key: cord-0878791-cy3p149s authors: Stanford, Gemma E.; Dave, Kavita; Simmonds, Nicholas J. title: Pulmonary exacerbations in adults with cystic fibrosis - a grown-up issue in a changing CF landscape date: 2020-09-20 journal: Chest DOI: 10.1016/j.chest.2020.09.084 sha: ccfe3bb6e7b7bc8fa230ac4bf1ec7918cc28b9b9 doc_id: 878791 cord_uid: cy3p149s Pulmonary exacerbations (PEx) are significant life events in people with cystic fibrosis (CF), associated with declining lung function, reduced quality of life (QoL), hospitalisations and decreased survival. The adult CF population is increasing worldwide, with many patients surviving prolonged periods with severe multi-morbid disease. In many countries the number of adults with CF exceeds the number of children, and PEx are particularly burdensome for adults as they tend to require longer courses and more intravenous treatment than children. The approach to managing PEx is multifactorial and needs to evolve to reflect this changing adult population. In this review, we discuss PEx definitions, precipitants, treatments and the wider implications to healthcare resources. We review current management strategies, their relevance in particular to adults with CF, and highlight some of the gaps in our knowledge. A number of studies are underway to try to answer some of the unmet needs, such as the optimal length of treatment and the use of non-antimicrobial agents alongside antibiotics. We provide an overview of these issues, concluding that with the changing landscape of adult CF care, the definitions and management of PEx may need to evolve to enable continued improvements in outcomes across the age spectrum of CF. Pulmonary exacerbations (PEx) are recognised as important events in the lives of people with cystic fibrosis (pwCF), with prolonged and frequent exacerbations associated with declining lung function, reduced quality of life (QoL), and decreased survival 1 . Cystic fibrosis (CF) demography is changing -national registries containing data on over 90 000 pwCF 2 reveal that in many countries, the adult CF population far out-numbers the pediatric CF population 2 . Although PEx are significant events across all age groups, the prevalence is higher in adulthood, requiring more antibiotic treatments for longer periods compared to children with CF (Fig 1) 1 . In 2018, based on US CF registry data, approximately 43% of adults (≥18 years) required intravenous antibiotics for a pulmonary exacerbation compared to only 23% of children 1 . In the UK, median (interquartile range) days of intravenous (IV) antibiotics per year for adults (≤16 years) was 28 compared to 16 (14-38) for children 3 . Using western European data, Burgel et al predicted that the number of adults with CF would expand by up to 78% by 2025 4 , while the number of pediatric CF cases would increase by just 20%. An increasing adult CF population (Fig 2) , who have increasing multi-morbidities 2 , will require the approach to PEx management to evolve to recognise these differences. This review article focuses on PEx specifically in adults with CF to discusses these important emerging issues. There remains no universally agreed definition of a PEx, making it difficult to standardise treatments. Historically, a PEx was defined as a deterioration in symptoms and biochemical markers, causing a physician to change treatments. However, by definition, this only accounts for exacerbations that cause management change, excluding those that resolve without antibiotics, so carries inherent problems due to variations in practice. Physician-led treatment remains the simplest definition of a PEx, and has successfully been used in clinical trials 5 , though this is unhelpful as a clinical tool to facilitate antibiotic-initiation decisionmaking. Models have been developed to try to standardise this, with the definition by Fuchs et al 5 being perhaps the most widely recognised, but they are not commonly used clinically ( Table 1 ) and none of these definitions are exclusively for adult populations. Antibiotic initiation is often based on a deterioration in forced expiratory volume in one second (FEV 1 ). As a measurable and reproducible marker of lung health, possible for the majority of adults to complete, it remains a driver for guiding clinical decision-making. The Standardised Treatment of Pulmonary exacerbations (STOP) study highlighted that some pwCF experience PEx without a change in FEV 1 6 ; in these cases, newer modalities such as the lung clearance index (LCI) and/or magnetic resonance imaging (MRI) 7,8 may be helpful, although they are yet to be established in this role, particularly for adults as most of the data is derived from children. In some countries, clinicians rely on C-reactive protein in clinical practice, although this and other biomarkers of inflammation have not yet been effectively incorporated as part of a PEx definition and its associated treatment. Rather than the clinician-led diagnosis of PEx, patient-reported outcome measures (PROMs) are an attractive and promising approach 9 . There have been several attempts to standardise these into scoring systems 9 , such as the Chronic Respiratory Infection Symptom Score (CRISS) 10 . However, currently they have largely been used to show the impact of PEx on patients and are mostly used in research studies. The current suggested definitions 5,11-13 aim to identify a PEx, but none categorise severity or direct treatment. Importantly, they were all developed in an era pre-dating cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new class of small molecule drug which treat the basic defect. These drugs have been shown to significantly reduce the rates of PEx 14,15 with recent phase 3 trials of "triple therapy" modulators reducing PEx frequency by 63% 15 . The exact etiology of PEx and the underlying biological mechanisms driving disease are poorly understood. Pathogens infecting the pulmonary tract are thought to be the most common cause of PEx, but a variety of insults can change the homeostatic balance. PEx are most frequently caused by bacterial infections