumonia), and a decline in rates of tuberculosis. In contrast to these projections the available data on the prevalence of bronchiectasis has consistently shown an increase although the exact incidence remains unclear.25 There are now recent data from developed nations in Europe, the United States, and Asia Pacific.8,9,14,15,18,19 These have consistently shown bronchiectasis is increasing in prevalence with the greatest rates seen in the elderly. The rates in China reached as high as 135 per 10,000, while in 18–34 year-olds in the United States they were 4.2 per 100,000.8,15 In one of the largest series using healthcare codes from primary care records in the United Kingdom, Quint et al. reported rates in excess of 1/1,000 in those 70 years or older.9 The pathophysiology of bronchiectasis Aspergillus may drive the progression of bronchiectasis or lead to bronchiectasis directly. In addition to Aspergillus-complicating bronchiectasis linked to common conditions such as asthma and COPD there are case reports of it complicating congenital forms of bronchiectasis including Kartageners and Swyer-McLeod syndromes. Collectively, these suggest Aspergillus can complicate the course of bronchiectasis of any etiology. Hence two models for the overlap between bronchiectasis and Aspergillus arise (Fig. 1). Figure 1. Open in new tabDownload slide Possible routes to Aspergillus disease in bronchiectasis. Model 1 assumes Aspergillus exposure in normal lungs leads to secondary damage and the subsequent development of bronchiectasis, while model 2 portrays mechanisms that arise within a patient with pre-existing bronchiectasis. This Figure is reproduced in color in the online version of Medical Mycology. Figure 1. Open in new tabDownload slide Possible routes to Aspergillus disease in bronchiectasis. Model 1 assumes Aspergillus exposure in normal lungs leads to secondary damage and the subsequent development of bronchiectasis, while model 2 portrays mechanisms that arise within a patient with pre-existing bronchiectasis. This Figure is reproduced in color in the online version of Medical Mycology. The pathophysiology of bronchiectasis is widely viewed as following a vicious cycle model as proposed by Cole (Fig. 1).26,27 Three main components are noteworthy with relevance to Aspergillus diseases.28 Impairment of mucociliary clearance can either facilitate persistent infection with bacteria, fungi, and may also increase the risk of viral infections. Hence abnormalities in mucociliary clearance will facilitate Aspergillus infections such as fungal bronchitis or allow persistence of Aspergillus-associated antigens that are directly injurious to airways; for example, Aspergillus proteases might drive mucus abnormalities via MUC5AC, resulting in mucus retention bronchiectasis progression.29 Similarly impaired clearance of Aspergillus antigens may promote an allergic response through prolonged engagement with TH2 skewed immune cells thereby facilitating ABPA.30 The significant neutrophilic component to bronchiectasis particularly high elastase levels may impair host defence and prevent effective opsonophaocytosis or other methods of bacterial clearance. These mechanisms may play a role in Aspergillus disease but remain poorly described in the setting of bronchiectasis.28 Lastly, structural aspects of established bronchiectasis can contribute to Aspergillus disease. Cystic bronchiectasis or conditions leading to bronchiectasis that also destroy normal terminal bronchial/alveolar structure, for example, tuberculosis, can clearly facilitate aspergilloma development through parenchymal destruction and cavity formation. Second, Aspergillus infections may directly damage the airways especially fungal bronchitis or the bronchiectasis seen in ABPA may both lead to Aspergillus-driven bronchiectasis. Given the ubiquity of Aspergillus, it is likely this only Aspergillus-derived bronchiectasis only occurs in susceptible individuals. Aspects of the excessive inflammatory and tissue damaging aspects seen in bronchiectasis include the high levels of neutrophils and matrix metalloproteinases have also been described as part of the ABPA inflammatory phenotype suggesting overlapping pathophysiology (Fig. 1).28,31 As above, the retention of Aspergillus allergens in already established bronchiectatic airways may help drive ABPA. However, it is also possible that Aspergillus proteases in normal (or asthmatic/COPD) airways in susceptible individuals drive airway inflammation toward frank bronchiectasis through upregulating mucus production and/or driving a Th2 phenotype (see model 1 in Fig. 1).29,32 It is also notable that some patients with bronchiectasis have an eosinophil rich phenotype suggesting TH2 skewing is entirely possible.33 Recent data support there is a hypoxic environment within the lower airway mucus as suggested by the oral anerobes identified in bronchiectasis sputa.34,35 This hypoxia is noteworthy given that recent experimental data suggests that human dendritic cells are less effective at mounting Aspergillus response in hypoxia.36 Standard care in bronchiectasis There are few high-quality clinical trials in bronchiectasis, and much of the therapy is empiric as recently concluded by a Cochrane overview.2,25,37 There are however significant spends on unproven therapies without a good evidence base.14 For example, UK national audits have demonstrated that inhaled corticosteroids (80%), 30% received long-term antibiotics, and nebulized antibiotics were used in 10%; however, the use of long-term antifungals reported was not reported.38 The effect of these empiric therapies on the lung microbiome and the susceptibility to fungal infections is unknown.34,35 Recently, a European registry of adult patients with bronchiectasis (European Multicentre Bronchiectasis Audit and Research Collaboration, EMBARC, www.bronciectasis.eu) has