key: cord-0035511-h6r6qdna
authors: Polverino, Eva; Rosales-Mayor, Edmundo; Torres, Antoni
title: Exacerbation of Bronchiectasis
date: 2017-12-23
journal: Bronchiectasis
DOI: 10.1007/978-3-319-61452-6_15
sha: 9a2e93a562a700ce22c997770b24175c61e302de
doc_id: 35511
cord_uid: h6r6qdna

Please check the hierarchy of the sections and correct if necessary.

Bronchiectasis is a heterogeneous chronic respiratory disease that is characterized by frequent respiratory infections. In fact, both acute and chronic respiratory infections are considered typical determinants of the natural history of bronchiectasis, and they strongly predict patients' quality of life and disease progression. In general, it is common belief that most of the exacerbations of bronchiectasis in adults are infectious events.

The role of exacerbations is so important that many authors define bronchiectasis as a syndrome characterized by permanent bronchial dilatation and recurrent respiratory infections (exacerbations). In addition, the pathophysiological theory of "Cole's vicious cycle," which explains the development of bronchiectasis, is based on an initial infectious episode that triggers the local inflammatory response and permanent bronchial damage. As a result of the vicious cycle, patients with bronchiectasis usually suffer from chronic airway inflammation, functional limitation (fatigue, dyspnea), and recurrent acute infections (exacerbations) or chronic airway infections.

Various studies have shown that an increased frequency of exacerbations is associated with increased airway and systemic inflammation, [1] and progressive lung damage [2, 3] . In addition, more severe (i.e., requiring hospitalization) and more frequent exacerbations (>2/year) are associated with a worsened quality of life, daily symptoms [4] , lung function decline [5] , and mortality [3] .

Consequently, the prognostic score most used in bronchiectasis-the Bronchiectasis Severity Index-includes both exacerbations and hospitalizations (more severe exacerbations) between the nine determinants for disease severity assessment [3] . The FACED score (FEV1, Age, Chronic colonization, Extension, Dyspnoea), the alternative prognostic score for mortality risk, has recently been updated to include the exacerbations as a relevant determinant of the risk of mortality and future exacerbations [6] [7] [8] .

As a result, most of the therapeutic interventions suggested in bronchiectasis and the most relevant clinical trials, are directed at preventing exacerbations or reducing their frequency and severity [9, 10] . For instance, influenza and pneumococcal vaccines, continual use of macrolides and inhaled antibiotics, and respiratory physiotherapy, are all aimed at minimizing the impact of exacerbations on patients' quality of life and disease progression [9] [10] [11] [12] [13] . In particular, the threshold of three or more exacerbations per year is usually considered to classify patients with unstable clinical conditions who should be considered for continuous (inhaled or oral) antibiotics [9] .

Taking all these factors into consideration, it is clear that identification, treatment, and prevention of exacerbation is crucial in the management of bronchiectasis. In line with this, the most recent and relevant clinical trials of inhaled antibiotics use "time to first exacerbation" or "the mean/median number of exacerbations" as primary outcomes [14, 15] .

Numerous definitions have been given so far to define exacerbations of bronchiectasis.

Most of them include an acute change in cough, sputum (color, viscosity, and volume), and a number of additional symptoms, such as increased dyspnea, wheezing, fatigue, malaise, thoracic pain, spirometric and oxygenation worsening, hemoptysis, fever, etc. Many studies have included in their definitions of exacerbation the need for antibiotic therapy according to the decision of the attending physician. This criterion is frequently controversial, because (1) it assumes that only bacterial infections are the real cause of exacerbations, and (2) the administration of antibiotics should be a consequence of the definition, and not part of it. More recently, during the First World Bronchiectasis Congress held in Hanover in July 2016, an international (from Europe [EMBARC], the USA, Australasia, and South Africa) task force of 28 experts in bronchiectasis generated an agreed-upon definition of exacerbations of bronchiectasis [16] . Firstly, a review of exacerbations used in clinical trials between 2000 and 2015 was performed [1, [11] [12] [13] [14] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] . Secondly, a Delphi process [32] , followed by a round table discussion, was used to identify the most relevant elements to include in a definition of exacerbations and to achieve a final agreement on it. Finally, the definition proposed included a deterioration in three or more of the following key symptoms, for at least 48 h: cough; sputum volume and/ or consistency; sputum purulence; breathlessness and/or exercise tolerance; fatigue and/or malaise; hemoptysis, and a clinician who determines that a change in bronchiectasis treatment is required (Table 15 .1).