precipitating an amplified inflammatory response, leading to progressive and irreversible airway damage 16 Respiratory viruses are not found more frequently in pwCF than people with genetically normal lungs 19 , but they are thought to increase susceptibility to new bacterial infections or allow chronic bacteria to flare causing a PEx 20 . Data from a small sample of CF adults highlighted that most PEx were caused by an existing strain of Psa not a new bacterial growth 21 . It remains unclear how much of an impact viruses have on deterioration in adults whereas this is well established in pediatrics; studies in adults are varied, indicating minimal impact on lung function or rate of exacerbations 19, 22 . Influenza A and B, RSV, rhinovirus, parainfluenza, CMV, and adenovirus are found in CF 19, 22 , but influenza A is thought to be the most deleterious in adults 22 . To date, the recent worldwide Coronavirus 2019 (COVID-19) pandemic appears to have had a lower impact upon pwCF than predicted 23 . A multinational report of 40 cases (median age 33yrs) concluded that this may be due to effective shielding from exposure, but that the medium and long term impacts on PwCF from this emerging pathogen are unknown 23 . Not infrequently the precise cause of the PEx is unknown, but patients respond to treatments regardless. Particularly relevant to adults is variable treatment adherence due to time constraints from work or family commitments. Reducing treatment burden and strategies to improve adherence were highlighted as research priorities in a recent survey of J o u r n a l P r e -p r o o f the CF community 24 . Self-monitoring is an emerging field in CF -it may be effective to motivate patients to complete therapies and be vigilant for signs of exacerbations, while giving them greater responsibility away from a hospital-based environment. To date, research is scarce on the effectiveness of home monitoring; one large cohort study 25 reported increased PEx identification, but no difference in FEV 1 decline over 52 weeks which led to early trial termination. The multifactorial presentation of a PEx in CF adults requires a multifaceted approach. Prevention of PEx in PwCF protects against lung injury and reduces rate of lung function decline. A number of pathways are targeted to achieve this, including optimising nutrition and achieving diabetes control. Mucoactive agents are added early in infancy and airway clearance techniques (ACTs) are used throughout the lives of PwCF. More specific interventions have been developed to eradicate bacteria and suppress chronic infections, including using oral and nebulised antibiotics 26 . In severe presentations, adjunctive therapies such as non-invasive ventilation (NIV) and oxygen support may be required. Currently there is no unified consensus for the best treatment or prevention of PEx, and there is a lack of robust evidence to guide clinical practice 27 . Antibiotics are key to PEx management and can be administered orally, by inhalation or IV. Traditionally, particularly in Psa treatment 27 , antibiotic combinations are used, aiming for synergistic antibacterial activity and reducing drug resistance. The STOP study reported that 54% of patients were prescribed two antibiotics, and 35% had three or more 6 . This strategy is currently recommended by European CF Society (ECFS) 26 and US 27 guidelines, despite a lack of robust evidence 27, 28 . While a consensus document on antibiotic treatment for CF 29 identified aminoglycosides, polymixins, b-lactams, cephalosporins and carbopenems as potential antibiotics for use, a systematic review concluded that "no specific antibiotic combination can be considered superior to any other" 30 . The CF community has highlighted the identification of the most effective/least toxic antibiotics as a research priority 24 , while an international survey on antimicrobial stewardship perceptions showed healthcare professionals wanted help with antibiotic choice, dose and minimising resistance 31 . Most initial isolates of Psa are susceptible to commonly used antimicrobial therapies, however with repeated courses of antibiotics resistance develops 32 . Selection of the optimal antibiotic to use is highly debated, treatments based on antibiotic susceptibility tests (AST) from traditional sputum cultures do not always predict an optimal clinical response 33, 34 . AST has limitations, especially in the context of phenotypic and genotypic diversifications of the CF lung microbiome and CF pathogens 33 , although work has shown the airway microbiome to be relatively stable except for transient change with antibiotic treatment in PEx 35 . The recent 'CFMATTERS' trial compared standard antibiotic therapy to standard therapy plus an additional antibiotic selected from microbiome analysis of sputum; results showed no significant difference in clincal endpoints, additionally the active arm required more IV days than standard therapy 36 . In the context of AST, a delphi consensus group recently recommended that decision making is guided by clinical response to interventions instead of AST results 34 . It has been suggested that 25-45% of adults with CF have chronic airway infection of multiresistant bacteria 37 , which has been linked with faster disease progression 32 . This creates an increasing challenge for adult CF teams as this prevalence could increase as median survival continues to improve 32 . Given the complex issue of multiple bacterial growths, more research into optimal antibiotic combinations is required 15 39 . Current evidence for the use of oral antibiotics gives conflicting results, one study suggested oral antibiotics prevented IV use in 79% of mild PEx 41 , whilst another retrospective study concluded a significant proportion of patients did not recover baseline lung function when treated with orals leading to decreased lung function long term 42 . Whilst there is a relatively strong evidence-base for inhaled antibiotics used as a chronic bacterial suppressive therapy, there is minimal evidence to support inhaled antibiotics being used alone