ABSTRACT

Objective: Pulmonary disease in cystic fibrosis (CF) is characterised by recurrent episodes of pulmonary exacerbations (PExs), with acute and long-term declines in lung function (FEV1). The study sought to determine whether routine spirometry increases the frequency of PEx diagnosis, resulting in benefits to long-term pulmonary function. Methods: CF patients in the 5- to 18-year age bracket were followed for 1 year, during which they underwent spirometry before every medical visit. The main variables were the frequency of PEx diagnosis and use of antibiotics; the use of spirometry as a criterion for PEx diagnosis (a decline = 10% in baseline FEV1); and median percent predicted FEV1 over time. The data were compared with those for the previous 24-month period, when spirometry was performed electively every 6 months. Results: The study included 80 CF patients. PExs were diagnosed in 27.5% of the visits, with a mean frequency of 1.44 PExs per patient/year in 2014 vs. 0.88 PExs per patient/year in 2012 (p = 0.0001) and 1.15 PExs per patient/year in 2013 (p = 0.05). FEV1 was used as a diagnostic feature in 83.5% of PExs. In 21.9% of PExs, the decision to initiate antibiotics was solely based on an acute decline in FEV1. The median percent predicted FEV1 during the follow-up year was 85.7%, being 78.5% in 2013 and 76.8% in 2012 (p > 0.05). The median percent predicted FEV1 remained above 80% during the two years after the study. Conclusions: Routine spirometry is associated with higher rates of diagnosis and treatment of PExs, possibly impacting long-term pulmonary function.

Keywords: Cystic fibrosis; Respiratory function tests; Respiratory tract infections; Spirometry.

RESUMO

Objetivo: A doença pulmonar na fibrose cística (FC) é caracterizada por episódios recorrentes de exacerbações pulmonares (EP), com declínio agudo e em longo prazo da função pulmonar (VEF1). O objetivo deste estudo foi determinar se a espirometria de rotina aumenta a frequência de diagnóstico de EP, beneficiando a função pulmonar em longo prazo. Métodos: Pacientes com FC na faixa etária de 5 a 18 anos foram acompanhados durante 1 ano, ao longo do qual foram submetidos a espirometria antes de cada consulta médica. As principais variáveis foram a frequência de diagnóstico de EP e uso de antibióticos; o uso da espirometria como critério de diagnóstico de EP (declínio do VEF1 basal ≥ 10%); e a mediana do VEF1 em porcentagem do previsto ao longo do tempo. Os dados foram comparados àqueles referentes aos 24 meses anteriores, período durante o qual a espirometria era realizada eletivamente a cada 6 meses. Resultados: O estudo incluiu 80 pacientes com FC. EP foram diagnosticadas em 27,5% das consultas, com média de frequência de 1,44 EP por paciente/ano em 2014 vs. 0,88 EP por paciente/ano em 2012 (p = 0,0001) e 1,15 EP por paciente/ano em 2013 (p = 0,05). O VEF1 foi usado como recurso diagnóstico em 83,5% das EP. Em 21,9% das EP, a decisão de iniciar a antibioticoterapia baseou-se exclusivamente no declínio agudo do VEF1. A mediana do VEF1 em porcentagem do previsto foi de 85,7% durante o ano de acompanhamento, de 78,5% em 2013 e de 76,8% em 2012 (p > 0,05). A mediana do VEF1 em porcentagem do previsto permaneceu acima de 80% durante os dois anos após o estudo. Conclusões: A espirometria de rotina está associada a taxas mais elevadas de diagnóstico e tratamento de EP e possivelmente tem impacto na função pulmonar em longo prazo.

Palavras-chave: Fibrose cística; Testes de função respiratória; Infecções respiratórias; Espirometria.