It is possible that in the future, the need to grade severity of exacerbations will emerge as a useful clinical tool to decide on appropriate therapy and diagnostic tests (as for pneumonia). At the moment, only the Spanish guidelines provide a definition of severe exacerbation in the presence of any of these factors: tachypnea; acute respiratory failure; exacerbated chronic respiratory failure; a significant decline in SaO 2 , respiratory function, or hypercapnia; fever of more than 38°C; hemoptysis; hemodynamic instability; or impaired cognitive function [10] . More recently, the updated version of Spanish guidelines introduced the concept of "very severe exacerbations" when characterized by hemodynamic instability, altered mental status, or the need to be admitted to an intensive or intermediate care unit (Table 15 

Although various studies in the 1980s and 1990s suggested a frequency of exacerbations greater than four events/year [33] [34] [35] [36] [37] [38] , more recent data from the European Bronchiectasis Registry (EMBARC) [39] have shown that the majority of patients suffer two exacerbations/year. Likely, a serious referral bias of sicker patients to more specialized centers was responsible for overestimating the frequency of exacerbations.

However, it is worth mentioning that >45% of all patients might have more than two exacerbations year, and it is has been reported that one-fourth of all BE patients might be responsible for 80% of the total costs of the disease [40] . In addition, various authors have described an increasing trend in the number of hospitalizations due to bronchiectasis [41, 42] . In particular, in Germany, an increasing rate of hospitalizations has been reported in the last decade [41] . It is possible that the increased awareness of the disease-such as the improved availability of diagnostic tools (high-resolution CT scan) have contributed to better identification of bronchiectasis patients and their exacerbations.

Interestingly, some researchers have written that bronchiectasis exacerbations may require a mean length of hospital stay (LOS) in the United Kingdom of 10 days, which is longer than that required for COPD [43] , while another publication from the USA describes a mean stay of 6 days [44] . However, we realize that factors such as local healthcare organization and other socio-economic aspects can highly influence this outcome. For this reason, it is very difficult to evaluate the economic burden of the disease by measuring the mean length of stay through LOS.

Otherwise, De la Rosa et al have clearly identified the frequency of exacerbations as one of the main determinants of the economic burden of bronchiectasis in more advanced patients (high FACED score) [45] . Apart from the economic problem, exacerbations can also negatively influence prognosis. In fact, various longitudinal studies have described a considerable increase in mortality risk after an exacerbation of bronchiectasis, particularly in the subset of patients with comorbid chronic obstructive pulmonary disease (COPD) [39, 44, 46, 47] .

Despite the fact that the etiology of exacerbations is not always clear (bacteria, virus), the factors associated with an increased risk of suffering an exacerbation of bronchiectasis are well described. A broad radiological extension (>2 lobes, bilateral), a cystic aspect, a moderate to severe BSI score, and a history of recurrent exacerbations in the last year-are clear predictors of further exacerbations [3, 48] . In particular, the BSI score was developed according to the analysis of risk factors for hospitalizations (severe exacerbations needing hospitalization) [3] . Independent predictors of future hospitalization included prior hospital admissions; severe dyspnea; FEV 1 < 30% predicted; Pseudomonas aeruginosa colonization; colonization with other pathogenic organisms; and three or more lobes with bronchiectasis. Two recent prognostic scores have incorporated exacerbations into the original FACED score; both E-FACED and Exa-FACED scores showed better prognostic capacity and improved risk classification [7, 8] .

A chronic infection by P. aeruginosa is associated with an increased risk of hospitalization [49, 50] and, in the long run, of mortality [51] . However, McDonnell et al. also showed that chronic airway infections by Haemophilus influenzae have increased outpatient morbidity due to frequent exacerbations not requiring hospitalization [49] .

A good model of risk stratification based on the airway microbiome analysis in stable clinical conditions was proposed by Rogers and colleagues [52] . The microbiome analysis on induced sputum from 107 adult patients identified three main groups: P. aeruginosa-dominated, H. influenza-dominated, and other taxadominated. Although both P. aeruginosa and H. influenzae were characterized by poorer lung function, as well as increased systemic and airway inflammation, only P. aeruginosa was finally associated with higher exacerbations frequency.

