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      Reply to Chacko et al.: Limited Assessment of Respiratory Muscle Response to Nusinersen Treatment in Infants with Spinal Muscular Atrophy


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          From the Authors: We thank Chacko and colleagues for their interest in our study (1). We agree that multiple factors must be considered when discussing access and reimbursement criteria, and that a combination of tests is advisable to assess the therapeutic effects of drugs. In fact, we also reported Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (2, 3) scores and daily hours of mechanical ventilation (1). In our study, motor function, ventilatory support, respiratory rate, and Vt improved in patients with spinal muscular atrophy (SMA) treated with nusinersen compared with untreated patients irrespective of disease severity, with those with type 1C showing the highest values. Inspiratory paradox of the rib cage (IPRC) was present in treated patients with SMA1 A and B but not in those with type 1C. Optoelectronic plethysmography (OEP) allows one to gather additional information about the pathophysiology of SMA in a noninvasive manner by providing nonvolitional global and specific indexes of respiratory function. We think that the alternative tools proposed by Chacko and colleagues—respiratory impedance plethysmography (RIP) (4) and forced oscillation technique (FOT) (5)—may have some limitations and may not provide additional information about the effect of nusinersen on respiratory function. RIP provides qualitative information regarding thoracoabdominal asynchronies by measuring changes in only two cross-sectional areas. Its limited calibration methods to estimate chest wall/lung volume require subject-specific calibration during a long period of regular breathing, which can be problematic in infants and children because they frequently may cry, babble, or speak. Conversely, OEP provides accurate chest wall volumes and anatomical thoracoabdominal subdivision, and its calibration does not depend on the subject. We agree, however, that studies comparing the two techniques would be of interest, because RIP is more widely available. FOT has great clinical potential, but it provides data on passive properties (resistance and reactance) of the respiratory system rather than on the force/action of respiratory muscles. FOT does not discriminate between obstructive and restrictive lung disorders (5) and was shown by Gauld and colleagues to not differentiate between SMA2 and SMA3 (6), while OEP data were sensitive to disease severity (7). FOT still needs to be extensively investigated in SMA1 (8), and no reliable reference values are available for young children (6). Our data provide further insights into the mechanisms underlying different individual responses to treatment, but they cannot be interpreted as supporting access to or exclusion from treatment or as parameters for starting or stopping treatment, as several other factors must be considered. We showed that IPRC was still present in our treated children with SMA1 A and B (1), but IPRC per se is not a problem, as it is present in healthy infants (9). When IPRC is accompanied by breathing difficulties, it becomes a medical emergency. In SMA, it is the consequence of progressive ribcage muscle weakness/atrophy that triggers a cascade of events: inefficient cough (coughing relies principally on ribcage muscles [10]), bell-shaped chest (11), hypoventilation, atelectasis (associated with recurrent aspiration due to bulbar impairment), excessive work of breathing, and ventilatory failure. Future larger studies are needed to identify drug responders and nonresponders, with age of symptoms onset, clinical presentation (including IPRC), and SMN2 copy numbers as independent factors. Of note, SMN2 copy numbers did not affect our results, as they were equally distributed (50% with two copies and 50% with three copies) with no difference between the two groups. We do not think that age may have played a role in our results, because 1) clinical evidence suggests that IPRC gets worse with age in natural-history SMA1 owing to the progression of weakness/atrophy of the ribcage muscles (12, 13), 2) the two treated groups were similar in age (21 mo [1A and 1B] and 29.7 mo [1C]) (1), and 3) physiological IPRC should not be present in the awake state at those ages. In conclusion, we believe that our study provides important data for future studies seeking to better understand the effects of nusinersen and other emerging drugs on respiratory function in patients with SMA.

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          The forced oscillation technique in clinical practice: methodology, recommendations and future developments.

