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Review
Management of pulmonary exacerbations in cystic fibrosis: still an unmet medical need in clinical practice Expert Rev. Respir. Med. Early online, 1–12 (2015)
Jose Luis Justicia1, Amparo Sole2, Esther Quintana-Gallego3, Silvia Gartner4, Javier de Gracia4, Concepcion Prados5 and Luis Ma´iz*6 1 Gilead – Respiratory Department, Madrid, Spain 2 Hospital La Fe, Valencia, Spain 3 Hospital Vı´rgen del Rocı´o, Sevilla, Spain 4 Hospital Vall d´Hebron, Barcelona, Spain 5 Hospital La Paz, Madrid, Spain 6 Hospital Ramon y Cajal – Pneumology, Crta. de Colmenar Km 9.100, Madrid 28034, Spain *Author for correspondence: [email protected]
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Pulmonary exacerbation (PEx) is a hallmark of cystic fibrosis. Although several criteria have been proposed for the definition of PEx, no consensus has yet been reached. Very often, many PEx cases go unreported. A standardized and validated definition is needed to reduce variability in clinical practice. The pathophysiology of recurrent episodes remains unclear, and both onset and risk are multifactorial. PEx leads to increased healthcare costs, impaired quality of life and a cycle in which PEx causes loss of lung function, which predisposes to further episodes. The number of episodes affects survival. Although early diagnosis and aggressive treatment are highly recommended, measures to prevent the emergence of new PEx are even more important. In particular, inhaled antibiotics administered under new treatment schedules could play a key role in preventing exacerbations and thus delay decline in lung function and reduce mortality. The primary objective is zero exacerbations. KEYWORDS: cystic fibrosis . inhaled antibiotics . prevention . prognosis . pulmonary exacerbations
Cystic fibrosis (CF) is a genetic disease that causes complications in several organs, particularly the lungs and the pancreas. With an incidence of 1 in 1800–25,000 live births, depending on the country [1], CF is the most common fatal autosomal recessive disease in Caucasians [2], affecting about 70,000 people in Europe and the USA [1,3]. Although CF affects several systems, progressive pulmonary involvement is responsible for most of the associated morbidity and mortality. No cure for CF has been found. The disease is caused by mutations in CFTR, a 250-kb gene on the long (q) arm of chromosome 7 that encodes the CF transmembrane conductance regulator protein [4,5]. This protein is an epithelial ion channel that regulates the absorption and secretion of salt and water in a variety of tissues, including the lung, sweat glands, gastrointestinal tract and pancreas [5–7]. The resultant viscous mucosal obstruction of exocrine glands with neutrophil-dominated debris is one of the hallmarks of the disease and 10.1586/17476348.2015.1016504
can cause inadequate airway hydration, vulnerability of the airway to chronic infection and inflammation with subsequent irreversible lung damage [8–10]. Although the use of medications to slow the progression of lung disease has led to a significant improvement in survival – the median age of survival in CF patients in the USA increased from 14 years in 1969 to 41 years in 2012 [3] (similar data were collected in the UK cohort [11]) – 80% of patients with CF still die of end-stage lung disease [3] and lung transplantation remains the only effective treatment to delay premature death [12,13]. Pulmonary exacerbation (PEx) is a hallmark of CF. It is characterized by an increase in pulmonary symptoms, which is often accompanied by decreased lung function and systemic symptoms [14]. PEx have been associated with higher health care costs [15,16], reduced quality of life [17], faster decline in lung function [18] and increased mortality [19]. In this article, we review current definitions of PEx and investigate the incidence and
2015 Informa UK Ltd
ISSN 1747-6348
1
Review
Justicia, Sole, Quintana-Gallego et al.
pathogenesis of this condition. We examine risk factors and clinical consequences (including impact on survival), as well as early diagnosis and treatment. Prevention of PEx in patients with CF is also addressed. Pulmonary exacerbations in cystic fibrosis
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/25/15 For personal use only.
