Recovery of Baseline Lung Function After Pulmonary Exacerbation in Children with Primary Ciliary Dyskinesia
Meera Sunther, MD,[1] Andrew Bush, PhD,[1] Claire Hogg, MD,[1]Lauren McCann[1]and Siobhan Carr, MD[1]
ABSTRACT
Rationale: Spirometry in children with cystic fibrosis (CF) frequently fails to return to baseline after treatment for a pulmonary exacerbation.
It is unclear whether the same is true for children with primary ciliary dyskinesia (PCD).
Objectives: To determine in children with PCD treated with intravenous antibiotics for a pulmonary exacerbation: (1) the proportion who recover to baseline forced expiratory volume at 1 second (FEV1) within 3 months after treatment and (2) to try to identify factors which are associated with failure to regain pre-exacerbation FEV1.
Methods: Cohort study using the PCD database for children at the Royal Brompton Hospital, 2003 to 2013. We selected the first pulmonary exacerbation treated with intravenous antibiotics. The best FEV1 within 3 months after treatment was compared to the best FEV1 in the 12 months before treatment (baseline). Recovery to baseline was defined as any FEV1 after treatment that was greater than or equal to 90% of the baseline FEV1.
Results: 32/150 children (21%) had at least one pulmonary exacerbation. 23/30 (77%) regained baseline spirometry within 3 months of treatment. There was no difference between responders and non-responders in any baseline characteristics.
Conclusions: Around 25% of children with PCD fail to recover to baseline lung function within three months following treatment for a pulmonary exacerbation, similar to CF. Better treatment strategies are needed, and the results also suggest that prevention of exacerbations would be a useful end-point in clinical trials.
Key words: primary ciliarydyskinesia; pulmonary exacerbation; lung function.
INTRODUCTION
Primary ciliary dyskinesia (PCD) is an inherited disease characterised by abnormal motile ciliary function, which leads to lung damage from recurrent and chronic airway infections. The best way of monitoring pulmonary disease is controversial but currently spirometry is most used clinically. [1],[2],[3]
The course of lung function in PCD is variable. Although many stabilise,[4],[5],[6] some patients have a more rapid downhill course for reasons which are unclear.[7] Marthin et al.[7] found approximately one-third of the patients with PCD lost more than 10% of forced expiratory volume in one second (FEV1)during follow up (range, 1.5-30.2 years). Change in lung function over time was related neither to age at diagnosis nor initial spirometry.[7]
There are no randomised controlled trials of treatment in PCD, and thus treatment guidelines[8] are not evidence based, and strategies vary across Europe. Children with PCD experience pulmonary exacerbations (for which there is no standard definition) however there is no data on the role of intravenous antibiotics on recovery of lung function after an exacerbation. Identification of patients who are at risk of not recovering might allow for earlier or more aggressive interventions. Previous studies in children with cystic fibrosis (CF) have noted that while treatment with intravenous antibiotics for a pulmonary exacerbation generally results in improvement in spirometry, some patients fail to recover to previous baseline pulmonary function levels.[9],[10],[11],[12] In CF, a higher annual rate of pulmonary exacerbations treated with intravenous antibiotics is associated with a greater subsequent decline in pulmonary function.[13]
The aim of the study was therefore to determine in children with PCD treated with intravenous antibiotics for a pulmonary exacerbation: (1) the proportion who recover to baseline FEV1 within 3 months after treatment and (2) to try to identify factors which are associated with failure to regain pre-exacerbation FEV1.
MATERIALS AND METHODS
Participants and Study Design
This was a retrospective, observational study using the PCD database for children at the Royal Brompton Hospital from January 2003 to April 2013. Diagnosis of PCD included a combination of nasal nitric oxide measurement, ciliary beat frequency and pattern, and ultrastructural analysis in children with a clinical phenotype of PCD [Eur Respir J. 2009; 34: 1264-76]. We analysed the first pulmonary exacerbation requiring admission to hospital for each patient in the database. A pulmonary exacerbation was defined as a change in respiratory status for which intravenous antibiotics were prescribed.
Subjects were included if they were aged 6 to 16 years old and able to perform spirometry. Spirometry is assessed at each clinic visit as well as during admission, discharge and within 3 months of follow up. Patients are generally followed up in clinic 6-8 weeks after discharge from hospital. A 3-month follow up period was therefore chosen to encompass the majority of patients.We excluded individuals who had an incomplete set of spirometric assessments.
The regimes employed during admission were standardized as far as possible, comprising a tailored program of airway clearance, antibiotics driven by the sensitivities of the isolated microorganisms, and any mucolytic deemed appropriate. There was no systematic difference between the two groups.