INTRODUCTION
 
Pulmonary disease is the main cause of morbidity and mortality for patients with cystic fibrosis (CF), which is characterised by recurrent episodes of acute worsening of pulmonary symptoms, known as pulmonary exacerbations (PExs).(1-3) The severity of lung disease is assessed by FEV1, which is a well-documented predictor of mortality(4,5) and which is used as an outcome in clinical trials(6,7) and as a parameter to indicate and monitor therapeutic responses,(8) as well as to refer patients for lung transplantation.(9) The annual rate of decline in FEV1 has been used as a predictor of survival and is a robust outcome measure in clinical trials, although it is still underused because of the individual variability of FEV1 over time.(10-12)
 
FEV1 is also routinely used as one of the parameters for diagnosing PExs, which are established by a combination of clinical features and spirometry results.(6) PExs have a major impact on long-term survival, quality of life, and deterioration of lung function.(13) Roughly a quarter of patients do not recover their baseline lung function after intravenous or oral antibiotic treatment. (14,15) Despite their significant role in the progression of lung disease, PExs are still not fully understood, and a clear definition and well-established criteria for their diagnosis are lacking. This results in discrepancies in the treatment approach to PExs between many CF centres, increasing the risk of significant pulmonary function decline for the patients. (16) In recent years, some authors have recommended antibiotic therapy for an acute decline in FEV1 (a decline ≥ 10% in percent predicted FEV1 at baseline), even in the absence of clinical signs and symptoms.(17,18) They argue that this approach is associated with a greater likelihood of recovering lung function and has long-term benefits.(17,18)
 
Several international CF guidelines recommend routine FEV1 measurements at all medical encounters,(19-21) but this practice is not universally adopted for several reasons. In developing countries such as Brazil, there are centres with limited technical and financial resources, which limit the availability of pulmonary function tests. In our CF centre, patients usually undergo medical consultations every 2 months, and spirometry used to be performed every 6 months. The objective of the present study was to evaluate the impact that performing spirometry at every encounter has on the frequency of diagnosis of PExs, as well as on long-term pulmonary function.
 
METHODS
 
This was a prospective study including CF patients in the 5- to 18-year age bracket followed at the outpatient clinic of our institution. The diagnosis of CF was based on newborn screening or clinical manifestations, in combination with two positive sweat chloride tests (> 60 mmol/L) and/or identification of two pathogenic variants in the CFTR gene. The study was approved by the local research ethics committee (CAAE: 28176614.7.0000.0068), and parents or caregivers gave written informed consent. A modified written informed consent was obtained from all of the patients over 7 years of age.
 
Beginning in January of 2014, all of the CF patients visiting our outpatient clinic underwent spirometry, with the results being immediately available to the attending physician during the consultation. Spirometry was performed with a previously calibrated Koko® spirometer (nSpire Health, Inc., Longmont, CO, USA), in accordance with the recommendations of the American Thoracic Society and the European Respiratory Society. Percent predicted FEV1 values were calculated with the Global Lung Initiative equation.(22) All included patients were followed for 12 consecutive months from the date of entry, and encounters were usually scheduled 2-3 months apart, with unscheduled, urgent visits when necessary. At the end of each encounter, the attending physician completed a questionnaire about whether or not a PEx was diagnosed at the time, whether or not antibiotic therapy was prescribed, and whether or not the pre-consultation spirometry had contributed to the treatment decision. Only the PExs diagnosed during patient encounters were considered for the analyses of frequency, but many patients were seen at unscheduled encounters. The choice of antibiotics was guided by culture, in accordance with the Brazilian guidelines for the diagnosis and treatment of CF.(21)
 
Data collected during the 12-month follow-up period were compared with data for the 24 months prior to the study, during which spirometry was performed at 6-month intervals. To facilitate the description of the outcomes, the 24 months prior to the study were referred to as the years 2012 and 2013, and the follow-up year was referred to as 2014. The data for the 24 months prior to the study were collected from patient medical records. Additionally, FEV1 values for the years 2015 and 2016 were obtained from the Brazilian CF Patient Registry. The registry contains the best FEV1 (in L) in a given year and the anthropometric data collected on the same day, allowing the calculation of percent predicted FEV1 values.
 