Definition
Different criteria have been used for the definition and diagnosis of PEx in CF (TABLE 1) [14,20–25]. Despite these proposals, no consensus has been reached on the diagnostic criteria for identifying a PEx, as demonstrated in the study of Dakin et al. [26], who designed a questionnaire based on a comprehensive list of the symptoms, signs and investigations used to define PEx in published trials. Responses for the items considered helpful in the diagnosis of an exacerbation requiring treatment were requested from 62 physicians managing people with CF. Consensus (>74% or 74% of respondents. Conversely, few respondents considered investigations such as chest x-rays and blood tests to be helpful. The overall variability in responses was as great within clinics as between clinics. The criteria used by clinicians to define a PEx do not always coincide with the symptoms reported by patients. For many patients, the onset of an exacerbation is characterized by fatigue and changes in sleep patterns, cough, sputum, appetite, mood and daily activities. Those with mild disease typically report ‘cold’ symptoms, whereas those with severe disease find it more difficult to recognize the onset of an exacerbation [27]. In pediatric patients with early lung disease experiencing a PEx, cough is the predominant symptom, although it is not necessarily associated with decreased lung function, low oxygen saturation or weight loss [28]. In very young CF patients, PEx has been defined as ‘any change in respiratory symptoms from baseline’ [29]. If common criteria are not established to define what an exacerbation is and how to treat it, the clinical approach to PEx can vary widely, as in the study of Kraynack et al. [30], in which 112 CF clinicians from 13 American CF centers were given four options for treatment of patients described in 28 vignettes. No consensus was reached for any given scenario, and approaches varied within and between care centers, even at the level of the individual clinician. This variation in the identification of and treatment strategies for PEx can lead to paradoxical findings: more unstable patients may receive additional antibiotics to treat an exacerbation less frequently than patients with milder and fewer symptoms (FIGURE 1). A further consequence of the lack of a standardized definition of PEx in CF is the difficulty in comparing clinical trials in which reduction in the frequency of PEx or time to first PEx is a primary outcome measure of the study as pointed out by EuroCare CF Working Group [25]. doi: 10.1586/17476348.2015.1016504
Incidence
Several studies have assessed the frequency of PEx in patients with CF. One retrospective study of 94 patients aged >16 years recruited in five CF centers in the UK found the mean rate of PEx per patient per year to be 3.6 (1.5 treated in hospital and 2.2 at home). Over half of the patients (57%) had at least one PEx requiring hospitalization, and 83% of patients had hometreated exacerbations [31]. In a cross-sectional study of data from 341 CF patients collected in the south and west of England in 2002, the mean number of annual PEx requiring intravenous antibiotics was 1.5 (median 1.0, range 0–16); 62% of patients had at least one exacerbation and 25% had three or more [32]. A prospective evaluation of respiratory exacerbations in 168 children with CF followed from newborn screening to age 5 years revealed an average rate of 3.66 exacerbations per person per year, 19.9% of which required hospital admission [29]. The incidence of PEx seems to increase with age. In an analysis of data from 11,692 consecutive CF patients included in a large prospective multicenter database (Epidemiologic Study of Cystic Fibrosis), the percentage of patients with a PEx during the 6-month observation period increased from 23% for those aged 38 C
.
.
.
Anorexia or weight loss
.
.§
.
Sinus pain or tenderness
.
Change in sinus discharge
.
Change in physical examination of the chest
.
Decrease in pulmonary function by 10% or more from a previously recorded value
.
Radiographic changes indicative of pulmonary infection
.
Appetite
.
.‡‡ .
.‡
.
.§§
.
.#
.
. .
Energy
.
Crackles Work/school absenteeism
.¶
Symptoms of upper respiratory tract infection
.
Increased work of breath
.
Wheezing
.
Sore throat/runny nose
.
Decreased exercise tolerance †
Increased sputum volume (increase of 50%). More frequent coughing (increase of 50%). Weight loss of at least 1 kg. ¶ Absence from school or work (at least 3 of preceding 7 days) due to illness. # Decrease in breath sounds/wheezing (no. of lobes). †† Rate of breath is scored depending on the age. ‡‡ Includes three different items: increased sputum volume, change in sputum volume, change in sputum consistency. §§ Includes three different items: increased day cough, increased night cough and wet or congested cough. ¶¶ Includes four items: Increased sputum volume, change in sputum appearance, color or consistency. ## Increased dyspnea with exertion. ††† Temperature value is not defined. ‡‡‡ Decreased appetite/ anorexia are included as the same item, weight loss is an independent item. §§§ Change in sputum volume or color. CF: Cystic fibrosis. ‡ §
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Justicia, Sole, Quintana-Gallego et al.
Table 1. Different criteria used for the definition and diagnosis of a pulmonary exacerbation in CF (cont.).
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/25/15 For personal use only.
Fuchs
[20]
Ramsey
Kanga
[21]
ARIC
[23]
Type of study
Prospective
Controlled trial
Interventional randomized doubleblind trial
Exacerbation definition
At least four of 12
At least two of seven plus at least one of three additional criteria
Based on a scoring system (five symptoms + five signs)
[14]
Symptom score
Signs and symptoms (cont.) Chest congestion
Additional criteria Decrease in forced vital capacity of ‡10%
.
Increase in respiratory rate of ‡10 breaths/minute
.
Peripheral blood neutrophil count of ‡15,000 cells/mm3
.
RSSQ
[14]
Type of study
Exacerbation definition
Symptom score
Rosenfeld
.††
EuroCareCF Working Group [25]
CFF
Phase III randomized, controlled trial
Based on Fuchs’ criteria
Patients registry
Mathematical model (two models)
The need for additional antibiotic treatment by recent observation of at least two of the following
[24]
[3]
Signs and symptoms Change in sputum
.¶¶
.
.
.§§§
.
New or increased hemoptysis
.
Increased cough
.
.
.
.
.
Increased dyspnea
.##
.
.
Malaise, fatigue or lethargy
.
