Background
Amyotrophic lateral sclerosis (ALS) is a chronic, incurable and fatal neurodegenerative disease, pathologically characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Clinically, it is featured by adult onset, male predominance, upper limb muscle weakness and atrophy, and relentless progression involving trunk and bulbar muscles [
1]. Due to the rapidly progressive loss of motor function, most ALS patients die within 2 to 5 years after symptom onset, usually as a consequence of respiratory failure [
2]. The assessment of respiratory function and respiratory care are therefore of great importance for ALS patients [
3,
4]. Pulmonary function tests (PFTs) have been frequently applied for evaluating respiratory function [
5]. Forced vital capacity (FVC) is the most important respiratory index highly correlated with survival in ALS [
6]. For the time being, the pulmonary function tests are mainly performed by respiratory physiotherapists in hospitals with specialized instrumentation (MS-PFT spirometer), and largely depend on the cooperation of ALS patient [
7]. For those patients at the later stage of ALS, the pulmonary function tests are hardly carried out due to their unwillingness or inability to come to the hospital owing to their mobility inconvenience. So it is necessary to explore more practical and feasible pulmonary function indexes for the prediction of progression and survival in ALS. Peak expiratory flow (PEF) is another useful pulmonary function index, which was defined as the maximum expiratory flow per minute. Advantageously, PEF can be measured by a household peak flow meter, which is simple in structure, easy to use, cheap, and can be self-monitored at home [
8,
9]. In the present study, we aimed to screen the survival-related pulmonary function parameters, and subsequently explored the predictive value of PEF in disease severity and prognosis for ALS.
Methods
Subjects
For the discovery cohort, 221 ALS patients were recruited serially from the Department of Neurology, First Affiliated Hospital of Fujian Medical University from Dec. 2014 to Sep. 2019. For the validation cohort, 62 newly diagnosed ALS patients were enrolled from Oct. 2020 to Apr. 2021. All the patients fulfilled the diagnostic criteria of ALS according to the revised Escorial criteria, and the diagnosis was confirmed by two professional neurologists [
10]. Written informed consent was obtained from each participant. Patients who did not complete pulmonary function examination and refused to participate were excluded. This study was approved by the Ethics Board of the First Affiliated Hospital of Fujian Medical University and performed in accordance with the declaration of Helsinki.
Clinical data collection
Clinical profiles were recorded at the time of diagnosis, including demographic characteristics, age of onset, site of onset, body mass index, smoking history, history of hypertension and diabetes mellitus, family history of ALS, diagnostic category, diagnostic delay, and treatments. Smoking history was defined as smoking at least one cigarette per day, for more than 6 months. Diagnostic delay was defined as the time interval from disease onset to identified diagnosis of ALS. The revised ALS functional rating scale (ALSFRS-R) was used to assess the severity of the disease at the time of pulmonary function test. The linear change rate of ALSFRS-R (ΔALSFRS-R) was used to reflect disease progression, and calculated by the equation: ΔALSFRS-R = (48—ALSFRS-R score) / duration from disease onset to pulmonary function test in months. The use of riluzole was defined as treatment with riluzole (50 mg, twice per day) for longer than 3 months. The use of noninvasive positive pressure ventilation (NIPPV) was defined as an acceptance of NIPPV support by patients for longer than 4 h per day. For survival analysis, all the enrolled cases were followed up at least more than 24 months. The primary endpoint was defined by either death or tracheotomy.
Pulmonary function tests
All pulmonary function tests were performed with an MS-PFT spirometer (Jaeger, Germany), and carried out by the same experienced respiratory physiotherapist in compliance with the American Thoracic Society/European Respiratory Society guidelines [
11,
12]. A total of 12 pulmonary function parameters (expressed as the percentage of predicted values (%), except forced expiratory volume in 1 s (FEV1)/FVC presented as the measured value) were analyzed: tidal volume (VT), expiratory reserve volume (ERV), FVC, FEV1, FEV1/FVC, PEF, maximal expiratory flow at 75% of FVC (MEF75%), maximal expiratory flow at 50% of FVC (MEF50%), maximal expiratory flow at 25% of FVC (MEF25%), maximal mid-expiratory flow (MMEF), minute ventilation (MV) and maximal voluntary ventilation (MVV). In the validation cohort, 62 newly diagnosed ALS patients accepted the pulmonary function test by MS-PFT spirometer and household peak flow meter (KOKA) simultaneously. During pulmonary function test, the patient was encouraged to optimize performance. At least three acceptable and repeatable trials were performed, and the best out of these manoeuvres was chosen.
Statistical analysis
A statistical analysis was performed using the SPSS statistical software version 20.0 for Windows (SPSS, Inc, IL, USA). All continuous variables were examined for normal distribution and homogeneity test of variance prior to analysis, and presented as mean ± standard deviation. All categorical variables were expressed as number (percentage) and analyzed using chi-square test. The pulmonary function parameters were described by tertiles, selected by log rank test of Kaplan Meier analysis, and then adjusted using Multivariate Cox regression analysis. X-tile software was adopted to get the cut-off value. Correlations were calculated with the Pearson coefficient (r) or Spearman coefficient (rs). P value less than 0.05 was considered statistically significant.