The primary outcome analysed was a diagnosis of PEx, defined as a new prescription of antibiotic therapy for a clinical worsening of respiratory symptoms. A secondary outcome was the utility of the spirometry results for the diagnosis of PEx, established by the attending physician using as a criterion an FEV1 decline ≥ 10% with or without worsening pulmonary symptoms indicative of PEx. A tertiary outcome was percent predicted FEV1 at baseline, defined as the best percent predicted FEV1 in a given year. Qualitative data are described as absolute and relative frequencies (proportions), whereas quantitative data are summarised as means and standard deviations or medians and interquartile ranges, depending on the pattern of distribution of each variable. A paired t-test and the Wilcoxon signed-rank test were performed to evaluate the contribution of spirometry to the clinical decisions, as well as to compare mean FEV1 values before and after the intervention. For the comparative analysis of data in the three periods, only patients with historical data were included. Analysis of the three periods was performed in pairs, 95% CIs being included. The probability of making a type I error was set at p < 0.05. All analyses were performed with the IBM SPSS statistics software package, version 19.0 (IBM Corporation, Armonk, NY, USA).
 
RESULTS
 
The study included a total of 80 patients. The mean age was 12.1 years (Figure 1). The characteristics of the patients are displayed in Table 1. During the follow-up, there were 418 encounters and an average of 5.2 consultations per patient/year. PExs were diagnosed in 27.5% of the encounters (115 occasions), at an average frequency of 1.44 PExs per patient/year (Figure 2). This was a significantly higher frequency than that observed in the year 2012 (0.88 PExs/patient/year), but there was a marginal difference in the year 2013 (1.15 PExs/patient/year).

 
The vast majority of PExs were treated on an outpatient basis with oral antibiotics in 85% of the occasions and inhaled antibiotics in 5% of the cases (with or without oral antibiotics). Hospitalisation for intravenous antibiotics was indicated in 10.4% of the cases. Pulmonary function (FEV1) was cited by the attending physician as a criterion for the diagnosis of PEx in 83.5% of the cases. In 21.9% of the cases diagnosed with a PEx, the decision to initiate antibiotic therapy was exclusively defined by the acute decline in FEV1 (Figure 3). Furthermore, in approximately 9% of the occasions, physicians reported that spirometry contributed to excluding an episode of PEx.
 

The median percent predicted FEV1 was 85.7% (IQR: 54.7-102.7) during the follow-up period. The value was considerably higher than that for the 24 months prior to the study (76.9% [IQR: 57.6-95.2] for 2012 and 78.5% [IQR: 54.0-101.2] for 2013), but the difference was not statistically significant (Figure 4). When the data from the years 2015 and 2016 were included in the analysis, we observed a steady linear decline of approximately 2% per year in median percent predicted FEV1 values during the follow-up period. However, they remained above 80% in the years following the study (Figure 4).
 
DISCUSSION
 
This study shows that performing spirometry at each encounter has a significant impact on the diagnosis of PExs during the outpatient management of CF patients. Spirometry was also associated with a meaningful increase in lung function. These findings reinforce the recommendations of several guidelines that spirometry be performed at each patient encounter and also indicate that recognising and treating PExs more often results in better lung function for CF patients.
 
An FEV1 decline ≥ 10% was identified in 83.5% of PExs, and this finding was frequently used for the clinical decision to start antibiotics. Hence, a tendency was observed to diagnose more PExs and thus to prescribe more courses of antibiotics in comparison with the years prior to the study. Although there is still no clear definition of a PEx, the most used criterion(6) requires that a decline ≥ 10% in baseline FEV1 be associated with another 3 out of 11 clinical features to establish a PEx diagnosis.(6) Currently, there is still much controversy regarding the definition of PEx.(16) Most definitions usually involve a medical decision to start a new course of antibiotics guided by worsening of the respiratory disease, as evidenced by intensification or new pulmonary signs and symptoms. Nevertheless, it is clear that FEV1 measurements are very important.(16,23)
 
Frequent measurement of FEV1 is vital to monitor its variations and to assess the severity of pulmonary disease in CF. Morgan et al.(24) showed that baseline FEV1 variability is a predictor of subsequent declines in lung function at all stages of the disease. They concluded that quantification of FEV1 changes is important for identifying patients with a greater risk of decline in lung function.(24) Additionally, there are data suggesting that patients with higher baseline FEV1 have a higher risk of FEV1 decline over time,(17) which may be due to the fact that they receive fewer therapeutic interventions when facing a decline in their FEV1 (such as antibiotics and hospitalisations).(25) The current study showed that 21.9% of PEx diagnoses were recognised exclusively by the acute decline in FEV1 in the absence of other signs and symptoms of worsening pulmonary disease.
 