.
Temperature >38 C
.†††
Anorexia or weight loss
.‡‡‡
Sinus pain or tenderness
.
Change in sinus discharge
.
.
†
Increased sputum volume (increase of 50%). More frequent coughing (increase of 50%). Weight loss of at least 1 kg. ¶ Absence from school or work (at least 3 of preceding 7 days) due to illness. # Decrease in breath sounds/wheezing (no. of lobes). †† Rate of breath is scored depending on the age. ‡‡ Includes three different items: increased sputum volume, change in sputum volume, change in sputum consistency. §§ Includes three different items: increased day cough, increased night cough and wet or congested cough. ¶¶ Includes four items: Increased sputum volume, change in sputum appearance, color or consistency. ## Increased dyspnea with exertion. ††† Temperature value is not defined. ‡‡‡ Decreased appetite/ anorexia are included as the same item, weight loss is an independent item. §§§ Change in sputum volume or color. CF: Cystic fibrosis. ‡ §
doi: 10.1586/17476348.2015.1016504
Expert Rev. Respir. Med.
Management of pulmonary exacerbations in CF
Review
Table 1. Different criteria used for the definition and diagnosis of a pulmonary exacerbation in CF (cont.). RSSQ
Rosenfeld
[14]
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Type of study
Exacerbation definition
Symptom score
EuroCareCF Working Group
[24]
CFF
[3]
[25]
Phase III randomized, controlled trial
Based on Fuchs’ criteria
Mathematical model (two models)
The need for additional antibiotic treatment by recent observation of at least two of the following
Patients registry
Signs and symptoms (cont.) .
Change in physical examination of the chest
.
Decrease in pulmonary function by 10% or more from a previously recorded value
.
Radiographic changes indicative of pulmonary infection
.
Decreased appetite
.‡‡‡
.
.
. .
Decreased energy Crackles .
.
.
Decreased exercise tolerance
.
.
.
Chest congestion
.
Work/school absenteeism Symptoms of upper respiratory tract infection Increased work of breath Wheezing Sore throat/runny nose
Change in FEV1 (% predicted)
.
Additional criteria Decrease in forced vital capacity of ‡10% Increase in respiratory rate of ‡10 breaths/min Peripheral blood neutrophil count of ‡15,000 cells/mm3 †
Increased sputum volume (increase of 50%). More frequent coughing (increase of 50%). Weight loss of at least 1 kg. ¶ Absence from school or work (at least 3 of preceding 7 days) due to illness. # Decrease in breath sounds/wheezing (no. of lobes). †† Rate of breath is scored depending on the age. ‡‡ Includes three different items: increased sputum volume, change in sputum volume, change in sputum consistency. §§ Includes three different items: increased day cough, increased night cough and wet or congested cough. ¶¶ Includes four items: Increased sputum volume, change in sputum appearance, color or consistency. ## Increased dyspnea with exertion. ††† Temperature value is not defined. ‡‡‡ Decreased appetite/ anorexia are included as the same item, weight loss is an independent item. §§§ Change in sputum volume or color. CF: Cystic fibrosis. ‡ §
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doi: 10.1586/17476348.2015.1016504
Review
Justicia, Sole, Quintana-Gallego et al.
caused by intrapulmonary spread of infection rather than by changes in air10 way microbiota [37], although oropharyngeal contamination could limit the 5 accuracy of DNA-based measurements [46]. Panel B Some pharmacologic agents have been also described as related to PEx. For 10 example, in a multivariate model of fac5 tors predicting PEx, inhaled corticosteroids and azithromycin were respectively associated to higher and lower risk of Weeks PEx during the first year of follow-up Figure 1. One of the consequences of the lack of common criteria to define PEx [47]. is the fact that patients with a more stable clinical course may receive additional It has been demonstrated that environantibiotics to treat an exacerbation more frequently (panel A) than unstable mental and genetic factors make contripatients (panel B). Arrows Use of additional antibiotics to treat a PEx. butions of approximately similar This figure is only illustrative; it does not come from real patient’s data actually. magnitude to variation in CF lung disPEx: Pulmonary exacerbation. ease [48]. Second-hand smoke exposure [49–53], socio-economic status [54], strain of P. aeruginosa could be associated with a PEx in adult healthcare access [55–57], air pollution [58] and more recently CF patients was excluded in the study by Aaron et al. [39], who ambient temperature [59] have been described as factors that showed that in 94% of patients, the P. aeruginosa recovered affect CF lung disease, and so they may influence the appearduring periods of clinical stability