Published ahead of print on August 2, 2007, doi:10.1164/rccm.200612-1870OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200612-1870OC
Fog-induced Cough with Impaired Respiratory Sensation in Congenital Central Hypoventilation Syndrome1 Dipartimento di Area Critica Medico Chirurgica, 2 Dipartimento di Scienze Fisiologiche, and 3 Dipartimento di Pediatria, Università degli Studi di Firenze, Florence, Italy; and 4 University of London, London, United Kingdom Correspondence and requests for reprints should be addressed to Giovanni A. Fontana, M.D., Dipartimento di Area Critica Medico Chirurgica, Sezione di Medicina Respiratoria, Università degli Studi di Firenze, Viale G.B. Morgagni, 85-50134 Florence, Italy. E-mail: g.fontana{at}dac.unifi.it
Rationale: Congenital central hypoventilation syndrome (CCHS) is a genetic disorder mainly characterized by failure of automatic control of breathing, causing alveolar hypoventilation. Little is known regarding cough in CCHS. Parental reports indicate that patients cough normally during airway infections; however, previous studies have demonstrated no cough response to fog inhalation. Objectives: To evaluate the sensory and motor components of cough, respiratory sensations, and changes in ventilation evoked by fog inhalation in children with CCHS and in sex- and age-matched control subjects. Methods: Cough threshold was measured and cough intensity was indexed in terms of cough peak expiratory flow and integrated abdominal electromyographic activity. The pattern of breathing was recorded by inductive plethysmography. Respiratory sensations were also investigated. Measurements and Main Results: All control subjects and six of seven patients coughed in response to fog inhalation. The seventh coughed with citric acid aerosol inhalation. Cough threshold values were similar in control subjects (range, 0.40–2.22 ml/min) and patients (range, 0.40–3.26 ml/min). Mean values of cough peak expiratory flow and of integrated abdominal electromyographic activity–related variables during coughing were also similar and corresponded to 80% of those recorded during maximum voluntary cough. Cough appearance was preceded by respiratory sensations and increases (P < 0.01) in ventilation in the control subjects but not in the patients. Conclusions: Children with CCHS have normal cough threshold and motor responses to fog inhalation. However, the lack of respiratory sensations and the likely related ventilatory changes typically elicited by tussigenic fog concentrations suggest a neural sensory deficit that may increase the risk of respiratory disease in these patients.
Key Words: cough • respiratory sensations • control of breathing • central nervous system.
Congenital central hypoventilation syndrome (CCHS) is a rare condition mainly characterized by absent or greatly diminished central hypercapnic sensitivity and failure of automatic control of ventilation in the absence of obvious anatomic lesions (1). CCHS manifests as alveolar hypoventilation, which is typically more severe during non-REM sleep (2). Thus, the level of spontaneous breathing may be adequate during wakefulness but ventilation must be supported mechanically or by phrenic nerve pacing during sleep (1, 2). We are aware of about 20 living children with this condition in Italy (3). A genetic basis for CCHS has long been suspected based on familial cases (4–6), associations with Hirschsprung disease (5, 7, 8), vertical transmission (9–11), and high prevalence of reported symptoms of autonomic dysfunction in families (12, 13). PHOX2B is now considered to be the disease-defining gene (3, 14–18). CCHS results from polyalanine repeat expansion mutations in the PHOX2B gene in more than 90% of cases, and nonpolyalanine mutations in the remaining cases (18). In addition to the well-known disorder of ventilatory control, CCHS is also characterized by a more generalized involvement of the autonomic nervous system (12, 13, 19–23). In a previous study, it was found that patients with CCHS had an absent or diminished cough reflex in response to inhalation of up to four deep breaths of ultrasonically nebulized distilled water (fog), thus suggesting that a defective cough reflex may be a feature of the disease (24). However, children with CCHS do cough during respiratory infections such as pneumonia (20), a phenomenon that reveals a functional cough reflex at least in this clinical condition. It may therefore be hypothesized that, as in other conditions affecting the central nervous system (25–27), patients with CCHS also have impaired sensory and/or motor components of cough; short-lasting experimental stimuli, such as those used previously (24), are ineffective in eliciting a cough response, whereas longer lasting and perhaps more intense stimuli, such as those possibly associated with respiratory infections (20), may be able to evoke coughing in these patients. Indeed, there are no previous measurements of cough threshold and of the intensity of motor responses during cough produced either voluntarily or reflexively in children with CCHS. In the present study, we investigated noninvasively (25, 28–30) the cough threshold and the intensity of motor responses during voluntary and reflex cough in a group of children with CCHS and in age- and sex-matched control subjects. Because children with CCHS appear to lack sensations during some respiratory tasks, such as breath-holding and CO2 rebreathing (20), we also attempted to investigate whether children with CCHS also have impaired respiratory sensations during inhalation of fog concentrations of increasing tussigenic strength. Preliminary accounts of this work have been published in abstract form (31).