As a confirmation, Aliberti et al. identified a specific "Pseudomonas" clinical phenotype through a cluster analysis based on demographics, comorbidities, and clinical, radiological, functional, and microbiological data [4] . Patients with chronic P. aeruginosa showed significant differences in terms of quality of life, exacerbations, hospitalizations, and mortality during follow-up compared with "other chronic infection," "daily sputum," and "dry bronchiectasis" patients [4] .

A Chinese group has developed a specific score to identify patients with bronchiectasis at risk of exacerbations, including: P. aeruginosa colonization (OR = 3.227), ≥3 affected lobes at HRCT scan (OR = 3.179), prior ICU admissions (OR = 2.499), and FEV 1 < 50% predicted (OR = 2.497) [53] . A broader external validation of this score would be helpful to integrate it into clinical practice.

The coexistence of COPD or asthma in bronchiectasis patients has been widely recognized to increase the risk of exacerbations [47, 54] . In particular, a metaanalysis of COPD patients showing bronchiectasis on CT scans has described a clear increase in the exacerbation risk [55] . In asthmatic patients, the association with bronchiectasis has been described only for severe patients [56, 57] in whom obstruction severity seems to be associated with the risk of BE, but its predictive value is poor [57] .

This association between asthma and bronchiectasis is more frequent in the presence of Aspergillus sensitivation [56] or in the case of neutrophilic inflammation [57] , which is described usually only in a minority of asthma patients and seems to be associated with an increased exacerbation risk [54] . However, the scarce literature on this clinical association requires further investigation in order to define clinical outcomes of this subset of bronchiectasis population.

Interestingly, a British study of adult bronchiectasis patients also identified airway reflux as independently associated with an increased risk of ≥3 bronchiectasis exacerbations in 1 year [58] . Although gastro-esophageal reflux has been reported as a potential etiology of bronchiectasis, its association with the disease has never been completely shown; similarly, it is not clear whether airway reflux can be a real causative factor of exacerbations, or simply a marker of associated conditions. Another factor to consider in terms of risks of exacerbations is nutritional status. It is well known that the immune response of the general population is highly influenced by nutritional status [59] . Although the relationship with body mass index (BMI) is not as strong as for cystic fibrosis [60] , long-term survival of bronchiectasis patients seems to be influenced by BMI [61] . Chalmers et al have described an association between Vitamin D deficiency and the risk of exacerbations and chronic infections [62] . In addition, a BMI ≤ 18.5 Kg/m 2 has been associated with an increased mortality risk in bronchiectasis [3] .

Lastly, it has been reported in some regions that socio-economic factors can also influence the risk of exacerbations in both children and adult populations [63, 64] (Table 15. 3).

As for all chronic respiratory diseases, the knowledge of the etiology of exacerbations of bronchiectasis is a crucial factor. In fact, due to the high impact of exacerbations on quality of life and long-term prognosis for bronchiectasis, the understanding of pathophysiology of these events can surely improve management of the disease.

In general, it is assumed that all exacerbations are due to infections, although there is probably no sufficient scientific evidence to identify exacerbations due to other causes, such as treatment incompliance or pulmonary embolism, as in COPD [65] . In addition, it is difficult to distinguish between bacterial, viral, and, more rarely, fungal exacerbations from clinical presentation and analytical data.

Recently [64] catharrhalis as the most frequent microorganisms in sputum cultures or nasopharyngeal swabs (PCR analysis of viruses) of exacerbated patients [66] . In contrast, atypical bacteria seem to be very infrequent in this population [66, 67] . However, patients suffering pneumonia showed S. pneumoniae to be the most frequent isolate, irrespective of previous airway chronic infection [66] . The same study identified a polymicrobial infection in more than 35% of all cases of exacerbations (both pneumonic and non-pneumonic): two bacteria were identified in16% of pneumonia cases and 13% of non-pneumonic exacerbations, while a combination of bacteria and virus was found in 22% and 11% of cases, respectively. Lastly, in 12% and 8% of cases, a fungal isolate was found in association with a bacteria [66] .

The role of viral infections during exacerbations of bronchiectasis has also been confirmed in previous studies in 25-50% of both adult and children's populations [68, 69] . Similar data have also been reported for CF [70] and COPD [71] . The most frequent viruses described in exacerbated bronchiectasis are coronavirus, rhinovirus, influenza virus (A and B), metapneumovirus, respiratory syncytial virus, and parainfluenza 3 [66, 68, 69] .

