The biology of pulmonary exacerbations in bronchiectasis

Amati, Francesco; Simonetta, Edoardo; Gramegna, Andrea; Tarsia, Paolo; Contarini, Martina; Blasi, Francesco; Aliberti, Stefano

doi:10.1183/16000617.0055-2019

Cited by 61 publications

(50 citation statements)

References 143 publications

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“…In terms of pathophysiology, one of the current paradigms for bronchiectasis onset and progression is represented by a vicious vortex in which bacterial infection, airway inflammation, lung tissue disruption, and impaired mucous clearance are regarded as the major components [ 6 , 7 ]. Each of those may be the entry point of the vortex, which eventually leads to bronchiectasis progression [ 8 ]. For instance, infection with non-tuberculous mycobacteria (NTM) induces a local inflammatory status which determines parenchymal structural damage [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Protease–Antiprotease Imbalance in Bronchiectasis

Oriano

Amati

Gramegna

et al. 2021

IJMS

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Airway inflammation plays a central role in bronchiectasis. Protease–antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may contribute to bronchiectasis onset and progression. Proteases’ over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of α1-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease–antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.

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Section: Introductionmentioning

confidence: 99%

Protease–Antiprotease Imbalance in Bronchiectasis

Oriano

Amati

Gramegna

et al. 2021

IJMS

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“…Exacerbations of other, rarer chronic respiratory diseases should also be considered such as interstitial lung diseases, 81 cystic fibrosis 82 and bronchiectasis, 83 but they are possibly easier to recognize.…”

Section: Definition and Diagnosis Of Ecopdmentioning

confidence: 99%

Chronic obstructive pulmonary disease exacerbation fundamentals: Diagnosis, treatment, prevention and disease impact

et al. 2021

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In chronic obstructive pulmonary disease (COPD), exacerbations (ECOPD), characterized by an acute deterioration in respiratory symptoms, are fundamental events impacting negatively upon disease progression, comorbidities, wellbeing and mortality. ECOPD also represent the largest component of the socioeconomic burden of COPD. ECOPDs are currently defined as acute worsening of respiratory symptoms that require additional therapy. Definitions that require worsening of dyspnoea and sputum volume/purulence assume that acute infections, especially respiratory viral infections, and/or exposure to pollutants are the main cause of ECOPD. But other factors may contribute to ECOPD, such as the exacerbation of other respiratory diseases and non‐respiratory diseases (e.g., heart failure, thromboembolism). The complexity of worsening dyspnoea has suggested a need to improve the definition of ECOPD using objective measurements such as blood counts and C‐reactive protein to improve accuracy of diagnosis and a personalized approach to management. There are three time points when we can intervene to improve outcomes: acutely, to attenuate the length and severity of an established exacerbation; in the aftermath, to prevent early recurrence and readmission, which are common, and in the long‐term, establishing preventative measures that reduce the risk of future events. Acute management includes interventions such as corticosteroids or antibiotics and measures to support the respiratory system, including non‐invasive ventilation (NIV). Current therapies are broad and better understanding of clinical phenotypes and biomarkers may help to establish a more tailored approach, for example in relation to antibiotic prescription. Other unmet needs include effective treatment for viruses, which commonly cause exacerbations. Preventing early recurrence and readmission to hospital is important and the benefits of interventions such as antibiotics or anti‐inflammatories in this period are not established. Domiciliary NIV in those patients who are persistently hypercapnic following discharge and pulmonary rehabilitation can have a positive impact. For long‐term prevention, inhaled therapy is key. Dual bronchodilators reduce exacerbation frequency but in patients with continuing exacerbations, triple therapy should be considered, especially if blood eosinophils are elevated. Other options include phosphodiesterase inhibitors and macrolide antibiotics. ECOPD are a key component of the assessment of COPD severity and future outcomes (quality of life, hospitalisations, health care resource utilization, mortality) and are a central component in pharmacological management decisions. Targeted therapies directed towards specific pathways of inflammation are being explored in exacerbation prevention, and this is a promising avenue for future research.

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“…8,9,54 The choice of antibiotic agent should be based on sputum culture taken either at the start of the current episode or previously isolated, as in the majority of cases there is stability of bacterial infection over time, including during PEx. 13,55 The BTS guidelines recommend first-and second-line antimicrobial therapies according to the bacteria isolated. 9 The recently published EMBARC manual suggests a similar approach, but with a difference of using the Spanish guidelines' definition of PEx with referral to severity of the event.…”

Section: Acute Management Of Exacerbations Antimicrobial Therapymentioning

confidence: 99%

Bronchiectasis Exacerbations: Definitions, Causes, and Acute Management

Perl¹,

Shteinberg

2021

Semin Respir Crit Care Med

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Pulmonary exacerbations (PExs) are events in the course of bronchiectasis which are defined as an increase in disease symptoms lasting a period of a few days. It is established that the tendency toward having PEx is stable throughout the course of the disease. Certain conditions were found to be associated with an increased risk of developing a PEx. Among these are chronic airway infection with Pseudomonas aeruginosa or Aspergillus species, concomitant airway diseases (asthma, chronic obstructive pulmonary disease, and chronic rhinosinusitis), genetic factors such as primary ciliary dyskinesia, and nutritional factors. The immediate events underlying the onset of a PEx are less clearly determined. Although acute changes in bacterial airway composition have been the paradigm for decades, recent microbiome-focused research has not uniformly established such acute changes at the onset of PEx. Other acute changes such as air pollution, viral infection, and changes in bacterial metabolic activity have also been implicated as causes of a PEx. Despite these gaps in our knowledge of the biology of PEx, antimicrobial therapy directed against the identified pathogens in sputum is currently the recommended therapeutic strategy. Various long-term therapies, including antimicrobial and anti-inflammatory strategies, have been proven effective in reducing the frequency of PEx, leading to a recommendation for the use of these strategies in people with frequent PEx.

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The biology of pulmonary exacerbations in bronchiectasis

Cited by 61 publications

References 143 publications

Protease–Antiprotease Imbalance in Bronchiectasis

Protease–Antiprotease Imbalance in Bronchiectasis

Chronic obstructive pulmonary disease exacerbation fundamentals: Diagnosis, treatment, prevention and disease impact

Bronchiectasis Exacerbations: Definitions, Causes, and Acute Management

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