been launched.39 In an exploratory analysis of the EMBARC data set of 2,031 patients in this cross European registry revealed a rate of reported ABPA of 4%.40 In the 81 patients recorded as having ABPA, 79 were receiving inhaled corticosteroids, 27 were receiving current treatment (for presumed active ABPA), and 27 received oral corticosteroids with 9 receiving itraconazole (∼10% of those with a diagnosis of ABPA). No other ‘conazole drugs were reported (J Chalmers, Dundee University/EMBARC, personal communication). The available bronchiectasis treatment guidelines are predominantly based upon expert opinion or extrapolation from other diseases areas such as cystic fibrosis.2,25 This latter approach is best avoided given licenced therapies with proven efficacy in cystic fibrosis such as mannitol (inhaled mucoactive drug) or aztreonam have not achieved the primary outcomes when trialled in bronchiectasis.41,42 Beyond medical management surgical resection of affected bronchiectasis lung tissue is infrequently used. It is limited to highly selected cases with severe symptoms uncontrolled by medical therapy but with localized disease.2 Lung transplantation is used in highly selected cases and in this setting Aspergillus infection is a complication to post-transplant recovery especially if there is extensive pleural disease preventing lung explants being removed intact (J Dark, Freeman Hospital Lung transplant program, Newcastle, UK personal communication). The available bronchiectasis management guidelines suggest a variety of strategies to managing the bronchiectasis by targeting components of the vicious cycle.2 These include nonpharmacological and pharmacological approaches, which are frequently combined.25,38 For example, with chest physiotherapy and nebulise hypertonic saline may be combined to aid chest clearance. Targeting the infective element of the ‘vicious cycle’ is usually through either more aggressive and prolonged antibiotic therapy in the event of exacerbations.43 For example, the BTS guidelines recommend 2 weeks minimum duration of antibiotics.2 Another strategy is long-term nebulized antimicrobial therapy, for example, colistin or gentamicin with the aim of suppressing bacterial load and thereby aim to deliver a consequent reduction in inflammatory load.43,–45 This strategy may protect against both inflammation induced tissue destruction and minimizes the risk of exacerbations. Consequently, if the number of exacerbations is reduced, a concurrent improvement in symptoms could be anticipated.7,46 Inhaled therapies directly targeting the site of infection may enable high drug doses to be delivered often beyond that which can be attained with systemic therapy.47 The effect of these long-term targeted therapies on the risk of fungal overgrowth and/or sensitisation have previously raised concerns in cystic fibrosis (D. Bilton, Royal Brompton Hospital, personal communication), but significant problems with fungal ‘overgrowth’ have not been reported in bronchiectasis. This is important as several new therapies targeting the airway have recently reported or are undergoing assessment phase 3 assessment.42,45,48,49 Recently, Aspergillus load measured by quantitative PCR has been shown to fall after IV antibiotics for cystic fibrosis.50 This may suggest an as yet undescribed bacterial-fungal synergy. Additional strategies include the use of long-term systemic macrolides which reduce exacerbations in bronchiectasis.51,–53 Undoubtedly they are associated with an increase in macrolide resistance. The effect of such therapy on long-term fungal infection or sensitization is unknown, but there are clear data that they alter the bacterial microbiome and may increase susceptibility to Pseudomonas.54 While there is considerable evidence for an inflammatory component to bronchiectasis, there are no significant data demonstrating a primarily anti-inflammatory therapy improves outcomes in bronchiectasis.2,28,37,43 A summary of the work in this area would be that there is an absence of evidence (i.e., lack of high quality adequately powered trials) rather than evidence of absence of effect. Small-scale trials at phase 2 do exist suggesting that these targets may be useful.55,56 Anti-inflammatory therapies that remain unclear in their role include oral steroids and inhaled steroids.37 There are no trials of anti-IgE therapy in bronchiectasis with associated allergic fungal sensitisation. The microbiology of bronchiectasis Bronchiectasis is associated with lower airway bacterial infection based on studies of sputum or bronchoalveolar lavage. Common pathogens isolated from spontaneously expectorated sputa in bronchiectasis include those seen in other respiratory disorders such as COPD, pneumonia, and also cystic fibrosis. These include Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella spp. ( Table 2). Pseudomonas is also key pathogen.24,57 It is unclear if spontaneously expectorated sputa in bronchiectasis is sufficiently robust to detect fungal diseases; some data suggest a better yield with physiotherapy and sputum induction regimens.58 Table 1. Rates of bronchiectasis by etiology across several European centers.5 . Dundee . Newcastle . Leuven . Galway . Monza . Athens . Barcelona . . (UK) . (UK) . (Belgium) . (Ireland) . (Italy) . (Greece) . (Spain) . . 286 pts . 110 pts . 253 pts . 208 pts . 205 pts . 113 pts . 83 pts . Post-infective 18% 5% 19% 20% 25% 43% 15% COPD 2% 12% 16% 13% 15% 5% 7% CTD 9% 10% 13% 21% 2% 6% % Immunodeficiency 6% 8% 7% 6% 4% 5% 5% Asthma 0 7% 0 10% 2% 2% 7% ABPA 11% 1% 6% 2% 2% 0 1% Ciliary dysfunction 0.3% 1% 3% 3% 0.5% 2% 2% IBD 2% 2% 2% 2% 3% 0 0 Aspiration/GORD 0 0 0 4% 0 0 0 Other 0.7% 1% 2% 2% 0.5% 0.9% 1% Idiopathic 51% 54% 31% 18% 44% 37% 58% . Dundee . Newcastle . Leuven . Galway . Monza . Athens . Barcelona . . (UK) . (UK) . (Belgium) . (Ireland) . (Italy) . (Greece) . (Spain) . . 