was of the same genotype as ance of PEx. that detected in the exacerbation episodes. Besides microbiological, pharmacological and environmental Bacterial biofilms are effective physical and metabolic bar- factors, a longitudinal retrospective review of adherence to riers to antibiotic susceptibility, even in organisms that are sus- medication and health outcomes has shown that poor adherceptible when growing under planktonic conditions. How ence was a significant predictor of PEx during a concurrent biofilms contribute to clinical outcomes in CF remains unde- 12-month period [60]. fined; however, given that bacterial biofilms are always present in chronically infected patients and these patients only experi- Risk factors ence periodic exacerbations, biofilms could act as resilient reser- Identification of risk factors associated with PEx could enable voirs from which planktonic bacteria ‘bloom.’ Consequently, it early detection and close monitoring of high-risk patients. The has been hypothesized than an intense inflammatory response predictors of an increased risk of PEx include impaired lung and clinical symptoms that characterize exacerbations could be function [32,47,61] (including lung clearance index [62]), age [47,61], triggered [40]. P. aeruginosa infection [32], CF-related diabetes [32], chronic use Infections by viruses (mainly rhinovirus) are major causes of of inhaled corticosteroids [47], low levels of hemoglobin [63] and PEx [39–43], and the results of a recent study showed that viral serum estradiol levels in women [64]. respiratory tract infections were associated with 65% of PEx in In a study of 249 CF patients who were prospectively folchildren and adults [41]. Some authors have proposed an inter- lowed for up to 4.5 years, administration of more than three esting pathogenic mechanism by which rhinovirus infection lib- courses of intravenous antibiotics for PEx in the previous erates P. aeruginosa from biofilms [41,44]. Planktonic bacteria, 24 months was associated with a 20-fold increased risk of which are more pro-inflammatory than bacteria that grow as exacerbation within the first year of follow-up [47]. These findbiofilm, stimulate increased chemokine responses in CF airway ings clearly show that a previous history of recent PEx is highly epithelial cells that may in turn contribute to the pathogenesis predictive of future exacerbations. of PEx [44]. In addition, respiratory syncytial virus has been shown to disrupt CF epithelial monolayer integrity in vitro [45]. Consequences Given the microbial complexity of CF airways, it has been The main consequences of PEx in patients with CF include postulated that microorganisms other than those typically con- higher drug consumption, the need for in-patient care, and sidered causative of acute exacerbations (P. aeruginosa, Staphylo- absenteeism (school and work) of patients and caregivers, all of coccus aureus, Haemophilus influenzae, Burkholderia cepacia which are in turn associated with an increase in the total cost complex, Stenotrophomonas maltophilia and Achromobacter xylo- of the disease [15,65]. Moreover, PEx has a profound and negasoxidans) have a direct or indirect role in the pathogenesis of tive impact on physical and psychosocial health-related quality PEx. However, the results of genomic studies of the lung of life [17] and adversely affects sleep and neurobehavioral microbiome suggest that PEx in patients with CF may be performance [66].
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Symptoms score
Panel A
doi: 10.1586/17476348.2015.1016504
Expert Rev. Respir. Med.
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Management of pulmonary exacerbations in CF
Review
Follow-up studies have revealed a strong relation between the number of exacerbations per year and the time between exacerbations and the decline in FEV1 [18,29,67]. Approximately, one in four CF patients (children and adults) was unable to regain 90% of baseline lung function after a PEx despite treatment with intravenous antibiotics [68,69]. In many cases, patients experience a substantial decline in lung function with an exacerbation followed by recovery of baseline values immediately after treatment, although long-term lung function is not necessarily preserved (the new baseline FEV1 after a PEx can be lower than the original baseline FEV1 before the PEx) [70]. A vicious circle is thus created in which PEx causes a decrease in lung function, and impaired lung function predisposes to further exacerbations. Measures can be taken to prevent exacerbations, but few options are available to treat the irreversible loss of lung function. Therefore, measures to prevent PEx are crucial for delaying the decline in lung function in CF.