A significant increase in the diagnosis of PEx was observed in the current study as a result of frequent FEV1 measurements. However, other studies have shown that doctors do not treat all episodes of FEV1 decline, even when they occur at a rate ≥ 10%.(23) In a retrospective analysis of data from an epidemiologic study of CF,(26) Wagener et al.(23) showed that 29.3% of patients with an acute decline in FEV1 ≥ 10% were not treated with antibiotics, particularly if they had not been admitted for intravenous treatment for PEx in the previous year. This may result in a significant decline in lung function over time because half of the functional declines seen in CF patients are associated with the occurrence of PExs.(16) A higher frequency of PExs and a shorter interval between them are associated with a greater decline in FEV1, especially if the interval between PExs is less than 6 months.(13)
 
Most of the PExs identified in the present study had a mild to moderate presentation characterised by a higher proportion of oral antibiotic use (85%), with only 10% of patients requiring hospitalisation for intravenous antibiotics. Although these events appeared to have a minor impact, most of the orally treated patients with PExs exhibited a decline in FEV1. This could indicate a slow or long-term decline and a lack of perception. Recent data indicate that even orally treated PExs may have a significant impact on lung function decline, even in patients without a significant decline in FEV1 at the time of the PEx diagnosis.(15) There are still controversies in establishing a patient’s baseline FEV1 and defining how much recovery is expected following the treatment of a PEx. Nevertheless, it is reasonable to suggest that it is more detrimental to fail to diagnose and treat a PEx than to overtreat patients for an incorrect diagnosis.(16)
 
This study has several limitations. The study was not randomised, and we did not assess FEV1 variations over time as an outcome measure or other aspects that could impact lung function decline, such as microbiological colonisation and adherence to treatment. Patients who had more advanced lung disease and who experienced frequent and prolonged hospitalisations were not included, because they had few outpatient consultations. The FEV1 data for the years 2015 and 2016 were not obtained during regular consultations, being instead obtained from the Brazilian CF Patient Registry. In addition, a longer follow-up would be necessary to determine the annual rate of decline in FEV1 and to identify additional risk factors. A possible bias is a change in behaviour of attending physicians facing more frequent lung function data. On the other hand, this was a real-life study, and the results were so impressive for our practice that spirometry was definitely incorporated into the routine of CF outpatient consultations, providing data for future studies.
 
The hypothesis that earlier diagnosis and more frequent treatment of PExs are associated with improved lung function in CF patients seems to be very likely. The median percent predicted FEV1 increased from 78.5% to 85.7% during the follow-up period. Although this difference was not statistically significant, the improvement was sustained in the following years in which the pre-consultation spirometry protocol was maintained, with a median percent predicted FEV1 above 80%.
 
New data stemming from the use of technological resources such as electronic home monitoring suggest that serial measurements of FEV1 can improve the ability to detect a PEx at home, with high sensitivity and specificity.(27) Furthermore, in a recent study, Schechter et al. reported the promising results of a standardised approach to recognising and treating PExs as early as possible.(28) The approach emphasised frequent measurements of FEV1, being very sensitive and consistent with regard to intervention, which is triggered by changes as small as 5% in percent predicted FEV1. They reported a significant and marked improvement in lung function, with mean percent predicted FEV1 values increasing from 87% to 98% in 5 years.(28)
 
In conclusion, the present study demonstrated that performing spirometry in CF patients during routine visits resulted in a significant increase in the frequency of PEx diagnosis and treatment. The impact of such a simple initiative can be substantial and even more relevant in countries such as Brazil, with reduced treatment resources and financial constraints. Further studies could be of value to identify other aspects that impact lung function in CF patients in Brazil.
 