However, the mechanisms of virus-induced bronchiectasis exacerbation need to be further investigated. In fact, a human model of rhinovirus infection has been shown to be able to impair IFN production and neutrophilic inflammation, and trigger a COPD exacerbation through inflammatory mechanisms [72] , or by inducing a secondary bacterial infection [73] . These pathophysiological patterns have not been clearly demonstrated in bronchiectasis but they are likely, considering the fact that, like in COPD, airway inflammation is neutrophilic.

In addition, in COPD, increased bacterial concentration due to the acquisition of a new strain of chronic H. influenzae has been described as a cause of exacerbations [74] . Unfortunately, there is no information to support this theory in bronchiectasis, but a change in the host-pathogen interaction could also be hypothesized during exacerbations on the base of current evidence on microbiome, classical microbiology, and inflammatory patterns [67] [68] [69] . In fact, Tunney et al. investigated the lung microbiome in bronchiectasis patients and surprisingly found no significant differences between stable conditions and exacerbations [75] .

In line with this hypothesis, Brill et al. prefer to define bronchiectasis exacerbations of non-CF bronchiectasis as inflammatory events, with worsened symptoms, lung function, and health status [76] . Nonetheless, we have clear scientific evidence of the association between antibiotic administration and a consequent drop in bacterial load and systemic and local inflammation [1] . In fact, the available guidelines (SEPAR, BTS) suggest treating exacerbation with antibiotic therapy for 14 days [9, 10, 16].

As most exacerbations are considered to be the result of bacterial infections, current guidelines recommend antibiotic treatment [9, 10, 16] . As the microbiological etiology of exacerbation is quite variable, a sputum culture is suggested before administering antibiotics in order to adjust treatment to microbiological results [9, 10, 16] . However, in the presence of previous chronic airway infections, the empiric antibiotic coverage should cover the microorganism formerly isolated [9, 10, 16] . In fact, some preliminary findings from a multicenter study show that the rate of concordance between the microbiology of chronic bronchial infection and exacerbation is about 80%, particularly in the case of chronic P. aeruginosa; in contrast, in the case of pneumonia, the microbiological etiology of exacerbation is often different from stable conditions and a complete microbiological investigation is recommended [66] .

The choice of the antibiotic drug therefore depends on various factors, such as previous airway infection, allergies, intolerances and preferences, comorbidities (renal or hepatic failure), and concomitant medication, as well as on microbiological data when available. Only systemic antibiotics are currently recommended for the treatment of exacerbations, due to potential side effects or limited tolerability of inhaled antibiotics in these conditions (bronchospasm, wheezing, coughing) of the administration route (oral or intravenous) variable, depending on the severity of the exacerbation, drug availability, and pharmacokinetics and patient characteristics.

In case of H. influenzae, amoxicillin-clavulanic acid or doxycycline or a fluoroquinolone (levofloxacin or ciprofloxacin) are usually recommended (Table 15. 2).

In case of P. aeruginosa, unfortunately the only active oral antibiotic is ciprofloxacin, which is generally used at the dosage of 750 mg BID. Alternatively, intravenous ceftazidime, carbapenem, piperacillin-tazobactam, or cefepime should be considered, according to antibiogram data. Despite the absence of scientific evidence regarding the use of combined antibiotic therapy in bronchiectasis, it is possible to consider it in case of severe exacerbations or mucoid or multidrug-resistant strains of P. aeruginosa. In particular, a combination therapy with tobramycin, colistin, gentamycin, or amikacin should be contemplated.

Unfortunately, an empiric antibiotic coverage is frequently needed due to the unavailability of a previous microbiological culture. In these cases, ciprofloxacin is usually recommended in order to cover the risk of P. aeruginosa, although in a recently diagnosed bronchiectasis patient with few or no previous exacerbations, amoxicillin-clavulanic can also be considered; it is highly recommended to perform a sputum culture before antibiotic administration in order to eventually adjust antibiotic therapy once microbiology results become available [9, 10] (Table 15. 