Seven children with CCHS (male:female, 5:2; age range, 9–16 yr) and seven sex- and age-matched healthy children participated in this study. Control subjects were recruited on the basis of personal acquaintance (n = 3) or among children referred to the local pediatric hospital for minor surgical procedures. All patients with CCHS were recruited on a national basis from those referring to the local pediatric hospital for routine examinations and follow-up. All had been diagnosed soon after birth and required assisted ventilation only during sleep via diaphragmatic pacing (n = 6) or intermittent positive-pressure ventilation via a face mask (Table 1). None of the patients had a tracheostomy at the time of the study, or required ventilatory support during the experiments. Clinical sleep studies performed annually confirmed that all patients had severe hypoventilation exclusively during non-REM sleep. They were all able to attend school and participate in normal daily activities, and were selected on the basis of their presumed ability to perform lung function tests and inhalation challenges. Mutational screening of the PHOX2B gene in the patients revealed heterozygous 5 or 6 alanine expansions, corresponding to duplications of 15 or 18 nucleotides, respectively (Table 1). Control children were not genotyped because families denied their consent. We are therefore unable to demonstrate their genetic normality because it was not tested. Nevertheless, none of the control subjects displayed, nor did their parents report, clinical signs suggesting any respiratory abnormality or autonomic defect. Routine pulmonary function tests (32) were performed in patients and control subjects; these included spirometry and functional residual capacity measurements (gas dilution method). None of the participants had suffered from respiratory tract infections during the 6 weeks preceding the study. The experimental protocol adhered to the Recommendations of the Declaration of Helsinki for Human Experimentation. This study was approved by the Università degli Studi di Firenze hospital ethical committee; informed parental consent and child assent in the presence of a parent were obtained for all participants.
Interview In an initial interview in the presence of one or both parents, we asked each participant if he or she understood the terms "urge to cough," "air hunger," "difficulty with breathing," "burning," "irritation," "choking," and "smoke in the throat." We also asked parents if the child coughed during respiratory infections, and if such coughing was considered normal in terms of frequency and apparent intensity.