Discussion
Most ALS patients tend to develop progressive respiratory muscle weakness and paralysis, leading to respiratory failure, which is the principal cause of death. At the early stage, patients often report nocturnal hypoventilation symptoms, such as morning headache, daytime sleepiness and loss of concentration or memory. However, those symptoms are not specific and are easily ignored. Therefore, pulmonary function testing is a powerful avenue for monitoring respiratory status, and FVC is one of the most common measured pulmonary function parameters reflecting lung capacity, which is highly related to disease progression and survival in ALS, and helps the neurologists to determine when to initiate noninvasive ventilation for ALS patients [
17,
18]. In the present study, a total of 12 pulmonary function parameters were analyzed in a cohort of 202 ALS patients. After Kaplan Meier and Multivariate Cox regression analysis, FVC, FEV1, PEF, MEF75%, and MVV were identified to be highly associated with survival.
Aiming to explore more practical and feasible pulmonary function index for the prediction of progression and survival in ALS, we put a heavy emphasis on PEF. PEF is another commonly used index to reflect the pulmonary ventilation function, which has received increasing attention as useful measurement in patients with respiratory diseases [
9,
19]. PEF can also be used to reflect the expiratory muscle function reliably in patients with neuromuscular disease [
20]. The prominent advantage of PEF lies in the feasibility of self-monitoring at home, which could be achieved by a simple household peak flow meter [
21,
22]. The advent of smart spirometer has allowed for several pulmonary function parameters (for instance slow vital capacities (SVC), FVC and FEV1); however, compared to the peak flow meter, the cost of smart spirometer examination is relatively higher, and the operation is more complex (necessary to be calibrated with calibration pump), which could limit its wide application to some extent, especially at home. Until now, there is no recommendation with respect to the application of PEF in ALS patients. In order to make home usage-PEF better reflect respiratory function of ALS patients, we had taken the following corresponding measures. Firstly, sufficient education and training were provided during their first visits in hospital, aiming to master the key points of operation in PEF. Secondly, household PEF measure needs the supervision and help of caregiver. Thirdly, it is necessary to repeat the PEF measurement three times at least, and it is also necessary to perform at different time periods (including morning, afternoon and evening), and record the best result. Lastly, for the patients with bulbar involvement, it’s often hard to get the FVC or PEF result correctly, partly due to the air leak during pulmonary function testing. Therefore, we proposed a revised peak flow meter with oronasal mask (supplemental Fig.
3). It is also well known that for those ALS patients at the later stage with bulbar involvement, the noninvasive ventilation support is necessary, and the measurement of PEF is of little significance.
In the present study, we observed that PEF was an independent predictive factor for ALS survival, even after multiple adjustments of sex, age of onset, site of onset, BMI, use of riluzole, ALSFRS-R score at pulmonary function test, progression rate (ΔALSFRS-R), and time interval between disease onset and pulmonary function test. Furthermore, PEF was highly correlated with other ALS survival-related pulmonary function parameters, including FVC, MVV, FEV1, and MEF75%, which showed that PEF was as good as FVC in reflecting lung function in ALS patients. Additionally, the values of PEF were moderately correlated with disease severity (assessed by ALSFRS-R score at baseline) and disease progression rate (expressed as ΔALSFRS-R), which was consistent with the results from Pirola A and colleagues [
17]. However, Carvalho et al. recently observed that PEF did not significantly reflect the progression rate of ALS in a small (
n = 51) but longitudinal ALS cohort [
23], and further large and prospective study is necessary to confirm the correlation between PEF and disease progression. Yamada et al. also reported that PEF could be a specific respiratory marker for the severity and progression of patients with spinal and bulbar muscular atrophy, a rare neuromuscular disease, also known as Kennedy’s disease [
24]. Besides, the values of PEF could be measured by household peak flow meter (KOKA) effectively. Taken together, the results from this study suggested that PEF may be a second candidate pulmonary function index, which could reliably predict disease progression and survival in ALS patients.
In the pulmonary function test, there are different PFTs that could reflect lung volume, lung ventilation, and small airway functions in clinical. Understanding whether these parameters are related to disease progression and survival in ALS patients is useful for clinical decision. Similar to FVC, SVC has also received recent attention. Paillisse et al. evaluated the pulmonary function parameters in a cohort of 2069 patients, and concluded that SVC was a predictor of survival in ALS [
25]. Further studies confirmed that SVC and FVC were very strongly associated and declined similarly in ALS, and were inter-changeable in predicting survival in ALS [
26,
27]. Andrews JA et al. also identified that the rate of decline in SVC was correlated with respiratory failure, tracheostomy, or death in patients with ALS [
28]. Besides, Pirola A et al. found that supine position FVC (sFVC) and monthly decline of sFVC% were significantly associated with the survival of ALS patients [
17]. In our study, we also observed that VC max, which was equal to the maximum value of SVC and FVC, was an important indicator of clinical progression.
Some limitations were also noted in our study. Firstly, some pulmonary function parameters were not mentioned in our study, such as supine position FVC, slow vital capacities, and peak expiratory cough flow. Besides, as a single research center, the sample size was relatively small, and it was not a population-based study, which lead to the presence of admission rate bias. Lastly, the present study was a cross-sectional design, and it is necessary to confirm the application of PEF in future multi-center prospective and longitudinal studies.
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