Based on clinical practice, experts' opinions, and certain scientific evidence, 14 days of antibiotic therapy are usually recommended [9, 10, 16, 28, 77] . However, in cases of mild exacerbations with a prompt resolution of symptoms (fewer than 5 days) and potential viral infection, a shortened antibiotic course could be considered; however, clinical follow-up could be useful to ensure complete recovery. Similarly, in case of late or partial treatment response, a longer antibiotic therapy could be considered, although,if a treatment failure is suspected (clinical worsening despite antibiotic therapy or insufficient improvement at the end of the antibiotic cycle), a new microbiological investigation should be performed, and other noninfectious causes of clinical deterioration (such as pulmonary embolism or heart failure) should be investigated.

In the case of high fever, C-reactive protein >5 mg/dl and unusual findings upon thoracic auscultation, a pneumonia should be ruled out through a chest X-ray or CT scan. In risk of S. pneumoniae should be covered, but also micro-organisms responsible for pre-existing chronic bronchial infections need to be considered [66, 78] .

There are no specific recommendations regarding corticosteroids or inhaled bronchodilators for exacerbations of bronchiectasis, but their use usually follows general indications for these drugs [16] . With regard to inhaled hyperosmolar agents such as hypertonic saline or mannitol, there is scientific evidence to support their use during exacerbations. Moreover, the risk of side effects-such as bronchospasm-could be increased during exacerbations, due to increased airway inflammation.

In general, there is a widespread belief-among both doctors and patients-that airways' clearance techniques can facilitate and accelerate a patient's recovery from exacerbations. unfortunately there is no evidence that airways' clearance techniques can be useful during exacerbations to facilitate and accelerate patient recovery and further investigation is surely needed for the future. (Table 15 .5)

The long-term management of bronchiectasis is generally directed at preventing exacerbations; therefore, numerous recommendations appear in the Spanish and British guidelines [9, 10] . In particular, the use of chronic oral macrolides and inhaled antibiotics have been widely supported by experts worldwide. Since then, a number of interesting trials have provided increasing scientific evidence for these therapies. In particular, there have been three major randomized clinical trials (BLESS, EMBRACE, and BAT) that showed a clear reduction of exacerbations (time from the first exacerbation or frequency of exacerbations) with continued use of azithromycin (from 250 mg daily to 500 mg 3 times a week), or erythromycin (400 mg BID) [11] [12] [13] .

Despite some methodological differences between these trials, the three of them can provide common evidence to recommend using these antibiotics in the cases of patients with three or more exacerbations in the previous year, despite optimization of therapeutic management. It is worth mentioning again that important adverse events have been reported so far; in particular, diarrhea and an increase in the proportion of macrolide-resistant microorganisms in the oropharyngeal mucosa (Streptococci) are quite common. Less frequent potential treatment-related adverse events, such as QTc prolongation, tinnitus/hearing loss, and selection of macrolideresistant non-tuberculous mycobacteria (NTM) should be carefully considered when beginning long-term treatment with macrolides. In particular, 2-3 sputum cultures negative to NTM are recommended before beginning macrolides, since it is known that NTM infections caused by macrolide-resistant strains are usually more difficult to treat [79] . Conversely, other chronic regimens with oral antibiotics, such as amoxicillin or tetracycline, have been reported to improve sputum purulence, but do not show such clear benefits in terms of exacerbations as frequently as macrolides [34, 80] .

Most clinical experts in bronchiectasis feel that inhaled antibiotics are potentially the best option for reducing exacerbations in bronchiectasis due to the high local concentrations achieved in the airways, minimal systemic side effects, and limited occurrence of antibiotic resistance. Numerous antibiotics have been developed in the past few years for inhaled administration (e.g., dry powder, nebulized solutions); these include ciprofloxacin, aztreonam, colistin, and tobramycin. Unfortunately, the level of evidence supporting their use in clinical practice is still controversial due to the fact that, unexpectedly, some clinical trials failed to achieve primary outcomes. For instance, inhaled aztreonam, which had shown positive results for CF [81, 82] , did not improve quality of life (primary outcome of the LQ-B questionnaire) significantly more than placebos [23] . Haworth et al (2014) could not prove that inhaled colistin could significantly prolong the time to the first exacerbation in the overall population (primary outcome). However, patients who stayed with the treatment during the trial, showed a median time to exacerbation of 168 (65) vs. 103 (37) days in the colistin and placebo groups, respectively (P = 0.038) [27] .