Experimental Procedures The hypercapnic ventilatory response of all participants was tested by having them breathe 5% CO2 in 50% O2, balance N2, for 5 minutes each. The inspired air mixture was warmed and humidified and flowed via a 2–l reservoir bag past the inspiratory port of a two-way non-rebreathing valve (modified Lloyd valve; Warren E. Collins, Inc., Braintree, MA) with a dead space of 46 ml. After up to 10 minutes of breathing air, the inspiratory CO2 concentration was allowed to increase by 10 mm Hg in the control subjects. To ensure a strong test of chemoreceptor function, the inspiratory CO2 concentration was increased by 20 mm Hg in the patients with CCHS. Increased inspiratory CO2 concentrations were maintained for 10 minutes. During cough challenges, all participants breathed through the two-way valve: the expiratory port of the valve was connected to a no. 4 Fleisch pneumotachograph and a flow transducer to record expiratory flow; the inspiratory port of the valve was in series with the ultrasonic nebulizer. The accuracy of the pneumotachograph–transducer assembly had preliminarily been assessed, in ATPS conditions, by using a calibration device similar to that developed by Petusevsky and colleagues (34). Maximal voluntary cough (MVC) efforts were obtained by encouraging each participant to cough as forcefully as possible through the pneumotachograph as in a strong attempt to clear the airways. The lung volume at which these expulsive efforts were commenced was not controlled. Reflex cough (RC) was induced by inhalation of ultrasonically nebulized distilled water (fog) produced by a Mist-O2-Gen EN143A ultrasonic nebulizer (Medical Equipment Services, Inc., Fulton, IL). The mass median aerodynamic diameter of aerosol particles generated by the nebulizer has been reported to be 5.7 ± 1.4 µm (35). The nebulizer jar was filled with 180 ml distilled water; the output could be adjusted by means of a potentiometer and monitored as a DC signal on an oscilloscope. The output could be progressively augmented in steps corresponding to 5% of the maximum attainable output level. Fog was inhaled during resting tidal breathing, and the inhalation time for each concentration was standardized at 1 minute; 2 to 3 minutes of rest were scheduled between concentrations. The range of nebulizer outputs used in the present experiments was from 30 to 100% of the maximum DC signal; the corresponding amount of nebulized water (mean values) ranged from 0.08 to 4.45 ml/minute. Cough threshold was taken as the lowest fog concentration capable of evoking at least one cough effort during two distinct challenges separated by a time interval of at least 30 minutes. This procedure ensured that the cough recorded was a reflex response to the challenge rather than a random event (28). Possible changes in airway caliber induced by fog inhalation were monitored by FEV1 measurements (conventional spirometry) performed before and after each challenge. The intensity of voluntary and RC efforts was indexed in terms of the peak and rate of rise of the electromyographic (EMG) activity of the abdominal muscles, as well as of the cough peak expiratory flow (PFC). The latter was recorded by means of the pneumotachograph. The EMG activity was recorded from the abdominal muscles using surface Ag-AgCl electrodes positioned 3 cm apart along the line of right obliquus externus fibers, with the lower medial electrode 10 to 20 mm lateral to the edge of the rectus sheath and just above the level of the umbilicus. The EMG activity recorded with these electrodes during cough was considered to reflect the activation of the obliquus externus muscle, as well as the activity of deeper abdominal muscles with minimal contamination of the EMG signal by the rectus abdominis electrical activity. The EMG signals were differentially amplified (x2,000), band-pass filtered (50–1,000 Hz), full-wave rectified, and passed through a "leaky" integrator (low-pass resistance x capacitance filter; time constant, 50 ms) to obtain the so-called integrated EMG activity (IEMG). The IEMG activity was also fed to a DC amplifier whose gain could be adjusted to obtain recordings of such an amplitude to allow accurate measurements (25, 28). Before each challenge, children were asked to change their posture (trunk flexion), and the IEMG waveforms evoked by these maneuvers were compared with those recorded during voluntary coughing for differentiation. To the same end, children were also asked to simulate events such as exhalation of a long, audible breath and throat-clearing.
The pattern of breathing was recorded by means of a calibrated respiratory inductive plethysmograph (Non-Invasive Monitoring System; Respitrace, Ardsley, NY). The technical features of the respiratory inductive plethysmograph are well known. Calibration and validation of the inductive plethysmograph were performed according to the method described by Sackner and colleagues (36). We measured, on a breath by breath basis, the tidal volume (VT), the duration of inspiratory and expiratory times (TI and TE, respectively), and the total duration of the respiratory cycle (Ttot). The mean inspiratory flow (VT/TI), the duty cycle (TI/Ttot), and inspiratory minute ventilation ( The intensity of the sensation of an urge to cough was rated using a 10-cm-long visual analog scale continuously. The extremes of the sensation (i.e., "no urge to cough at all" and "extreme urge to cough") were represented by the two ends of a visual display. "Extreme urge to cough" was explained to each participant as a need to cough that is impossible to resist. A light could be placed at any point within the display by using a hand-controlled linear potentiometer located on a small horizontal platform attached to the armrest of a dentist's chair on the subject's dominant side. Both the display and the potentiometer were 10 cm in length. Equal distances were meant to represent equal variations in the intensity of the sensation. To assess the intensity of the urge to cough, children were recommended to ignore other sensations, and were told that their sensation of an urge to cough could increase, decrease, or stay the same during the fog challenge, and that their use of the visual analog scale should reflect this. No verbal cues were given as to when ratings were to be made. Children were also requested to concentrate on their sensation during challenges and to adjust the scale accordingly by sliding the potentiometer in a direction toward or away from their body to rate an increase or a decrease in the sensation, respectively. With this method, the distance in centimeters indicated by the light on the visual display represented the intensity of the urge to cough.