          The forced oscillation technique (FOT) is a noninvasive method with which to measure respiratory mechanics. FOT employs small-amplitude pressure oscillations superimposed on the normal breathing and therefore has the advantage over conventional lung function techniques that it does not require the performance of respiratory manoeuvres. The present European Respiratory Society Task Force Report describes the basic principle of the technique and gives guidelines for the application and interpretation of FOT as a routine lung function test in the clinical setting, for both adult and paediatric populations. FOT data, especially those measured at the lower frequencies, are sensitive to airway obstruction, but do not discriminate between obstructive and restrictive lung disorders. There is no consensus regarding the sensitivity of FOT for bronchodilation testing in adults. Values of respiratory resistance have proved sensitive to bronchodilation in children, although the reported cutoff levels remain to be confirmed in future studies. Forced oscillation technique is a reliable method in the assessment of bronchial hyperresponsiveness in adults and children. Moreover, in contrast with spirometry where a deep inspiration is needed, forced oscillation technique does not modify the airway smooth muscle tone. Forced oscillation technique has been shown to be as sensitive as spirometry in detecting impairments of lung function due to smoking or exposure to occupational hazards. Together with the minimal requirement for the subject's cooperation, this makes forced oscillation technique an ideal lung function test for epidemiological and field studies. Novel applications of forced oscillation technique in the clinical setting include the monitoring of respiratory mechanics during mechanical ventilation and sleep.
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            Developmental changes in chest wall compliance in infancy and early childhood.

            Development of chest wall stiffness between infancy and adulthood has important consequences for respiratory system function. To test the hypothesis that there is substantial stiffening of the chest wall in the first few years of life, we measured passive chest wall compliance (Cw) in 40 sedated humans 2 wk-3.5 yr old. Respiratory muscles were relaxed with manual ventilation applied during the Mead-Whittenberger technique. Respiratory system compliance (Crs) and lung compliance (Cl) were calculated from airway opening pressure, transpulmonary pressure, and tidal volume. Cw was calculated as 1/Cw = 1/Crs - 1/Cl during manual ventilation. Mean Cw per kilogram in infants 1 yr old (2.80 +/- 0.87 vs. 2.04 +/- 0.51 ml.cmH2O-1.kg-1; P = 0.002). There was an inverse linear relationship between age and mean Cw per kilogram (r = -0.495, slope -0.037; P < 0.001). In subjects with normal Cl during spontaneous breathing, Cw/spontaneous Cl was 2.86 +/- 1.06 in infants < 1 yr old and 1.33 +/- 0.36 in older children (P = 0.005). We conclude that in infancy the chest wall is nearly three times as compliant as the lung and that by the 2nd year of life chest wall stiffness increases to the point that the chest wall and lung are nearly equally compliant, as in adulthood. Stiffening of the chest wall may play a major role in developmental changes in respiratory system function such as the ability to passively maintain resting lung volume and improved ventilatory efficiency afforded by reduced rib cage distortion.
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              Validation of respiratory inductance plethysmography ("Respitrace") for the measurement of tidal breathing parameters in newborns.

              The ratio of the time to reach peak (maximum) tidal expiratory flow (Tme) to total expiratory time (Te) is smaller in infants who later develop lower respiratory tract disease. In previous studies infants have been sedated and flow measured using a pneumotachograph with face-mask. These methodological factors are known to affect tidal breathing, and the frequent need for sedation limits the use of the technique to relatively small studies. The aim of this study was to validate uncalibrated respiratory inductance plethysmography (Respitrace) to measure Tme/Te in unsedated newborns.

                Author and article information

                Am J Respir Crit Care Med
                Am. J. Respir. Crit. Care Med
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1 March 2020
                1 March 2020
                1 March 2020
                1 March 2020
                : 201
                : 5
                : 624-626
                [ 1 ]Politecnico di Milano

                Milan, Italy
                [ 2 ]Fondazione IRCCS Cà’ Granda Ospedale Maggiore Policlinico

                Milan, Italy
                [ 3 ]Fondazione IRCCS Istituto Neurologico Carlo Besta

                Milan, Italy

                [ 4 ]UCL Great Ormond Street Institute of Child Health London

                London, United Kingdom
                Author notes
                [* ]Corresponding author (e-mail: antonella.lomauro@ 123456polimi.it ).
                Copyright © 2020 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

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