Similar results were described in a study investigating the efficacy of nebulized liposomal ciprofloxacin in bronchiectasis patients with P. aeruginosa infection [14] . A 1-year single blind study of nebulized gentamicin showed a significant reduction in the frequency of exacerbations (0 [0-1] vs. 1.5 [1] [2] , p < 0.0001), compared to 0.9% saline-treated patients and a prolonged time to the first exacerbation (120 [87-161.5 ] d vs. 61.5 [20.7-122.7] d; P = 0.02) [83] . A 1-month phase II RCT investigating inhaled ciprofloxacin dry powder showed promising results in terms of microbiological response, [15] but results of the subsequent long-term phase III RCT are currently awaited [84] . Again, some relevant side effects have been described in association with the use of inhaled antibiotics, such as increased cough, bronchospasm, and breathlessness, while minimal or non-significant antimicrobial resistance are currently known. Very recently, the European Guidelines on bronchiectasis have suggested the use of inhaled antibiotics to prevent exacerbations of patients with chronic P. aeruginosa infection and the use of macrolides to prevent exacerbations of patients with any other chronic airways infection, although an individualized approach is always to be considered [16] .

Despite the fact that hypertonic saline has been proved to improve airways' clearance, quality of life, and FEV 1 in bronchiectasis when combined with respiratory physiotherapy [19, 85] , there is still no evidence that its chronic use can prevent exacerbations. Considering these promising results and the low cost of this intervention, further investigation is surely an urgent need.

Other, more expensive hyperosmolar agents such as mannitol, failed to show a significant reduction in the annual frequency of exacerbation (primary outcome, rate ratio 0.92, p = 0.31). However, compared with low-dose mannitol control, mannitol prolonged time to the first exacerbation (HR 0.78, p = 0.022) and quality of life (−2.4 units, p = 0.046) (two secondary outcomes). Luckily, similar side effects were reported for both arms [18] . Otherwise, deoxyribonuclease (RhDNase) is currently contraindicated in bronchiectasis due to the fact that the only RCT showed an increased rate of exacerbation in association with this mucolytic agent, which is frequently used in CF [86] .

Although respiratory physiotherapy is currently not recommended during exacerbations, its use in stable clinical conditions is considered a pillar in the long-term management of bronchiectasis. Ideally, excellent physiotherapy (including airway clearance techniques and/or pulmonary rehabilitation) is able to reduce mucus retention, limiting the accumulation of micro-organisms, inflammatory cells, and molecules. Therefore, physiotherapy should be able to disrupt the Cole vicious cycle that perpetuates lung damage in bronchiectasis.

Unfortunately, the scientific evidence regarding airway clearance techniques is extremely heterogeneous due to various methods of intervention and outcome measures. This heterogeneity makes it almost impossible to suggest a standardized protocol for airway clearance. Nonetheless, there are numerous studies that indicate the advantages of regular physiotherapy on sputum volume [87] [88] [89] and the impact of coughing on quality of life.

The airway clearance techniques are especially indicated in those patients with copious phlegm and/or difficult expectoration, but each intervention should be personalized, based on patients' characteristics and preferences, as well as the availability of physiotherapists and/or devices. Herrero-Cortina et al. compared autogenic drainage (a technique performed autonomously by patients), ELTGOL (requiring the intervention of a physiotherapist), and UNIKO, a temporary positive-expiratorypressure (T-PEP) device, in a population of stable bronchiectasis patients. They could demonstrate that the three interventions achieved similar results by enhancing mucus clearance during treatment sessions and reducing expectoration for the rest of the day [90] .

More evidence is available regarding the efficacy of pulmonary rehabilitation in improving exercise capacity and a trend towards better quality of life [22, [91] [92] [93] [94] .

Lee et al. performed a randomized controlled trial aimed at investigating the effects of exercise training and airway clearance techniques on exercise capacity, quality of life.

(HRQOL), and the incidence of acute exacerbations in bronchiectasis [22] . This is the only study found in the literature that shows that physiotherapy was able not only to reduce dyspnea and increase exercise capacity, but also to reduce the incidence of exacerbations at 1 year.

As in COPD and CF, the regular performance of physical activity or pulmonary physiotherapy has to be recommended to all patients with bronchiectasis in order to reduce the overall burden of the disease in terms of respiratory symptoms (dyspnea, fatigue, cough, and expectoration) and to reduce frequency and severity of exacerbations. It is likely that all physiotherapeutic interventions will be useful in bronchiectasis if optimized and personalized to specific patients and health conditions. The recent European guidelines recommend the use of hypertonic saline or mannitol in bronchiectasis patients with chronic productive cough or difficulty to expectorate sputum and rehabilitation in case of impaired exercise capacity [16] .