ACKNOWLEDGEMENTS
 
The authors gratefully acknowledge the patients, parents, and clinicians for their contributions to this study.
 
AUTHOR CONTRIBUTIONS
 
CSBA, JCR, and LVRFSF: conception and planning of the study. CSBA and LVRFSF: drafting and revision of the manuscript. LVRFSF: approval of the final version.
 
CONFLICT OF INTEREST
 
None declared.
 
REFERENCES
 
1.            Elborn JS. Cystic fibrosis. Lancet. 2016;388(10059):2519-2531. https://doi.org/10.1016/S0140-6736(16)00576-6
2.            Simmonds NJ. Ageing in cystic fibrosis and long-term survival. Paediatr Respir Rev. 2013;14 Suppl 1:6-9. https://doi.org/10.1016/j.prrv.2013.01.007
3.            Bhatt JM. Treatment of pulmonary exacerbations in cystic fibrosis. Eur Respir Rev. 2013;22(129):205-216. https://doi.org/10.1183/09059180.00006512
4.            Quon BS, Aitken ML. Cystic fibrosis: what to expect now in the early adult years. Paediatr Respir Rev. 2012;13(4):206-214. https://doi.org/10.1016/j.prrv.2012.03.005
5.            Schluchter MD, Konstan MW, Drumm ML, Yankaskas JR, Knowles MR. Classifying severity of cystic fibrosis lung disease using longitudinal pulmonary function data. Am J Respir Crit Care Med. 2006;174(7):780-786. https://doi.org/10.1164/rccm.200512-1919OC
6.            Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994;331(10):637-642. https://doi.org/10.1056/NEJM199409083311003
7.            Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290(13):1749-1756. https://doi.org/10.1001/jama.290.13.1749
8.            Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013;187(7):680-689. https://doi.org/10.1164/rccm.201207-1160OE
9.            Yankaskas JR, Mallory GB Jr. Lung transplantation in cystic fibrosis: consensus conference statement. Chest. 1998;113(1):217-226. https://doi.org/10.1378/chest.113.1.217
10.          Que C, Cullinan P, Geddes D. Improving rate of decline of FEV1 in young adults with cystic fibrosis. Thorax. 2006;61(2):155-157. https://doi.org/10.1136/thx.2005.043372
11.          Konstan MW, Wagener JS, Pasta DJ, Millar SJ, Jacobs JR, Yegin A, et al. Clinical use of dornase alpha is associated with a slower rate of FEV1 decline in cystic fibrosis. Pediatr Pulmonol. 2011;46(6):545-553. https://doi.org/10.1002/ppul.21388
12.          Konstan MW, Wagener JS, Yegin A, Millar SJ, Pasta DJ, VanDevanter DR. Design and powering of cystic fibrosis clinical trials using rate of FEV(1) decline as an efficacy endpoint. J Cyst Fibros. 2010;9(5):332-338. https://doi.org/10.1016/j.jcf.2010.05.004
13.          Waters V, Stanojevic S, Atenafu EG, Lu A, Yau Y, Tullis E, et al. Effect of pulmonary exacerbations on long-term lung function decline in cystic fibrosis. Eur Respir J. 2012;40(1):61-66. https://doi.org/10.1183/09031936.00159111
14.          Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med. 2010;182(5):627-632. https://doi.org/10.1164/rccm.200909-1421OC
15.          Stanojevic S, McDonald A, Waters V, MacDonald S, Horton E, Tullis E, et al. Effect of pulmonary exacerbations treated with oral antibiotics on clinical outcomes in cystic fibrosis. Thorax. 2017;72(4):327-332. https://doi.org/10.1136/thoraxjnl-2016-208450
16.          Schechter MS. Reevaluating approaches to cystic fibrosis pulmonary exacerbations. Pediatr Pulmonol. 2018;53(S3):S51-S63. https://doi.org/10.1002/ppul.24125