Table 2. Treatment strategies for cystic fibrosis related pulmonary exacerbations. Strategy
Grade of recommendation
Maintenance of chronic therapies
B
Airway clearance therapies
B
Aminoglycoside dosing (1 or 3/day)
C
Synergic testing (routine)
D
Number of antibiotics
I
Duration of antibiotic treatment
I
Site of treatment (home or hospital)
I
Simultaneous use of inhaled and intravenous antibiotics
I
Continuous infusion of beta-lactam antibiotics
I
Impact on survival
Systemic corticosteroids
I
In addition to the increased morbidity of CF caused by PEx, the annual number of exacerbations has a considerable impact on survival. In a predictive model of 2-year mortality, patients who were hospitalized for acute exacerbations more than twice annually were 3.5-times more likely to die within 2 years than those who were not hospitalized, independently of the presence or absence of other risk factors [13]. In a 5-year validated survivorship model of CF using data from 5820 patients selected randomly from 11,630 patients in the Cystic Fibrosis Foundation Patient Registry, each acute PEx within the first year of follow-up increased by 1.5-times the risk of death in the following 4 years, so that four exacerbations in a single year had the same negative effect on survival as infection with B. cepacia [71]. In a 3-year prospective cohort study conducted among 446 adult patients with CF in Ontario, Canada, patients with >2 exacerbations per year had a greater risk of lung transplant or death during the study than patients with
Review
Management of pulmonary exacerbations in cystic fibrosis: still an unmet medical need in clinical practice Expert Rev. Respir. Med. Early online, 1–12 (2015)
Jose Luis Justicia1, Amparo Sole2, Esther Quintana-Gallego3, Silvia Gartner4, Javier de Gracia4, Concepcion Prados5 and Luis Ma´iz*6 1 Gilead – Respiratory Department, Madrid, Spain 2 Hospital La Fe, Valencia, Spain 3 Hospital Vı´rgen del Rocı´o, Sevilla, Spain 4 Hospital Vall d´Hebron, Barcelona, Spain 5 Hospital La Paz, Madrid, Spain 6 Hospital Ramon y Cajal – Pneumology, Crta. de Colmenar Km 9.100, Madrid 28034, Spain *Author for correspondence: [email protected]
informahealthcare.com
Pulmonary exacerbation (PEx) is a hallmark of cystic fibrosis. Although several criteria have been proposed for the definition of PEx, no consensus has yet been reached. Very often, many PEx cases go unreported. A standardized and validated definition is needed to reduce variability in clinical practice. The pathophysiology of recurrent episodes remains unclear, and both onset and risk are multifactorial. PEx leads to increased healthcare costs, impaired quality of life and a cycle in which PEx causes loss of lung function, which predisposes to further episodes. The number of episodes affects survival. Although early diagnosis and aggressive treatment are highly recommended, measures to prevent the emergence of new PEx are even more important. In particular, inhaled antibiotics administered under new treatment schedules could play a key role in preventing exacerbations and thus delay decline in lung function and reduce mortality. The primary objective is zero exacerbations. KEYWORDS: cystic fibrosis . inhaled antibiotics . prevention . prognosis . pulmonary exacerbations
Cystic fibrosis (CF) is a genetic disease that causes complications in several organs, particularly the lungs and the pancreas. With an incidence of 1 in 1800–25,000 live births, depending on the country [1], CF is the most common fatal autosomal recessive disease in Caucasians [2], affecting about 70,000 people in Europe and the USA [1,3]. Although CF affects several systems, progressive pulmonary involvement is responsible for most of the associated morbidity and mortality. No cure for CF has been found. The disease is caused by mutations in CFTR, a 250-kb gene on the long (q) arm of chromosome 7 that encodes the CF transmembrane conductance regulator protein [4,5]. This protein is an epithelial ion channel that regulates the absorption and secretion of salt and water in a variety of tissues, including the lung, sweat glands, gastrointestinal tract and pancreas [5–7]. The resultant viscous mucosal obstruction of exocrine glands with neutrophil-dominated debris is one of the hallmarks of the disease and 10.1586/17476348.2015.1016504
can cause inadequate airway hydration, vulnerability of the airway to chronic infection and inflammation with subsequent irreversible lung damage [8–10]. Although the use of medications to slow the progression of lung disease has led to a significant improvement in survival – the median age of survival in CF patients in the USA increased from 14 years in 1969 to 41 years in 2012 [3] (similar data were collected in the UK cohort [11]) – 80% of patients with CF still die of end-stage lung disease [3] and lung transplantation remains the only effective treatment to delay premature death [12,13]. Pulmonary exacerbation (PEx) is a hallmark of CF. It is characterized by an increase in pulmonary symptoms, which is often accompanied by decreased lung function and systemic symptoms [14]. PEx have been associated with higher health care costs [15,16], reduced quality of life [17], faster decline in lung function [18] and increased mortality [19]. In this article, we review current definitions of PEx and investigate the incidence and
2015 Informa UK Ltd
ISSN 1747-6348
1
Review
Justicia, Sole, Quintana-Gallego et al.
pathogenesis of this condition. We examine risk factors and clinical consequences (including impact on survival), as well as early diagnosis and treatment. Prevention of PEx in patients with CF is also addressed. Pulmonary exacerbations in cystic fibrosis
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/25/15 For personal use only.