286 pts . 110 pts . 253 pts . 208 pts . 205 pts . 113 pts . 83 pts . Post-infective 18% 5% 19% 20% 25% 43% 15% COPD 2% 12% 16% 13% 15% 5% 7% CTD 9% 10% 13% 21% 2% 6% % Immunodeficiency 6% 8% 7% 6% 4% 5% 5% Asthma 0 7% 0 10% 2% 2% 7% ABPA 11% 1% 6% 2% 2% 0 1% Ciliary dysfunction 0.3% 1% 3% 3% 0.5% 2% 2% IBD 2% 2% 2% 2% 3% 0 0 Aspiration/GORD 0 0 0 4% 0 0 0 Other 0.7% 1% 2% 2% 0.5% 0.9% 1% Idiopathic 51% 54% 31% 18% 44% 37% 58% Key, COPD: Chronic Obstructive pulmonary disease, CTD: connective tissue diseases including rheumatoid arthritis, ABPA: allergic bronchopulmonary aspergillosis, IBD: inflammatory bowel disease, GORD: gastro-oesophageal reflux disease. Open in new tab Table 1. Rates of bronchiectasis by etiology across several European centers.5 . Dundee . Newcastle . Leuven . Galway . Monza . Athens . Barcelona . . (UK) . (UK) . (Belgium) . (Ireland) . (Italy) . (Greece) . (Spain) . . 286 pts . 110 pts . 253 pts . 208 pts . 205 pts . 113 pts . 83 pts . Post-infective 18% 5% 19% 20% 25% 43% 15% COPD 2% 12% 16% 13% 15% 5% 7% CTD 9% 10% 13% 21% 2% 6% % Immunodeficiency 6% 8% 7% 6% 4% 5% 5% Asthma 0 7% 0 10% 2% 2% 7% ABPA 11% 1% 6% 2% 2% 0 1% Ciliary dysfunction 0.3% 1% 3% 3% 0.5% 2% 2% IBD 2% 2% 2% 2% 3% 0 0 Aspiration/GORD 0 0 0 4% 0 0 0 Other 0.7% 1% 2% 2% 0.5% 0.9% 1% Idiopathic 51% 54% 31% 18% 44% 37% 58% . Dundee . Newcastle . Leuven . Galway . Monza . Athens . Barcelona . . (UK) . (UK) . (Belgium) . (Ireland) . (Italy) . (Greece) . (Spain) . . 286 pts . 110 pts . 253 pts . 208 pts . 205 pts . 113 pts . 83 pts . Post-infective 18% 5% 19% 20% 25% 43% 15% COPD 2% 12% 16% 13% 15% 5% 7% CTD 9% 10% 13% 21% 2% 6% % Immunodeficiency 6% 8% 7% 6% 4% 5% 5% Asthma 0 7% 0 10% 2% 2% 7% ABPA 11% 1% 6% 2% 2% 0 1% Ciliary dysfunction 0.3% 1% 3% 3% 0.5% 2% 2% IBD 2% 2% 2% 2% 3% 0 0 Aspiration/GORD 0 0 0 4% 0 0 0 Other 0.7% 1% 2% 2% 0.5% 0.9% 1% Idiopathic 51% 54% 31% 18% 44% 37% 58% Key, COPD: Chronic Obstructive pulmonary disease, CTD: connective tissue diseases including rheumatoid arthritis, ABPA: allergic bronchopulmonary aspergillosis, IBD: inflammatory bowel disease, GORD: gastro-oesophageal reflux disease. Open in new tab Table 2. Bacterial pathogens isolated in bronchiectasis. Key, Bacterial pathogens isolated in bronchiectasis by %. Note Nicotra et al., Ho et al., and Pasteur et al. were cross sectional studies, while McDonnell et al. was a longitudinal study. * Notes not reported. This may explain why the Pseudomonas infection rates were higher in this latter study. Similarly, longitudinal studies defining Aspergillus culture rates are needed in bronchiectasis. . Nicotra et al. 1995 . Ho et al. chest 1998 . Pasteur et al. ARJCCM 2000 . McDonnell et al. Resp med 2015 . . n = 123 . n = 100 . n = 150 . n = 155 . S. aureus 6% 5% 10% 22% S. pnuemoniae 9% 6% 9% 34% H. influenza 24% 10% 23% 53% M. catarrhalis 2% 2% 13% 30% P. aeruginosa 45% 33% 21% 47% Other Gram neg. bacilli 13 5 11 * . Nicotra et al. 1995 . Ho et al. chest 1998 . Pasteur et al. ARJCCM 2000 . McDonnell et al. Resp med 2015 . . n = 123 . n = 100 . n = 150 . n = 155 . S. aureus 6% 5% 10% 22% S. pnuemoniae 9% 6% 9% 34% H. influenza 24% 10% 23% 53% M. catarrhalis 2% 2% 13% 30% P. aeruginosa 45% 33% 21% 47% Other Gram neg. bacilli 13 5 11 * Open in new tab Table 2. Bacterial pathogens isolated in bronchiectasis. Key, Bacterial pathogens isolated in bronchiectasis by %. Note Nicotra et al., Ho et al., and Pasteur et al. were cross sectional studies, while McDonnell et al. was a longitudinal study. * Notes not reported. This may explain why the Pseudomonas infection rates were higher in this latter study. Similarly, longitudinal studies defining Aspergillus culture rates are needed in bronchiectasis. . Nicotra et al. 1995 . Ho et al. chest 1998 . Pasteur et al. ARJCCM 2000 . McDonnell et al. Resp med 2015 . . n = 123 . n = 100 . n = 150 . n = 155 . S. aureus 6% 5% 10% 22% S. pnuemoniae 9% 6% 9% 34% H. influenza 24% 10% 23% 53% M. catarrhalis 2% 2% 13% 30% P. aeruginosa 45% 33% 21% 47% Other Gram neg. bacilli 13 5 11 * . Nicotra et al. 1995 . Ho et al. chest 1998 . Pasteur et al. ARJCCM 2000 . McDonnell et al. Resp med 2015 . . n = 123 . n = 100 . n = 150 . n = 155 . S. aureus 6% 5% 10% 22% S. pnuemoniae 9% 6% 9% 34% H. influenza 24% 10% 23% 53% M. catarrhalis 2% 2% 13% 30% P. aeruginosa 45% 33% 21% 47% Other Gram neg. bacilli 13 5 11 * Open in new tab Cross-sectional studies have often focused on bacterial pathogens with limited or no description of mycology studies.59 One aspect of the bacterial prevalence studies using culture is that the majority are cross-sectional, and few longitudinal studies are available. When such studies are conducted, they show a variation over time in bacteria isolated from a single patient; one therefore may presume that Aspergillus may be isolated on an intermittent basis.11 Current bronchiectasis guidelines do not include specific instructions on how frequently and which methodology should be used to conduct sputum mycology nor suggest specific therapy in the event of positive mycology cultures.2 Bronchiectasis has been recognised to be a polymicrobial state using techniques such as 16S RNA.34,35,60,61 The diversity of the bacterial microbiome is at least 10-fold greater than detected by standard culture in our experience even when specifically looking for bacterial pathogens; up to 100 species have been identified.11,34 The diversity of the microbiota appears to fall with more severe disease.61 No significant data have yet emerged detailing the fungal microbiome (mycobiome) in bronchiectasis. Our own (unpublished) experience is that 23S based techniques coupled with standard sputa DNA extraction protocols offers a poor yield, and other strategies perhaps focusing on the Internal Transcribed Spacer (ITS) regions on the fungal