Protocol The signals of all studied variables could be displayed on a chart recorder (HP 7758A; Hewlett Packard, Palo Alto, CA) and digitally acquired using a personal computer equipped with an analog-to-digital (AD) interface (Digidata 1302A; Axon Instruments, Inc., Union City, CA) and appropriate software (Axoscope 8.1; Axon Instruments, Inc.).
Data Analysis
The duration of the rising phase of the abdominal IEMG activity during both MVC and RC (i.e., the time duration of the expiratory IEMG ramp during cough) was termed TEC. The ratio of IEMGP to TEC (IEMGP/TEC, an index of expiratory drive) was subsequently calculated for all considered cough efforts. Regarding the MVC, the three maneuvers with the highest PFC and IEMGP values were considered in each subject. Because of the small variations in PFC and IEMG variables during both MVC and RC, average values were calculated in each subject and taken as single measurements for purpose of analysis. By analyzing high-speed ( For each participant, cough frequency was taken as the mean number of coughs recorded during the two 1-minute inhalation challenges required to assess the threshold fog concentration. The time to onset (i.e., the time [in s] elapsed from the beginning of fog inhalation and the appearance of the first cough effort during each of the two inhalations of the threshold concentration) was also measured. Between-group comparisons of values of cough threshold, PFC, IEMGP, IEMGP/TEC, cough frequency, duration of the cough compressive phase, and time to onset were made using Mann-Whitney tests. Breathing pattern variables were measured for an average of five consecutive breaths in the control periods and in the period preceding the appearance of cough. Mean values of control breathing pattern variables recorded before each of the two fog challenges were similar (Wilcoxon signed rank tests); they were therefore pooled and considered as a whole. Given the consistency of mean values of breathing pattern variables recorded during each of the two fog challenges before cough appearance (Wilcoxon signed rank tests), these values were similarly treated. At threshold level for the cough reflex, between-group changes in breathing pattern variables were compared by using Mann-Whitney tests. Changes in respiratory variables observed after cough cessation were obviously inconsistent and were not analyzed. Mann-Whitney tests were used to compare the intensity of the urge to cough recorded during inhalation of threshold fog concentrations in control children and in those with CCHS. All reported values are means ± SD unless otherwise stated; P < 0.05 was taken as significant.
General Results All participants were able to perform the respiratory maneuvers requested for lung function, maximum expiratory pressure, and voluntary cough assessments. Control children appeared to be familiar with respiratory sensations and displayed no major uncertainties in reporting perceived sensations or rating the urge to cough. As for the children with CCHS, four of them appeared to be scarcely familiar with language relating to the respiratory sensations, whereas the remaining three seemed to be reasonably aware of the sensations. Parental reports revealed that all children with CCHS coughed during respiratory infections; however, in three cases (42.8%), the children's cough was judged to be scarcely effective, both in terms of frequency and intensity, and airway clearing was difficult. The outcomes of routine lung function tests and PEmax measurements were normal in all participants (Table 2). Control children had normal or slightly reduced end-tidal CO2 values (37.5 ± 0.22 mm Hg) at rest, whereas patients were slightly hypercapnic at rest (46.4 ± 0.21 mm Hg). In the latter, the CO2 rebreathing test confirmed the absence of significant ventilatory chemosensitivity to hypercapnia, with a mean rate of increase in  I corresponding to 8.71 ± 9.79 ml/(min x kg x mm Hg); the mean rate of I increase in control subjects was 71.83 ± 23.20 ml/(min x kg x mm Hg) (P < 0.01).