Unfortunately, there are no data regarding the efficacy of influenza and pneumococcal vaccines in the specific population of bronchiectasis. Nevertheless, the incidence of bronchiectasis increases exponentially in the elderly, and it is generally recommended to use vaccines both for influenza virus and pneumococcal infection in people >65 years old, particularly in cases of chronic respiratory diseases [95] [96] [97] .

Moreover, it is well known that bronchiectasis patients suffer more pneumonias than the general population [78] . Since the first cause of community-acquired pneumonia in bronchiectasis is S. pneumoniae, it is wise to recommend pneumococcal vaccination to these patients in order to reduce respiratory morbidity [78] . While the 23-valent polysaccharide vaccine is widely and historically used in bronchiectasis to investigate the immune response (antibody production), the 13-valent conjugate vaccine was introduced only in the last few years, due to the recognized superiority in terms of reduced risk of pneumococcal pneumonia and of prolonged duration of protection (T-cell-mediated immunological memory) [98, 99] .

Nevertheless, more tailored research is needed in the future to better develop strategies to prevent infections in this subset of the population with bronchiectasis.

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Vitamin-D deficiency is associated with chronic bacterial colonisation and disease severity in bronchiectasis

Respiratory exacerbations in indigenous children from two countries with non-cystic fibrosis chronic suppurative lung disease/bronchiectasis

Socioeconomic deprivation, readmissions, mortality and acute exacerbations of bronchiectasis

Characterisation of exacerbations of chronic bronchitis and COPD in Europe: the GIANT study

Pneumonic vs. non-pneumonic exacerbations in bronchiectasis

Bronchiectasis exacerbations: the role of atypical bacteria and respiratory syncytial virus

The role of viral infection in pulmonary exacerbations of bronchiectasis in adults: a prospective study

Respiratory viruses in exacerbations of non-cystic fibrosis bronchiectasis in children

The role of respiratory viruses in cystic fibrosis

Role of viruses in exacerbations of chronic obstructive pulmonary disease

Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation

Rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease

Airway bacterial concentrations and exacerbations of chronic obstructive pulmonary disease

Lung microbiota and bacterial abundance in patients with bronchiectasis when clinically stable and during exacerbation

Lung function, symptoms and inflammation during exacerbations of non-cystic fibrosis bronchiectasis: a prospective observational cohort study

Assessing response to treatment of exacerbations of bronchiectasis in adults

Microbial aetiology and outcomes of CAP in bronchiectatic patients

Therapy of refractory nontuberculous mycobacterial lung disease

PROLONGED antibiotic treatment of severe bronchiectasis; a report by a subcommittee of the antibiotics clinical trials (non-tuberculous) committee of the medical research council

Inhaled aztreonam lysine for chronic airway Pseudomonas Aeruginosa in cystic fibrosis

Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis

A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis

LATE-breaking abstract: baseline demographic profile of subjects of the phase 3 RESPIRE 1 trial of ciprofloxacin dry powder for inhalation (DPI) in non-cystic fibrosis bronchiectasis (NCFB)

Effects of hypertonic saline on sputum clearance in patients with bronchiectasis

Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I

Effects of ELTGOL and flutter VRP1® on the dynamic and static pulmonary volumes and on the secretion clearance of patients with bronchiectasis. Rev Bras Fis

Flutter valve improves respiratory mechanics and sputum production in patients with bronchiectasis

Airway clearance in bronchiectasis: a randomized crossover trial of active cycle of breathing techniques versus Acapella®

Short-term effects of three slow expiratory airway clearance techniques in patients with bronchiectasis: a randomised crossover trial

Pulmonary rehabilitation in individuals with noncystic fibrosis bronchiectasis: a systematic review

Effects of pulmonary rehabilitation in patients with noncystic fibrosis bronchiectasis: a retrospective analysis of clinical and functional predictors of efficacy

A pilot study of pulmonary rehabilitation and chest physiotherapy versus chest physiotherapy alone in bronchiectasis

Exercise training and inspiratory muscle training in patients with bronchiectasis

The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England

Epidemiology of pneumococcal infections in the elderly

Prevention and control of seasonal influenza with vaccines

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults

Inflammatory responses, spirometry, and quality of life in subjects with bronchiectasis exacerbations