Definition
Different criteria have been used for the definition and diagnosis of PEx in CF (TABLE 1) [14,20–25]. Despite these proposals, no consensus has been reached on the diagnostic criteria for identifying a PEx, as demonstrated in the study of Dakin et al. [26], who designed a questionnaire based on a comprehensive list of the symptoms, signs and investigations used to define PEx in published trials. Responses for the items considered helpful in the diagnosis of an exacerbation requiring treatment were requested from 62 physicians managing people with CF. Consensus (>74% or 74% of respondents. Conversely, few respondents considered investigations such as chest x-rays and blood tests to be helpful. The overall variability in responses was as great within clinics as between clinics. The criteria used by clinicians to define a PEx do not always coincide with the symptoms reported by patients. For many patients, the onset of an exacerbation is characterized by fatigue and changes in sleep patterns, cough, sputum, appetite, mood and daily activities. Those with mild disease typically report ‘cold’ symptoms, whereas those with severe disease find it more difficult to recognize the onset of an exacerbation [27]. In pediatric patients with early lung disease experiencing a PEx, cough is the predominant symptom, although it is not necessarily associated with decreased lung function, low oxygen saturation or weight loss [28]. In very young CF patients, PEx has been defined as ‘any change in respiratory symptoms from baseline’ [29]. If common criteria are not established to define what an exacerbation is and how to treat it, the clinical approach to PEx can vary widely, as in the study of Kraynack et al. [30], in which 112 CF clinicians from 13 American CF centers were given four options for treatment of patients described in 28 vignettes. No consensus was reached for any given scenario, and approaches varied within and between care centers, even at the level of the individual clinician. This variation in the identification of and treatment strategies for PEx can lead to paradoxical findings: more unstable patients may receive additional antibiotics to treat an exacerbation less frequently than patients with milder and fewer symptoms (FIGURE 1). A further consequence of the lack of a standardized definition of PEx in CF is the difficulty in comparing clinical trials in which reduction in the frequency of PEx or time to first PEx is a primary outcome measure of the study as pointed out by EuroCare CF Working Group [25]. doi: 10.1586/17476348.2015.1016504
Incidence
Several studies have assessed the frequency of PEx in patients with CF. One retrospective study of 94 patients aged >16 years recruited in five CF centers in the UK found the mean rate of PEx per patient per year to be 3.6 (1.5 treated in hospital and 2.2 at home). Over half of the patients (57%) had at least one PEx requiring hospitalization, and 83% of patients had hometreated exacerbations [31]. In a cross-sectional study of data from 341 CF patients collected in the south and west of England in 2002, the mean number of annual PEx requiring intravenous antibiotics was 1.5 (median 1.0, range 0–16); 62% of patients had at least one exacerbation and 25% had three or more [32]. A prospective evaluation of respiratory exacerbations in 168 children with CF followed from newborn screening to age 5 years revealed an average rate of 3.66 exacerbations per person per year, 19.9% of which required hospital admission [29]. The incidence of PEx seems to increase with age. In an analysis of data from 11,692 consecutive CF patients included in a large prospective multicenter database (Epidemiologic Study of Cystic Fibrosis), the percentage of patients with a PEx during the 6-month observation period increased from 23% for those aged 38 C
.
.
.
Anorexia or weight loss
.
.§
.
Sinus pain or tenderness
.
Change in sinus discharge
.
Change in physical examination of the chest
.
Decrease in pulmonary function by 10% or more from a previously recorded value
.
Radiographic changes indicative of pulmonary infection
.
Appetite
.
.‡‡ .
.‡
.
.§§
.
.#
.
. .
Energy
.
Crackles Work/school absenteeism
.¶
Symptoms of upper respiratory tract infection
.
Increased work of breath
.
Wheezing
.
Sore throat/runny nose
.
Decreased exercise tolerance †
Increased sputum volume (increase of 50%). More frequent coughing (increase of 50%). Weight loss of at least 1 kg. ¶ Absence from school or work (at least 3 of preceding 7 days) due to illness. # Decrease in breath sounds/wheezing (no. of lobes). †† Rate of breath is scored depending on the age. ‡‡ Includes three different items: increased sputum volume, change in sputum volume, change in sputum consistency. §§ Includes three different items: increased day cough, increased night cough and wet or congested cough. ¶¶ Includes four items: Increased sputum volume, change in sputum appearance, color or consistency. ## Increased dyspnea with exertion. ††† Temperature value is not defined. ‡‡‡ Decreased appetite/ anorexia are included as the same item, weight loss is an independent item. §§§ Change in sputum volume or color. CF: Cystic fibrosis. ‡ §
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doi: 10.1586/17476348.2015.1016504
Review
Justicia, Sole, Quintana-Gallego et al.
Table 1. Different criteria used for the definition and diagnosis of a pulmonary exacerbation in CF (cont.).
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/25/15 For personal use only.
Fuchs
[20]
Ramsey
Kanga
[21]
ARIC
[23]
Type of study
Prospective
Controlled trial
Interventional randomized doubleblind trial
Exacerbation definition
At least four of 12
At least two of seven plus at least one of three additional criteria
Based on a scoring system (five symptoms + five signs)
[14]
Symptom score
Signs and symptoms (cont.) Chest congestion
Additional criteria Decrease in forced vital capacity of ‡10%
.
Increase in respiratory rate of ‡10 breaths/minute
.
Peripheral blood neutrophil count of ‡15,000 cells/mm3
.
RSSQ
[14]
Type of study
Exacerbation definition
Symptom score
Rosenfeld
.††
EuroCareCF Working Group [25]
CFF
Phase III randomized, controlled trial
Based on Fuchs’ criteria
Patients registry
Mathematical model (two models)
The need for additional antibiotic treatment by recent observation of at least two of the following
[24]
[3]
Signs and symptoms Change in sputum
.¶¶
.
.
.§§§
.
New or increased hemoptysis
.
Increased cough
.
.
.
.