Sensory Motor Components of Cough All subjects and six of the seven patients with CCHS (85.7%) coughed in response to fog inhalation. The mean time to cough onset was 34.35 ± 12.10 seconds in the control subjects and 37.42 ± 14.06 seconds in the patients (not significant). Fog-induced coughing consistently terminated within 15 seconds after stimulus cessation. In control children, cough threshold values ranged from 0.40 to 2.22 ml/minute (median value, 1.31 ml/min). In the fog-responsive patients, cough threshold values ranged from 0.40 to 3.26 ml/minute (median threshold value, 1.31 ml/min; not significant). The cough frequency observed at threshold level was equal in both groups (median, 2; range, 1–4). Of note, in the nonresponsive patient with CCHS, inhalation of an ultrasonically nebulized saline solution containing 20% citric acid was readily followed by the appearance of a cough epoch. Fog inhalation caused no significant change in FEV1 in any of the participants. Mean values of IEMGP and/or PFC attained by patients and control subjects during MVC and PEmax maneuvers were similar (Table 3). In contrast, values of IEMGP and/or PFC recorded during RC were consistently lower (P < 0.01), and corresponded to approximately 80% of those recorded during both MVC and PEmax (Table 3). Cough expiratory time during MVC and RC did not vary significantly. Consequently, IEMGP/TEC values of MVC were higher (P < 0.001) than those of RC and were similar in both groups (Table 3).
An unexpected finding observed in the patients during MVC efforts was the large variability in the duration of the cough compressive phase. Although patients' mean compression time value was very similar to that of control subjects (197.1 vs. 203.0 ms), the corresponding individual values ranged from 20 to 420 milliseconds in the former and from 180 to 230 milliseconds in the latter (Figure 1). Regrettably, due to the experimental set-up used, namely the fact that only expiratory flow could be recorded during RC (see METHODS), we were unable to ascertain if a more variable duration of the cough compressive phase was also present during RC in the patients.
In control children, inhalation of subthreshold fog concentrations caused only minimal and not significant changes in the pattern of breathing. However, coughing at threshold level was consistently preceded by significant increases in I and VT/TI that were due to a significant (P < 0.01) rise in VT without appreciable changes in respiratory timing (Table 4). The ventilatory adjustments that preceded the onset of cough usually caused only slight, not significant reductions in PETCO2. At variance with control subjects, all children with CCHS displayed only trivial changes in breathing pattern even during inhalation of threshold fog concentrations in the period immediately preceding the onset of cough (Table 4).
Awareness of Urge to Cough and Airway Irritation At threshold level for the cough reflex, the mean intensity of the urge to cough in the control subjects was 7.52 ± 0.37; a less intense urge to cough was also perceived during inhalation of just subthreshold fog concentrations. In addition to the urge to cough, inhalation of threshold or near-threshold fog concentrations evoked other sensations in most control subjects. Such sensations were perceived at the level of the throat or chest and were mainly described as "irritation." In all instances, the onset of respiratory sensations preceded the appearance of the above-mentioned ventilatory adjustments. In no instance was the sensation powerful enough to prevent the prosecution of the trial. Only one patient reported the perception of a low-intensity urge to cough (1.5) at threshold level, whereas all other children with CCHS denied both urge to cough and any other sensation during fog inhalation. Representative, original recordings of the ventilatory adjustments, cough motor responses, and intensity of the urge to cough elicited by inhalation of threshold fog concentrations in a control subject and in a patient with CCHS are illustrated in Figure 2.