17.          Morgan WJ, Wagener JS, Pasta DJ, Millar SJ, VanDevanter DR, Konstan MW, et al. Relationship of Antibiotic Treatment to Recovery after Acute FEV1 Decline in Children with Cystic Fibrosis. Ann Am Thorac Soc. 2017;14(6):937-942. https://doi.org/10.1513/AnnalsATS.201608-615OC
18.          Konstan MW, Morgan WJ, Butler SM, Pasta DJ, Craib ML, Silva SJ, et al. Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis. J Pediatr. 2007;151(2):134-139.e1. https://doi.org/10.1016/j.jpeds.2007.03.006
19.          Castellani C, Duff AJA, Bell SC, Heijerman HGM, Munck A, Ratjen F, et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018;17(2):153-178. https://doi.org/10.1016/j.jcf.2018.02.006
20.          Cystic Fibrosis Foundation, Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009;155(6 Suppl):S73-S93. https://doi.org/10.1016/j.jpeds.2009.09.001
21.          Athanazio RA, Silva Filho LVRF, Vergara AA, Ribeiro AF, Riedi CA, Procianoy EDFA, et al. Brazilian guidelines for the diagnosis and treatment of cystic fibrosis. J Bras Pneumol. 2017;43(3):219-245. https://doi.org/10.1590/s1806-37562017000000065
22.          Stanojevic S, Wade A, Cole TJ, Lum S, Custovic A, Silverman M, et al. Spirometry centile charts for young Caucasian children: the Asthma UK Collaborative Initiative. Am J Respir Crit Care Med. 2009;180(6):547-552. https://doi.org/10.1164/rccm.200903-0323OC
23.          Wagener JS, Williams MJ, Millar SJ, Morgan WJ, Pasta DJ, Konstan MW. Pulmonary exacerbations and acute declines in lung function in patients with cystic fibrosis. J Cyst Fibros. 2018;17(4):496-502. https://doi.org/10.1016/j.jcf.2018.02.003
24.          Morgan WJ, VanDevanter DR, Pasta DJ, Foreman AJ, Wagener JS, Konstan MW, et al. Forced Expiratory Volume in 1 Second Variability Helps Identify Patients with Cystic Fibrosis at Risk of Greater Loss of Lung Function [published correction appears in J Pediatr. 2018 Jun;197:322]. J Pediatr. 2016;169:116-21.e2. https://doi.org/10.1016/j.jpeds.2015.08.042
25.          Morgan WJ, Wagener JS, Yegin A, Pasta DJ, Millar SJ, Konstan MW, et al. Probability of treatment following acute decline in lung function in children with cystic fibrosis is related to baseline pulmonary function. J Pediatr. 2013;163(4):1152-7.e2. https://doi.org/10.1016/j.jpeds.2013.05.013
26.          Morgan WJ, Butler SM, Johnson CA, Colin AA, FitzSimmons SC, Geller DE, et al. Epidemiologic study of cystic fibrosis: design and implementation of a prospective, multicenter, observational study of patients with cystic fibrosis in the U.S. and Canada. Pediatr Pulmonol. 1999;28(4):231-241. https://doi.org/10.1002/(SICI)1099-0496(199910)28:4<231::AID-PPUL1>3.0.CO;2-2
27.          van Horck M, Winkens B, Wesseling G, van Vliet D, van de Kant K, Vaassen S, et al. Early detection of pulmonary exacerbations in children with Cystic Fibrosis by electronic home monitoring of symptoms and lung function [published correction appears in Sci Rep. 2018 Dec 13;8(1):17946]. Sci Rep. 2017;7(1):12350. https://doi.org/10.1038/s41598-017-10945-3
28.          Schechter MS, Schmidt HJ, Williams R, Norton R, Taylor D, Molzhon A. Impact of a program ensuring consistent response to acute drops in lung function in children with cystic fibrosis. J Cyst Fibros. 2018;17(6):769-778. https://doi.org/10.1016/j.jcf.2018.06.003