FEV1 percentage predicted values were calculated using the Global Lung Initiatives (GLI) equations.[14] Baseline FEV1 was defined as the best FEV1 in the 12 months before the pulmonary exacerbation. Recovery to baseline was defined as any FEV1 within three months after treatment that was greater than or equal to 90% of the baseline FEV1.[12]
We analysed whether there was any significant difference between responders and non-responders in their baseline characteristics and management. Baseline characteristics included age, gender, ethnicity, body mass index (BMI), baseline FEV1 < 40%, mean baseline FEV1, mean admission FEV1 and persistent infection. We also tried to determine whether prescription of an oral prophylactic antibiotic and nebulised hypertonic saline or DNase was related to outcome. A persistent infection was defined as at least 2 positive growths of the same microorganisms on cough swab or sputum culture in the 12 months before the pulmonary exacerbation.
Statistical Analyses
The sample size was opportunistic and there are no data to inform a power calculation. Spirometric data are presented as mean or median and interquartile range. Fisher’s exact test, Student’s t test and Mann-Whitney U test were used to assess whether there were any significant differences between responders and non-responders in their baseline characteristics and management. Statistical significance was set at a P-value of 0.05.
RESULTS
There were 150 children with PCD in the database over the 10-year period which was analysed. Of 150 children, 32 (21%) were admitted with at least one pulmonary exacerbation for intravenous antibiotics (chosen at the discretion of the Consultant Paediatrician). Of the 32 patients who were admitted, 2 were excluded as they had an incomplete set of spirometry data.These 2 patients had no discharge lung function data availableas they completed their second week of intravenous antibiotics at home.
There were 22 (73%) out of 30 patientstreated with an intravenous second- or third-generation cephalosporin and half of these also received an intravenous aminoglycoside. The remaining patients receiveddifferent combinations of meropenem, co-amoxyclav, tobramycin and ciprofloxacin.
Median age on admission was 11.4 years (range, 6-16.2). 18 (60%) out of 30 children were female. The median BMI was 17.5 kg/m2 (range, 12.2-24.6). The best baseline median forced vital capacity (FVC) and FEV1 were 84.7% and 74.1% predicted respectively. Admission spirometry was FVC 79% and FEV1 66.8% predicted. At discharge spirometry was FVC 88.4% and FEV1 77.4% predicted.
Of the 30 children who met inclusion criteria, 23 (77%) recovered to baseline pulmonary function within the 3 months after treatment referred to as “responders”. There were 2 patients who had baseline FEV1 <40%. Both of these patients recovered to baseline FEV1 after treatment. Removing these 2 patients from the group of responders did not impact on the results. The median FEV1 for responders and non-responders is shown in Figure 1 and Table 1. FEV1 percentage predicted for each individual non-responder and responder is shown in Figure 2 (A) and (B).
The median FEV1 and FVC at 3-months follow up for non-responders were 61.7% and 59.2% predicted respectively. The median FEV1 and FVC for the 7 non-responders at approximately 12-18 months following first admission was 60.5% and 79.7% respectively.
There was no difference between responders and non-responders in their baseline characteristics and management, which were: age, gender, ethnicity, BMI, baseline FEV1 < 40%, mean baseline FEV1, mean admission FEV1, persistent infection, use of oral prophylactic antibiotic and use of nebulised hypertonic saline or DNase (Table 2).The absolute changein mean FEV1 from baseline to admission was greater in the group of responders compared to non-responders (-6.9 vs. -4.9, p=0.007).
8 (35%) out of 23 responders had persistent infection (≥2 positive cultures) in the 12 months prior to admission and 3 (13%) out of 23 in the 12 months post admission.4 (57%) out of 7 non-responders had persistent infection in the 12 months prior to their first admission
and 1 (14%) had a single growth of H.influenzae.There were 2 (29%) out of 7 non-responders who had persistent infection with P.aeruginosain the 12 months prior to pulmonary exacerbation compared to none of the responders(p=0.05). These 2 patients had no further growths in the 12 months following treatment with intravenous antibiotics. Non-tuberculous mycobacteria were not isolated in any patient in the 12 months before or after the pulmonary exacerbation.
None of the non-responders had a bronchoscopy performed in the 12 months following admission for their first pulmonary exacerbation.
4 (57%) out of 7 non-responders were admitted for one further course of intravenous antibiotics in the 12 months following their first admission.
2 (29%) out of 7 non-responders had serum IgE checked in the 12 months following admission however levels were not significantly high.
Figure 1. Box and whisker plot for FEV1 percentage predicted. Responders vs. non-responders at 4 time points. The boxes of responders are clear and non-responders are shaded. The boxes represent the middle 50% of patients. The horizontal line represents the median FEV1. The whiskers represent all the patients within each group.