.
Increased dyspnea
.##
.
.
Malaise, fatigue or lethargy
.
.
Temperature >38 C
.†††
Anorexia or weight loss
.‡‡‡
Sinus pain or tenderness
.
Change in sinus discharge
.
.
†
Increased sputum volume (increase of 50%). More frequent coughing (increase of 50%). Weight loss of at least 1 kg. ¶ Absence from school or work (at least 3 of preceding 7 days) due to illness. # Decrease in breath sounds/wheezing (no. of lobes). †† Rate of breath is scored depending on the age. ‡‡ Includes three different items: increased sputum volume, change in sputum volume, change in sputum consistency. §§ Includes three different items: increased day cough, increased night cough and wet or congested cough. ¶¶ Includes four items: Increased sputum volume, change in sputum appearance, color or consistency. ## Increased dyspnea with exertion. ††† Temperature value is not defined. ‡‡‡ Decreased appetite/ anorexia are included as the same item, weight loss is an independent item. §§§ Change in sputum volume or color. CF: Cystic fibrosis. ‡ §
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Expert Rev. Respir. Med.
Management of pulmonary exacerbations in CF
Review
Table 1. Different criteria used for the definition and diagnosis of a pulmonary exacerbation in CF (cont.). RSSQ
Rosenfeld
[14]
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Type of study
Exacerbation definition
Symptom score
EuroCareCF Working Group
[24]
CFF
[3]
[25]
Phase III randomized, controlled trial
Based on Fuchs’ criteria
Mathematical model (two models)
The need for additional antibiotic treatment by recent observation of at least two of the following
Patients registry
Signs and symptoms (cont.) .
Change in physical examination of the chest
.
Decrease in pulmonary function by 10% or more from a previously recorded value
.
Radiographic changes indicative of pulmonary infection
.
Decreased appetite
.‡‡‡
.
.
. .
Decreased energy Crackles .
.
.
Decreased exercise tolerance
.
.
.
Chest congestion
.
Work/school absenteeism Symptoms of upper respiratory tract infection Increased work of breath Wheezing Sore throat/runny nose
Change in FEV1 (% predicted)
.
Additional criteria Decrease in forced vital capacity of ‡10% Increase in respiratory rate of ‡10 breaths/min Peripheral blood neutrophil count of ‡15,000 cells/mm3 †
Increased sputum volume (increase of 50%). More frequent coughing (increase of 50%). Weight loss of at least 1 kg. ¶ Absence from school or work (at least 3 of preceding 7 days) due to illness. # Decrease in breath sounds/wheezing (no. of lobes). †† Rate of breath is scored depending on the age. ‡‡ Includes three different items: increased sputum volume, change in sputum volume, change in sputum consistency. §§ Includes three different items: increased day cough, increased night cough and wet or congested cough. ¶¶ Includes four items: Increased sputum volume, change in sputum appearance, color or consistency. ## Increased dyspnea with exertion. ††† Temperature value is not defined. ‡‡‡ Decreased appetite/ anorexia are included as the same item, weight loss is an independent item. §§§ Change in sputum volume or color. CF: Cystic fibrosis. ‡ §
informahealthcare.com
doi: 10.1586/17476348.2015.1016504
Review
Justicia, Sole, Quintana-Gallego et al.
caused by intrapulmonary spread of infection rather than by changes in air10 way microbiota [37], although oropharyngeal contamination could limit the 5 accuracy of DNA-based measurements [46]. Panel B Some pharmacologic agents have been also described as related to PEx. For 10 example, in a multivariate model of fac5 tors predicting PEx, inhaled corticosteroids and azithromycin were respectively associated to higher and lower risk of Weeks PEx during the first year of follow-up Figure 1. One of the consequences of the lack of common criteria to define PEx [47]. is the fact that patients with a more stable clinical course may receive additional It has been demonstrated that environantibiotics to treat an exacerbation more frequently (panel A) than unstable mental and genetic factors make contripatients (panel B). Arrows Use of additional antibiotics to treat a PEx. butions of approximately similar This figure is only illustrative; it does not come from real patient’s data actually. magnitude to variation in CF lung disPEx: Pulmonary exacerbation. ease [48]. Second-hand smoke exposure [49–53], socio-economic status [54], strain of P. aeruginosa could be associated with a PEx in adult healthcare access [55–57], air pollution [58] and more recently CF patients was excluded in the study by Aaron et al. [39], who ambient temperature [59] have been described as factors that showed that in 94% of patients, the P. aeruginosa recovered affect CF lung disease, and so they may influence the appearduring periods of clinical stability was of the same genotype as ance of PEx. that detected in the exacerbation episodes. Besides microbiological, pharmacological and environmental Bacterial biofilms are effective physical and metabolic bar- factors, a longitudinal retrospective review of adherence to riers to antibiotic susceptibility, even in organisms that are sus- medication and health outcomes has shown that poor adherceptible when growing under planktonic conditions. How ence was a significant predictor of PEx during a concurrent biofilms contribute to clinical outcomes in CF remains unde- 12-month period [60]. fined; however, given that bacterial biofilms are always present in chronically infected patients and these patients only experi- Risk factors ence periodic exacerbations, biofilms could act as resilient reser- Identification of risk factors associated with PEx could enable voirs from which planktonic bacteria ‘bloom.’ Consequently, it early detection and close monitoring of high-risk patients. The has been hypothesized than an intense inflammatory response predictors of an increased risk of PEx include impaired lung and clinical symptoms that characterize exacerbations could be function [32,47,61] (including lung clearance index [62]), age [47,61], triggered [40]. P. aeruginosa infection [32], CF-related diabetes [32], chronic use Infections by viruses (mainly rhinovirus) are major causes of of inhaled corticosteroids [47], low levels of hemoglobin [63] and PEx [39–43], and the results of a recent study showed that viral serum estradiol levels in women [64]. respiratory tract infections were associated with 65% of PEx in In a study of 249 CF patients who were prospectively folchildren and adults [41]. Some authors have proposed an inter- lowed for up to 4.5 years, administration of more than three esting pathogenic mechanism by which rhinovirus infection lib- courses of intravenous antibiotics for PEx in the previous erates P. aeruginosa from biofilms [41,44]. Planktonic bacteria, 24 months was associated with a 20-fold increased risk of which are more pro-inflammatory than bacteria that grow as exacerbation within the first year of follow-up [47]. These findbiofilm, stimulate increased chemokine responses in CF airway ings clearly show that a previous history of recent PEx is highly epithelial cells that may in turn contribute to the pathogenesis predictive of future exacerbations. of PEx [44]. In addition, respiratory syncytial virus has been shown to disrupt CF epithelial monolayer integrity in vitro [45]. Consequences Given the microbial complexity of CF airways, it has been The main consequences of PEx in patients with CF include postulated that microorganisms other than those typically con- higher drug consumption, the need for in-patient care, and sidered causative of acute exacerbations (P. aeruginosa, Staphylo- absenteeism (school and work) of patients and caregivers, all of coccus aureus, Haemophilus influenzae, Burkholderia cepacia which are in turn associated with an increase in the total cost complex, Stenotrophomonas maltophilia and Achromobacter xylo- of the disease [15,65]. Moreover, PEx has a profound and negasoxidans) have a direct or indirect role in the pathogenesis of tive impact on physical and psychosocial health-related quality PEx. However, the results of genomic studies of the lung of life [17] and adversely affects sleep and neurobehavioral microbiome suggest that PEx in patients with CF may be performance [66].
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Symptoms score
Panel A
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Expert Rev. Respir. Med.
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Management of pulmonary exacerbations in CF
Review
Follow-up studies have revealed a strong relation between the number of exacerbations per year and the time between exacerbations and the decline in FEV1 [18,29,67]. Approximately, one in four CF patients (children and adults) was unable to regain 90% of baseline lung function after a PEx despite treatment with intravenous antibiotics [68,69]. In many cases, patients experience a substantial decline in lung function with an exacerbation followed by recovery of baseline values immediately after treatment, although long-term lung function is not necessarily preserved (the new baseline FEV1 after a PEx can be lower than the original baseline FEV1 before the PEx) [70]. A vicious circle is thus created in which PEx causes a decrease in lung function, and impaired lung function predisposes to further exacerbations. Measures can be taken to prevent exacerbations, but few options are available to treat the irreversible loss of lung function. Therefore, measures to prevent PEx are crucial for delaying the decline in lung function in CF.
Table 2. Treatment strategies for cystic fibrosis related pulmonary exacerbations. Strategy
Grade of recommendation
Maintenance of chronic therapies
B
Airway clearance therapies
B
Aminoglycoside dosing (1 or 3/day)
C
Synergic testing (routine)
D
Number of antibiotics
I
Duration of antibiotic treatment
I
Site of treatment (home or hospital)
I
Simultaneous use of inhaled and intravenous antibiotics
I
Continuous infusion of beta-lactam antibiotics
I
Impact on survival
Systemic corticosteroids
I
In addition to the increased morbidity of CF caused by PEx, the annual number of exacerbations has a considerable impact on survival. In a predictive model of 2-year mortality, patients who were hospitalized for acute exacerbations more than twice annually were 3.5-times more likely to die within 2 years than those who were not hospitalized, independently of the presence or absence of other risk factors [13]. In a 5-year validated survivorship model of CF using data from 5820 patients selected randomly from 11,630 patients in the Cystic Fibrosis Foundation Patient Registry, each acute PEx within the first year of follow-up increased by 1.5-times the risk of death in the following 4 years, so that four exacerbations in a single year had the same negative effect on survival as infection with B. cepacia [71]. In a 3-year prospective cohort study conducted among 446 adult patients with CF in Ontario, Canada, patients with >2 exacerbations per year had a greater risk of lung transplant or death during the study than patients with