to treat PEx 43 . The US CF pulmonary guidelines 27 and UK CF Trust antibiotic guidelines 29 acknowledge that inhaled antibiotics are often used alongside IVs when treating severe PExs, which might be more relevant to adults with CF, however both conclude that there is not enough evidence to scientifically support this practice. The STOP study highlighted heterogeneity in the prescribing of adjunctive inhaled and/or oral antibiotics across US physicians 6 . Using inhaled antibiotics alone as first line to treat PEx may be beneficial as they do not have the same potential drug-related toxicity risks as IV formulations 43 . Traditionally IV antibiotic courses last for 14 days 26,44 but range from 10 to 21 days or extend further in severe infections. The STOP study showed a 15.0 day (SD 6.0) mean IV treatment duration 6 , although patients with FEV 1 50% or below and those aged over 18 years were treated nearly two days longer. Retrospective data from the Epidemiological Study of CF has shown no relationship between IV treatment duration and recovery of FEV 1 45 . It may be argued that shorter IV courses have less risk of side effects and are better for the patient's QoL and adherence, while being cheaper for providers, however courses that are too short may lead to only partial recovery and therefore necessitate further treatment 44 . CFF registry data identified a significant increased risk of another PEx with treatment courses below nine days or above 23 days 46 ECFS best practice guidelines advocate assessing lung function at the beginning and end of PEx treatment 26 , as many patients do not recover baseline lung function at the end of treatment or have another PEx within a short time 47, 48 which is detrimental to future health 47 . Time to next exacerbation has been used in some trials as a marker of treatment success, but this is affected by many variables. It is important to note from the STOP data, changes in objective clinical outcomes did not correlate well with the physician's subjective judgement of treatment success 49 and neither did it correlate with the patients' symptom scores, particularly for adult patients 50 . This highlights the necessity to incorporate both objective measures and PROMs when evaluating treatment effects. Particularly relevant to adults with CF is the possibility of self-administering IV antibiotics at home, once trained to complete this safely and effectively. While this may be preferential for some, completing IV therapy alongside self-care can be time-consuming and effortful, with higher fatigue scores recorded in home IV candidates 51 26, 27 . With an increasingly multi-morbid adult population, treating patients at home -particularly with severe disease -may become even more of a challenge. Mucoactive medications include hyperosmolar drugs such as hypertonic saline (HTS) and mannitol -which work to increase the airway surface liquid -and dornase alfa, which breaks down DNA released by neutrophils in infected airways 55 NIV can be used to decrease the effort required by patients during ACT, and can be helpful for individuals having difficulty expectorating sputum 62 . NIV with ACT in adults has been shown to improve dyspnoea 63 , increase inspiratory muscle function 63 , decrease fatigue 64 and improve FEV 1 faster compared to usual ACT during PEx 64 . There are significant variations in medication use to treat the inflammatory component of As adults with CF have generally more severe disease than children, the use of oxygen and NIV is significantly higher (Fig 3 67 ) , and has been increasing steadily over the last decade 1,68 . Currently 8.9% of UK adults with CF use supplementary oxygen and 2.9% NIV, compared with 1.8% and 0.4% in the pediatric population, respectively 3 . In the US, the median FEV 1 for children in 2018 was 94.3% with only a very small minority in the severe lung disease category (<40% predicted FEV 1 ), whereas the median value for adults was 69.4% with J o u r n a l P r e -p r o o f around 20% of adults aged over 30 years in the severe category 1 . There is no specific guidance on the use of emergency oxygen for CF, so much of the advice is extrapolated from generic respiratory guidelines for emergency oxygen use in adult patients 69 The landscape in CF is changing with increasingly more adult patients. These patients have disease characteristics and treatment requirements that are diverging from the pediatric population, as they have more severe disease and multiple co-morbidities. The introduction of CFTR modulators may hail an era of PEx reduction, but there will remain an adult population for the foreseeable future with CF-related lung damage for whom PEx management is complicated and challenging. PEx etiology is multifactorial and the management often complex, requiring a multifaceted approach. A better definition of PEx is still required and more effective management of the infective and non-infective components of the PEx is needed, supported by a stronger evidence-base. Currently there are ongoing studies aiming to answer some of the key questions in PEx management. Until there is more robust evidence for many aspects of management clinicians need to supplement the evidence base by extrapolating data from stable-state studies, clinical guidelines and thorough assessment of the individual. It is not yet known if in the future adults with better lung function will experience PEx in the same way, but it is likely that definitions and management will need to evolve, as the issues we have highlighted will continue to change. At least 2 signs/symptoms from a pre-defined list AND one from a second list. List 1: Fever >38C; 50% increase in cough or more; 50% increase in sputum volume; loss of appetite; weight loss of 1kg or more; absence from school or work for at least 3 out of the preceding 7 days due to illness; symptoms of an upper respiratory tract infection. List 2: Decrease in FEV 1 of at least 10%; increase in respiratory rate of at least 10 breaths/min; peripheral neutrophil count of >15. 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