Figure 2.Line graphs for FEV1 percentage predicted at 4 time points. (A) Non-responders (n=7) and (B) responders (n=23).
A B
Table 1. FEV1percentage predicted median values for responders vs. non-responders at 4 time points.
Baseline / Admission / Discharge / 3 monthsResponders
N=23 / 77.2% / 69.1% / 78.9% / 78.3%
Non-responders
N=7 / 71.8% / 66.1% / 61.7% / 59.2%
Mann-Whitney U test p-value / NS / NS / 0.033 / 0.003
Table 2. Characteristics of patient cohort by responder and non-responder status.
Characteristic / Responder(n=23)
N (%) / Non-responder
(n=7)
N (%) / P-value
Median age, yrs / 11.4 / 12.2 / 0.65
Median BMI, kg/m2 / 17.7 / 16.8 / 0.49
Female sex / 14 (60) / 4 (57) / 1.0
Caucasian / 12 (52) / 4 (57) / 1.0
Baseline FEV1 < 40% / 2 (9) / 0 / 1.0
Mean baseline FEV1, % predicted / 72.7 / 71.3 / 0.85
Mean admission FEV1, % predicted / 65.8 / 66.4 / 0.94
Persistent infection
H. influenzae
S. aureus
S. pneumoniae
P. aeruginosa
Non-tuberculous mycobacteria / 5 (22)
1 (4)
2 (9)
0
0 / 1 (14)
1 (14)
0
2 (29)
0 / 1.0
0.4
1.0
0.05
Oral prophylactic antibiotic / 17 (74) / 6 (86) / 1.0
Use of either hypertonic saline or DNase / 7 (30) / 1 (14) / 0.64
DISCUSSION
We have shown that 7 (23%) of 30 PCD patients failed to recover baseline spirometry after a course of intravenous antibiotics for a pulmonary exacerbation, similar to findings in CF.[12] To our knowledge this is the first study in children with PCD assessing the role of intravenous antibiotics on lung function and its recoveryafter treatment of a pulmonary exacerbation. This suggests that an acute pulmonary exacerbation in PCD is a critical event. Earlier identification of pulmonary exacerbations and better treatment strategies in children with PCD are needed.
Our findings are similar to those in other pediatric airway diseases, which have led to the suggestion that ‘lung attack’ is a better descriptive term than pulmonary exacerbation [Thorax 2011; 66: 365-6 & 367.]. In a post-hoc analysis of the START study, children having asthma attacks and who were not randomised to inhaled corticosteroids had an accelerated decline in spirometry compared to all other study groups [Am J Respir Crit Care Med 2009; 179: 19-24]. Around 25% of CF patients treated for lung attacks do not recover to baseline spirometry [Pediatr Pulmonol 2010; 45: 127-34; Am J Respir Med 2010; 182: 627-32]. CF lung attacks are also associated with an accelerated decline in spirometry [Pediatr Pulmonol 2011; 46: 393-400;, Eur Respir J 2012; 40: 61-6] and a greater likelihood of death or lung transplantation [Thorax 2011; 66: 680-5]. Whether there is an adverse long term outlook for PCD patients treated for PCD ‘lung attacks’ cannot be determined from our study. The mechanisms of failure to respond are unclear in any of these diseases; in CF, extending the duration of antibiotic treatment is not helpful [Respiratory Research 2010; 11: 137]. However, just as there are differences between the inflammatory profiles in the airways of CF and PCD patients [Bush Chest 2006, Eur Respir J. 2016; 47: 829-36], we cannot assume that the mechanisms of failure to respond are the same in the two diseases. What these reports and the present study suggest is that a PCD lung attack (exacerbation) should result in a focussed response, especially if the patient does not respond, as suggested by recent guidelines published after the completion of the present study [Pediatr Pulmonol.2016; 51: 115-32]A strength of our study is that we analysed the first pulmonary exacerbation requiring admission for intravenous antibiotics for each patient in the PCD database. Weaknesses of our study include its retrospective nature and small sample size; the latter may well have precluded us being able to define any baseline characteristics of non-responders. The short follow up period also precluded us determining whether non-responders eventually do regain pre-exacerbation spirometry. An unavoidable weakness is the lack of a standardized definition of a ‘pulmonary exacerbation’ in children with PCD. We used
a ‘change in respiratory status that required treatment with intravenous
antibiotics’ as judged by an independent and experienced Consultant Respiratory Pediatrician, which has been used in previous database studies in CF torepresent a severe clinical event. Data regarding the severity and duration of symptoms prior to admission for treatment was not collected. Although this data is subjective it may have contributed towards the difference in response to treatment between the two groups; having said that, the fact that responders had more of a drop in lung function prior to treatment does not suggest they were treated any earlier.