genomes may be more appropriate (W. Cookson, Imperial College, London, personal communication). Specific treatment of the sputa appears to increase DNA based yields in cystic fibrosis and perhaps these techniques need applied in bronchiectasis.50 There are even fewer data on the effect of antibiotic therapy targeting bronchiectasis bacterial pathogens on the airway resident microbiome and the mycobiome. Notably, however, there may be a bacterial-fungal interaction that promotes mutual growth. Perhaps in contrast to a prevailing hypothesis that antibiotics disrupt the microbiome and universally enhance the potential for fungal overgrowth as can be seen in post-antibiotic candidiasis. Still, this is an evolving field and as has been recently highlighted by the EMBARC Roadmap on research priorities in bronchiectasis, a comprehensive study enrolling patients when stable and during exacerbation should be conducted, evaluating not only the impact of bacteria and viruses but also fungi to identify the cause(s) of bronchiectasis exacerbations.62 Aspergillus and other mycoses seen in bronchiectasis Reviewing the available literature, a variety of syndromes is seen in patients with bronchiectasis; these may either cause bronchiectasis or complicate already established bronchiectasis (Table 3).63,64 There are few robust data that have systematically assessed which fungal syndromes are seen in patients with bronchiectasis, and those available are from the developed world. The impact of Aspergillus syndromes is also poorly described in health economic and morbidity levels. In contrast to persistent infection with Pseudomonas where there are large data sets showing clear associations with increased morbidity and mortality there few significant studies define Aspergillus syndromes in bronchiectasis.23,24 The lack of data on Aspergillus in bronchiectasis contrasts to data in cystic fibrosis where Aspergillus does appear to drive disease progression.65 One recent study in Aspergillus does suggest a trend toward higher rates of ABPA in more severe bronchiectasis.5 In part, the paucity of data reflects the relative novelty of the bronchiectasis indices.66 Additionally, the lack of data reflects poor funding in bronchiectasis plus the complexities required to make a diagnosis, the lack of systematic screening for Aspergillus-associated diseases and limitations in diagnostics. There are concerns over the best culture method to detect Aspergillus in sputa the best sample (spontaneous or induced) and the role of DNA-based techniques such as PCR.58,67 Table 3. Aspergillus syndromes and their links with bronchiectasis. Key, Recognized Aspergillus syndromes and their links with bronchiectasis are annotated as Y: yes recognised association; N: no significant literature; ? may be linked but not recognized in our experience. . Causes . Complicates established . Syndrome . Bronchiectasis . bronchiectasis . Allergic bronchopulmonary aspergillosis Y Y Fungal bronchitis Y Y CPA chronic pulmonary aspergillosis Y Y Chronic cavitatory aspergillosis Y ? Chronic necrotizing aspergillosis ? ? Invasive aspergillosis N (?) Y Aspergilloma N Y . Causes . Complicates established . Syndrome . Bronchiectasis . bronchiectasis . Allergic bronchopulmonary aspergillosis Y Y Fungal bronchitis Y Y CPA chronic pulmonary aspergillosis Y Y Chronic cavitatory aspergillosis Y ? Chronic necrotizing aspergillosis ? ? Invasive aspergillosis N (?) Y Aspergilloma N Y Open in new tab Table 3. Aspergillus syndromes and their links with bronchiectasis. Key, Recognized Aspergillus syndromes and their links with bronchiectasis are annotated as Y: yes recognised association; N: no significant literature; ? may be linked but not recognized in our experience. . Causes . Complicates established . Syndrome . Bronchiectasis . bronchiectasis . Allergic bronchopulmonary aspergillosis Y Y Fungal bronchitis Y Y CPA chronic pulmonary aspergillosis Y Y Chronic cavitatory aspergillosis Y ? Chronic necrotizing aspergillosis ? ? Invasive aspergillosis N (?) Y Aspergilloma N Y . Causes . Complicates established . Syndrome . Bronchiectasis . bronchiectasis . Allergic bronchopulmonary aspergillosis Y Y Fungal bronchitis Y Y CPA chronic pulmonary aspergillosis Y Y Chronic cavitatory aspergillosis Y ? Chronic necrotizing aspergillosis ? ? Invasive aspergillosis N (?) Y Aspergilloma N Y Open in new tab These rates of Aspergillus infection in bronchiectasis are likely to vary widely by country and also by bronchiectasis etiology. For example, etiologies of bronchiectasis relevant to increased risk of fungal diseases include immunodeficiency states, for example, where T cell or humoral immune responses increase susceptibility to invasive or fungal diseases; this can be seen in congenital immunodeficiency (e.g., Stat3 mutations/ Hyper IgE syndrome, and Chronic Granulomatous disease) as well as acquired immunodeficiency in patients with established bronchiectasis, for example, peri-transplant immunosuppression especially in bone marrow transplant recipients and in chemotherapy patients. A recent multicenter study from Spain in 252 patients with bronchiectasis showed that those with persistent cultures for Aspergillus were more likely to have been hospitalized for respiratory tract infections have lower levels of lung function and greater sputum volume.68 Causality could not be attributed given the study design but the evidence, at the very least, suggests that Aspergillus infection is associated with a more severe bronchiectasis phenotype. One aspect that complicates the literature is the use of ‘severity.’ Currently bronchiectasis clinicians will use indices such as the BSI, which uses a multicomponent system, to define a subgroup of patients who are at greatest risk of hospitalization or morbidity.20 In contrast, radiological burden of bronchiectasis can be classed as ‘severe.’ This leads to confusion: distinction of severe radiological bronchiectasis associated with ABPA is problematic as it is used to define disease as well as more severe forms of ABPA. We suggest using severity to define clinical course is more practical. Most of the data available relates to Aspergillus fumigatus; this may reflect particular virulence factors this organism has that preferentially supports its targeting of the airways.69 Readers are directed to a review of Aspergillus virulence.70 The greatest proportion of the available literature relates to ABPA perhaps reflecting that this is the most prevalent condition identified. Allergic bronchopulmonary aspergillosis (ABPA) It is also important to note that other fungi can induce a disease process similar to ABPA, often referred to allergic bronchopulmonary mycosis (ABPM).71,72 A recent review of ABPM has suggested that the overlap between ABPM and a history of prior asthma is less close than that seen in ABPA and asthma.73 Characterizing rates of ABPA in bronchiectasis clinics is complex—in part as bronchiectasis is one of the diagnostic criteria for ABPA.63 Furthermore, there are significant variations in which diagnostic criteria are being applied and the serological testing used (and thresholds) vary widely in our experience.74,–78 There is likely to be a significant variation based on geography and to date many of the publications in bronchiectasis are from tertiary care centres often from Westernized centers and without a true population-based analysis. Furthermore, as there are variations in the prevailing etiology for bronchiectasis centers with higher rates of post-tuberculosis bronchiectasis would plausibly experience differing rates of Aspergilloma compared to those centers where idiopathic bronchiectasis is more common.5,8,11 The few data on how many patients with bronchiectasis are sensitized to Aspergillus or have seropositive ABPA; early data from the EMBARC registry of 2,000 patients, however, suggests a range across Europe ranging from 0% in Athens to 11% in Dundee (Fig. 1).5 These rates and presentation of ABPA as described appear very different to that seen in India.79 From the available data it appears that ABPA in the presence of significant bronchiectasis is associated with poorer lung function, a higher risk of exacerbations, greater rates of seropositivity (both IgE and IgG) and increased sputum eosinophilia.74,80,81 It remains unclear if these reflect causality (Aspergillus driving bronchiectasis disease severity) or co-association (Aspergillus syndromes more commonly encountered in severe bronchiectasis). The higher rates of seropositivity suggest an active role in disease progression but arguably might reflect case-ascertainment bias where sicker patients have additional testing for drivers of bronchiectasis severity. ABPA-associated bronchiectasis appears a relatively uncommon etiological cause of bronchiectasis although the limitations of current diagnostics may mean there is a significant rate of missed diagnoses (discussed below).5 Current bronchiectasis guidelines recommend specific testing for Aspergillus sensitization in the belief that recognising this may prompt alternative strategies for managing respiratory symptoms—in particular, higher doses of corticosteroids.2 Despite this a national audit of bronchiectasis care in the United Kingdom demonstrated only ∼60% of patients had been tested for evidence of Aspergillus sensitization, and this percentage goes down to 17% in countries in Southern Europe.38,82 It is unlikely that the previously reported studies in the field had robust definitions of ABPA that match the recently proposed criteria.30 Central bronchiectasis was previously felt to be characteristic of ABPA, but there is now a recognition that there are other causes of central bronchiectasis and that patients with other features of ABPA may only have peripheral bronchiectasis.74,75,83 Importantly, ABPA or ABPM appears to be associated with increased rates of other important pathogens infecting the airways with high rates of nontuberculous mycobacteria (NTM) reported in two single center series similar to that reported in cystic fibrosis.64,72,84 Recent multicenter data from the European Cystic Fibrosis registry noted nontuberculous mycobacterial infection, and ABPA were more commonly associated than by chance. It is unclear if this is co-association due to underlying defects in CF that are applicable to bronchiectasis or unique to CF.85 Treatment of patients with bronchiectasis and ABPA The aims of treatment of ABPA are to control symptoms, prevent and treat exacerbations, reduce inflammation, and prevent further progression of bronchiectasis. The mainstay of ABPA in the setting of frank bronchiectasis remains an anti-inflammatory strategy with corticosteroids, with or without the addition of antifungal agents.2,63 There are data suggesting early detection of Aspergillus sensitization, so called ABPA-S, may minimize the development or progression bronchiectasis, if recognized and treated early, the central bronchiectasis may be preventable.76 The initial treatment for ABPA once diagnosed is usually with corticosteroids with the aim to reduce the inflammatory response. Approaches suggested in bronchiectasis guidelines have included either oral or higher dose inhaled corticosteroids.2 No clear consensus lies in when and how to start treatment although pragmatically those with more severe symptoms or underlying bronchiectasis are often started on oral steroids. There are no large-scale trials confirming that inhaled steroids prevent the progression of lung fibrosis. Given that infective exacerbations of bronchiectasis are associated with mucus plugging, cough, and wheeze in the absence of ABPA, it may be challenging to discern if the primary driver of a ‘flare’ is bacterial or allergy. To date we are unaware of diagnostic tests that differentiate these. There are few high-quality randomized controlled trials of corticosteroids in ABPA and bronchiectasis. One recent study has suggested moderate doses of oral steroids provide as good an effect in preventing exacerbations as high doses.86 Defining good clinical outcomes of response would be challenging although monitoring IgE responses and radiology for infiltrates may help.87 Similar to targeting bacterial pathogens in bronchiectasis with pulmonary inhaled antibiotics, there is interest in targeting the Aspergillus by high doses of airway targeted anti-fungals.88 In the absence of hard clinical trials endpoints and data empirical therapy is tried. One prior small trial has shown the benefits of itraconazole in ABPA, but to date no large-scale trials have confirmed these data.89 A Cochrane review, however, suggests very scant evidence to support more widespread use of azoles in ABPA.90 CNPA Chronic necrotising pulmonary aspergillosis is most sensibly viewed as a condition complicating established bronchiectasis. There have been recent published diagnostic and management guidelines for chronic aspergillosis.91 Reflecting some uncertainties in diagnostics until this guidance there are few well-described cohorts of patients with bronchiectasis and chronic aspergillosis. Up to 26% of patients with chronic aspergillosis were felt to have underlying bronchiectasis as a risk factor in a series of 70 patients from S. Korea.92 High rates of chronic aspergillosis is Vietnam suggests there may be large variation in rates dependent on geography.93 Chronic fibrocavitary aspergillosis has been linked with coinfections of nontuberculous mycobacteria in bronchiectasis. In this setting high mortality rates have been reported from a UK study with an odds ratio of 8 for mortality in the presence of NTM and chronic Aspergillus syndrome.94 NTM was also a common co-infection in the case series from S.Korea.92 The rates of NTM infection appear much higher in the US bronchiectasis registry, and data on their Aspergillus-related comorbidities is awaited with interest.95 We suggest that in patients with known NTM infections in the setting of bronchiectasis that Aspergillus cultures (and possibly PCR testing) should be considered. If antifungal therapy is considered, then careful monitoring of drug toxicity, especially hepatotoxicity, should be considered given these are also recognised side effects of the anti-mycobacterial therapies. Acceptable results were reported with either itraconazole or voriconazole, usually over 6 months of treatment.92 Conversion of chronic aspergillus to a semi-invasive form is described.96 The clinical symptoms suggesting this conversion to an invasive form may, however, be difficult to identify in a bronchiectasis population. Invasive Aspergillus (IA) infections A. fumigatus can lead to invasive aspergillosis, defined as histologic evidence of tissue invasion by branched septate hyphae. Despite clear diagnostic criteria for IA, it is unknown how routinely these are applied/tested when bronchiectasis patients have more severe exacerbations or periods of sepsis that could be related to IA. While invasive Aspergillus infections are well-recognized complications in those with immunosuppression, this serious and life-threatening infection is also well described in those with underlying chronic lung diseases such as asthma, emphysema, and bronchiectasis, particularly in the setting of oral corticosteroid use. Importantly this feared complication is therefore not limited to those with neutropenia and indeed was only noted in 1/3 of a recent case series.97 Invasive infections appear to have outcomes as severe as those in the immunocompromised group in those with underlying lung disease reaching as high as 50% at 1 month in a case series of 50 patients, five of whom had bronchiectasis. A. fumigatus was the most common species isolated and had a poorer mortality compared to those with Aspergillus flavus or Aspergillus niger infections in a single center series from Massachusetts US. IA was also associated with a significant mortality even in the absence of in vitro testing showing no clear resistance- mortality reached as high as 50% in the series from Belgium.98 In sum, 23% of those diagnosed with IA were defined as having “structural lung disease/COPD/ILD” and were likely to have included those with bronchiectasis as their underlying risk factor for IA. Underlining the importance of raised awareness and early diagnosis in this series, susceptibility testing revealed azole resistance in only 2of the 58 patients who died of IA. This suggests the underlying conditions predisposing to IA and delays in diagnosis rather than antimicrobial resistance were underlying factors in the poor outcomes. The radiology may be more difficult to interpret in the setting of IA in bronchiectasis as it is likely that tree in bud in bronchiectasis has many more causes (e.g., NTM infection) than will be seen in patients with normal lungs; hence we suggest using both the ‘halo’ and ‘tree-in-bud’ signs as a prompt for further investigation rather than used as a pathognomonic appearance of IA.99,100 IA has also been described as a complication arising in those with Hyper IgE syndrome; this immunodeficiency syndrome is characterized by bronchiectasis and pneumatoceles.101 Chronic granulomatous disease (CGD), another immunodeficiency state associated with reduced phagocyte oxidative burst, is also complicated by bronchiectasis. CGD has proposed as one of the few other primary immunodeficiency syndromes to have a well described risk of IA.102,103 Interestingly CGD patients appear to have a greatest risk of IA in the first 2 decades of life, while Hyper IgE Syndrome patients are more frequently associated with