Our findings suggest that exacerbations or lung ‘attacks’[15],[16] in PCD may contribute towards an accelerated decline in lung function in some patients. In addition these patients may never regain pre-exacerbation spirometry. The cause of ‘attacks’ may be secondary to severe underlying lung disease, poor adherence with treatment or other unidentified risk factors. Identification of patients at risk of ‘attacks’ may be used to reduce the likelihood of such potentially preventable events from occurring.
In conclusion our results show that approximately 1 in 4 children with PCD fail to recover to baseline spirometry after treatment of a pulmonary exacerbation with intravenous antibiotics. Further research is required to understand the disease process in this group of patients and assess whether multiple pulmonary exacerbations lead to an accelerated decline in pulmonary function. Prevention of pulmonary exacerbations may be a useful end-point in clinical trials. We highlight the need for more effective treatment strategies and earlier identification of pulmonary exacerbations in children with PCD.
REFERENCES
[1]Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK.
[1]
[1]
[1]
[1]
Correspondence to: Siobhan Carr, MD, Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK.
E-mail:
[1]Maglione M, Bush A, Montella S, Mollica C, Manna A, Esposito A, Santamaria F. Progression of ldisease in primary ciliary dyskinesia: Is spirometry less accurate than CT. Pediatric Pulmonology 2012;47(5):498-504.
[2]Pifferi M, Bush A, Pioggia G, Caramella D, Tartarisco G, Di Cicco M, Zanani M, Chinellato I, Maggi F, Tezza G, Macchia P, Boner, A. Evaluation of pulmonary disease using static lung volumes in primary ciliary dyskinesia. Thorax 2012;67(11):993-999.
[3]Green K, Buchvald FF, Marthin JK, Hanel B, Gustafsson PM, Nielsen KG. Ventilation inhomogeneity in children with primary ciliary dyskinesia. Thorax 2012;67:49-53.
[4]Hellinckx J, Demedts M, De Boeck K. Primary ciliary dyskinesia: evolution of pulmonary function. Eur J Pediatr 1998;157:422-426.
[5]Ellerman A, Bisgaard H. Longitudinal study of lung function in a cohort of primary ciliary dyskinesia. Eur Respir J 1997;10:2376-2379.
[6]Maglione M, Bush A, Nielsen KG, Hogg C, Montella S, Marthin JK, Di Giorgio A, Santamaria F. Multicenter analysis of body mass index, lung function and sputum microbiology in primary ciliary dyskinesia. Pediatric Pulmonology 2014;49(12):1243-1250.
[7]Marthin JK, Petersen N, Skovgaard LT, Nielsen KG. Lung function in patients with primary ciliary dyskinesia. Am J Respir Crit Care Med 2010;181:1262-1268.
[7]
[7]
[8] Barbato A, Frischer T, Kuehni CE, Snijders D, Azevedo I, Baktai G, Bartoloni L, Eber E, Escibano A, Haarman E, Hesselmar B, Hogg C, Jorissen M, Lucas J, Nielsen KG, O’Callaghan C, Omran H; Pohunek P, Strippoli M-PF, Bush A. Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children. Eur Respir J 2009;34:1264-1276.
[9]Sanders DB, Hoffman LR, Emerson J, Gibson RL, Rosenfeld M, Redding GJ, Goss HG. Return of FEV1 after pulmonary exacerbation in children with cystic fibrosis. Pediatric Pulmonology 2010;45(2):127-134.
[10]Gozal D, Bailey SL, Keens TG. Evolution of pulmonary function during an acute exacerbation in hospitalized patients with cystic fibrosis. Pediatric Pulmonology 1993;16(6):347-353.
[11]Smith AL, Stanley B, Mayer-Hamblett N, Ramsey B, Burns JL. Susceptibility testing of Pseudomonas aeruginosa and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis. Chest 2003;123(5):1495-1502.
[12] Sanders DB, Bittner R, Rosenfeld M, Hoffman L, Redding G, Goss C. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med 2010;182:627-632.
[13] Sanders DB, Bittner RCL, Rosenfeld M, Redding GJ, Goss CH. Pulmonary exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis. Pediatr Pulmonology 2011;46:393-400.
[14] GLI-2012. All-age multi-ethnic reference values for spirometry.
[12]
[12]
[15] FitzGerald JM. Targeting lung attacks. Thorax. Published Online First: 2011. doi:10.1136/thx.2010.156760.
[16]Bush A, Pavord I. Following Nero: fiddle while Rome burns, or is there a better way? Thorax 2011. Doi:10.1136/thx.2011.160861.