IA beyond this age range.102,104 The reasons for differential presentation of IA in these conditions are poorly understood but could relate to immune-senescence developing in the Hyper IgE syndrome patients and immunological maturation in those with CGD. Fungal disease, however, has been reported as the major cause of death in CGD in one series, although pneumonia was reported as the cause in a multicenter European series.105 One small trial has suggested a benefit of itraconazole prohylaxis in CGD.106 Hence bronchiectasis physicians may encounter IA as a complication of the established bronchiectasis in their immunodeficiency patients and the age at presentation varies dependent on the immunodeficiency state. Fungal bronchitis In the authors experience, acute fungal bronchitis may both cause subsequent bronchiectasis and arise as a consequence of bronchiectasis. Aspergillus tracheo-bronchitis (ATB) is a unique form of invasive aspergillosis, where the infection is confined to the tracheobronchial tree. In ATB the tissue invasion is limited to the superficial mucosal layers and contrasts to the more invasive forms of aspergillosis where there is histological evidence of septate branching Aspergillus hyphae causing direct invasion of the lung parenchyma. ATB can cause airways ulceration or pseudomembrane formation and is probably under diagnosed. In a case series from Manchester, United Kingdom, assessing over 400 patient referrals, a distinct syndrome of fungal bronchitis without immunocompromise was identified in 16 patients (4% of the cohort).107 Of these 12/16 had bronchiectasis and the majority were sputum culture positive for Aspergillus species (A. fumigatus = 12, A. niger = 3 and one case with A. terreus). Most patients (71%) had elevated Aspergillus IgG, but only 29% had elevated Aspergillus precipitins. Six of 12 (50%) had a major response to antifungal therapy, and five of 12 (42%) patients relapsed, requiring long-term therapy. A smaller cohort of fungal bronchitis patients (n = 7) were noted in a much larger 18 center national study of azole resistance in Belgium; these patients were the minority of cases where Aspergillus was isolated with Invasive aspergillosis and ABPA being over 5 times more prevalent.98 Less frequently, ATB can present with an endobronchial obstructive mass or obstructive Aspergillus tracheobronchitis (OATB). Characteristically, OATB lacks any macroscopic evidence of airways inflammation, unlike the other IA or ATB. Although OATB is considered a type of ‘invasive aspergillosis,’ it can present without evidence of airway mucosal invasion. It has been described as a complication of immunosuppression after transplantation and can occur many years after transplantation.108 The role of resistance testing in managing all forms of IA is unclear but case reports suggest some role in ABPA and fungal bronchitis where a switch to posaconazole, after recognition of resistance likely to affect itraconazole therapy, was associated with improved outcomes.109 Aspergilloma Undoubtedly, aspergillomas are seen in those with chronic lung destruction. Common diagnostic groups may include those with include post pneumonic or post-tuberculous bronchiectasis where coexistent aspergilloma may arise. Hyper IgE syndrome, although a relatively rare immunodeficiency state, is perhaps disproportionately associated with both bronchiectasis and aspergillomas.104 The long-term sequelae of an aspergilloma are rupture, bronchial artery erosion and/or haemoptysis. Watchful waiting is often a common policy with surgical resection reserved for cases with hemoptysis refractory to embolization. The presence of prior bronchiectasis complicates the scenario given that hemoptysis may arise from the bronchiectasis syndrome or from the associated aspergilloma. Careful liaison with interventional radiology and thoracic surgery is needed in such cases. Known unknowns in Aspergillus in bronchiectasis There are so few robust large volume studies that definitively answer major clinical issues. The following are a selected set of questions that we propose are areas to focus on. Given that bronchiectasis and Aspergillus diseases are underfunded, under-researched and relatively rare there will be significant challenges in recruiting these patients for such epidemiological, observational, and interventional studies. It is for these reasons national and international collaborations in bronchiectasis are developing to tackle the very many known unknowns in bronchiectasis pathophysiology and treatment. EMBARC will collect data on over 10,000 patients from across Europe with longitudinal follow-up.39 The comparative outcomes between different etiologies of bronchiectasis as previously reported in single or clusters of centers will then be interrogated across much larger data sets.5,12 The EMBARC team has also developed a consensus on research priorities in bronchiectasis.62 This was codeveloped between patients across Europe and over 100 bronchiectasis physicians; one key priority is to develop studies to better understand microbes and other drivers of exacerbations.62 BronchUK (www.bronch.ac.uk) is collecting the same demographic data on a UK population of 3,500 patients but uniquely will have linked healthcare data and biobanked samples including those for genetics and serological testing. These resources will help us understand the complexities of Aspergillus disease in bronchiectasis; table 4 represents some key research questions. Intervention trials will undoubtedly need close interactions and careful planning with the pharmaceutical and regulatory authorities. Table 4. Research questions in Aspergillus and bronchiectasis. Epidemiology  • What is the true seroprevalence of Aspergillus sensitization in bronchiectasis and does it correlate with poorer outcomes?  • What are the factors associated with relapse in ABPA in bronchiectasis?  • Do radiological appearances of central vs peripheral bronchiectasis predict better/ poorer outcomes?  • Does longitudinal measurement of Aspergillus serology allow an “at risk” group to be identified and treated before more aggressive disease develops? Pathophysiology  • Which bronchiectasis etiologies increase the risk of ABPA developing?  • Are there underlying immunological defects present in those with NTM and chronic aspergillosis co-infection?  • Which tests predict invasive aspergillosis developing in a bronchiectasis population?  • What mechanisms drive bronchiectasis formation in ABPA and do these inform us of mechanisms leading to idiopathic bronchiectasis? Treatment  • What is the optimal treatment agent and duration for ABPA in those with established bronchiectasis?  • Do bronchiectasis etiologies determine treatment responses in ABPA?  • What is the most effective and least toxic regimen for treating NTM and chronic aspergillosis?  • What is the role for therapeutic drug monitoring in ABPA and chronic aspergillosis? Epidemiology  • What is the true seroprevalence of Aspergillus sensitization in bronchiectasis and does it correlate with poorer outcomes?  • What are the factors associated with relapse in ABPA in bronchiectasis?  • Do radiological appearances of central vs peripheral bronchiectasis predict better/ poorer outcomes?  • Does longitudinal measurement of Aspergillus serology allow an “at risk” group to be identified and treated before more aggressive disease develops? Pathophysiology  • Which bronchiectasis etiologies increase the risk of ABPA developing?  • Are there underlying immunological defects present in those with NTM and chronic aspergillosis co-infection?  • Which tests predict invasive aspergillosis developing in a bronchiectasis population?  • What mechanisms drive bronchiectasis formation in ABPA and do these inform us of mechanisms leading to idiopathic bronchiectasis? Treatment  • What is the optimal treatment agent and duration for ABPA in those with established bronchiectasis?  • Do bronchiectasis etiologies determine treatment responses in ABPA?  • What is the most effective and least toxic regimen for treating NTM and chronic aspergillosis?  • What is the role for therapeutic drug monitoring in ABPA and chronic aspergillosis? Open in new tab Table 4. Research questions in Aspergillus and bronchiectasis. Epidemiology  • What is the true seroprevalence of Aspergillus sensitization in bronchiectasis and does it correlate with poorer outcomes?  • What are the factors associated with relapse in ABPA in bronchiectasis?  • Do radiological appearances of central vs peripheral bronchiectasis predict better/ poorer outcomes?  • Does longitudinal measurement of Aspergillus serology allow an “at risk” group to be identified and treated before more aggressive disease develops? Pathophysiology  • Which bronchiectasis etiologies increase the risk of ABPA developing?  • Are there underlying immunological defects present in those with NTM and chronic aspergillosis co-infection?  • Which tests predict invasive aspergillosis developing in a bronchiectasis population?  • What mechanisms drive bronchiectasis formation in ABPA and do these inform us of mechanisms leading to idiopathic bronchiectasis? Treatment  • What is the optimal treatment agent and duration for ABPA in those with established bronchiectasis?  • Do bronchiectasis etiologies determine treatment responses in ABPA?  • What is the most effective and least toxic regimen for treating NTM and chronic aspergillosis?  • What is the role for therapeutic drug monitoring in ABPA and chronic aspergillosis? Epidemiology  • What is the true seroprevalence of Aspergillus sensitization in bronchiectasis and does it correlate with poorer outcomes?  • What are the factors associated with relapse in ABPA in bronchiectasis?  • Do radiological appearances of central vs peripheral bronchiectasis predict better/ poorer outcomes?  • Does longitudinal measurement of Aspergillus serology allow an “at risk” group to be identified and treated before more aggressive disease develops? Pathophysiology  • Which bronchiectasis etiologies increase the risk of ABPA developing?  • Are there underlying immunological defects present in those with NTM and chronic aspergillosis co-infection?  • Which tests predict invasive aspergillosis developing in a bronchiectasis population?  • What mechanisms drive bronchiectasis formation in ABPA and do these inform us of mechanisms leading to idiopathic bronchiectasis? Treatment  • What is the optimal treatment agent and duration for ABPA in those with established bronchiectasis?  • Do bronchiectasis etiologies determine treatment responses in ABPA?  • What is the most effective and least toxic regimen for treating NTM and chronic aspergillosis?  • What is the role for therapeutic drug monitoring in ABPA and chronic aspergillosis? Open in new tab Acknowledgments We acknowledge helpful discussions on the knowledge gaps in bronchiectasis with colleagues and collaborators within both bronchiectasis networks EMBARC (www.bronchiectasis.eu) and BronchUK (www.bronch.ac.uk). ADS acknowledges funding to the BronchUK network from the UK Medical Research Council (grant MR/L011263/1) and a prior Higher Education Funding Council (HEFCE senior lectureship). EMBARC is a European Respiratory Society Clinical Research Collaboration and has received funding from the European Respiratory Society, Bayer HealthCare, and Aradigm Corporation. 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TI - Bronchiectasis and Aspergillus: How are they linked?
JF - Medical Mycology
DO - 10.1093/mmy/myw109
DA - 2017-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/bronchiectasis-and-aspergillus-how-are-they-linked-j3Z5HCZjql
SP - 69
VL - 55
IS - 1
DP - DeepDyve
ER -