We have studied the sensory motor components of fog-induced cough and the associated respiratory sensations in children with CCHS affected by PHOX2B molecular changes resulting in relatively mild respiratory phenotypes (3). The novel findings are that these children cough normally in response to exogenous tussigenic stimuli—in this case, fog—and that the intensity of fog-induced cough motor responses is similar to that of healthy children. However, the results also show that, in children with CCHS, unlike healthy control subjects, inhalation of threshold or near-threshold fog concentrations for the cough reflex neither elicits any respiratory sensation nor provokes any change in the breathing pattern of children with CCHS. The finding of a normal cough response to fog inhalation in children with CCHS is at odds with the results of a previous study (24) showing absent or diminished coughing during inhalation of "up to four deep breaths" of fog, thereby suggesting that a reduced cough sensitivity is an additional feature of the syndrome. Admittedly, one of the seven children with CCHS examined here also failed to cough even during administration of the strongest attainable fog stimulus. However, refractoriness to fog is a well-established feature of 12 to 15% of normal subjects (28, 29). The lack of response appears to be specific: in fact, the fog-unresponsive child with CCHS coughed vigorously when exposed to citric acid. We believe that technical factors, as well as some distinctive features of the patients tested, can explain, at least to some extent, the differences between the present results and those previously reported by Shea and colleagues (24). The technical factors include differences in the modality of fog inhalation—namely, the duration of exposure to the tussigenic aerosol—and the selected stimulus strength. Patients' functional peculiarities relate to the fact that all those examined previously (24) required mechanical ventilation via a tracheostomy at the time of the study and had more severe hypoventilation and hypercapnia than those of the present study. Whether tracheostomy and lifelong mechanical ventilation during sleep can affect the sensitivity to fog has not been studied. In this connection, however, it is worth recalling that tracheostomized adult patients have a normal or even slightly increased cough sensitivity to fog (38). Furthermore, acute hypercapnia in anesthetized human adults and experimental animals (39, 40) is associated with a depression of the cough reflex. Children with CCHS may be hypercapnic at rest (see RESULTS), and conceivably, the magnitude of hypercapnia relates to the degree of ventilatory depression during wakefulness. It cannot be ruled out that the children examined by Shea and colleagues (24) had more severe hypoventilation and hypercapnia during wakefulness, possibly associated with a marked depression of their cough reflex. However, the effects of chronic hypercapnia on the cough reflex remain to be clarified. Finally, it should be recalled that the CCHS phenotype may result from polyalanine and nonpolyalanine expansion mutations in PHOX2B, and that nonpolyalanine mutations produce a more severe disruption of PHOX2B function, also associated with more prominent respiratory symptoms (3). Thus, it may be hypothesized that the patients examined by Shea and coworkers (24) mostly belonged to this phenotype group that might be characterized by an impaired cough reflex. This latter possibility, however, is unlikely because virtually all patients with nonpolyalanine expansion mutations also have Hirschsprung disease and are 24-hour ventilator dependent (3), which was not the case of the children studied by Shea and colleagues (24). Whatever the reason(s) for the discrepancy, the present findings indicate that mutational defects such as those identified in our CCHS group have little impact, if any, on the neural substrates underlying the cough reflex. Whether CCHS genotypes with nonpolyalanine expansion mutations or with a greater number of polyalanine expansion mutations have a defective cough reflex remains to be ascertained. However, according to parental reports, both the patients with CCHS examined here and those evaluated by others (20) do cough during respiratory infections. There are no previous reports on expiratory muscle force during MVC and RC in CCHS. We have indexed the intensity of the cough motor output in terms of abdominal IEMG activity and of peak expiratory flow rate. The fact that children with CCHS consistently displayed IEMGP/TEC, IEMGP, and PFC similar to those of normal children demonstrates a normal expiratory muscle force in CCHS, which is also confirmed by the normal PEmax values. The finding of normal values of abdominal IEMG-related variables during MVC and RC in CCHS also suggests that the neural substrates implicated in the recruitment of abdominal expiratory motor units, and in regulating their frequency of discharge, operate normally. On the other hand, some of the children with CCHS displayed an abnormal duration of their cough compressive phase during MVC, which could last either much more (in n = 2 children) or much less (in n = 3 children) than in control subjects (see Figure 1); in the latter, the duration of the compressive phase approximated 0.2 seconds, as expected (41). The reasons for this phenomenon are obscure at present, but hint at the possibility of an impaired motor control of laryngeal adductor muscles in CCHS. Additional studies are required to confirm this finding and, in particular, to ascertain if the phenomenon is also present during reflex coughing. In agreement with previous results obtained in human adults (28), we have also shown that, in both children groups, values of abdominal IEMGP/TEC, IEMGP, and PFC during RC were similar and approximated 80% of those recorded during MVC (Table 3). Conceivably, activation of the cough reflex recruits a considerable portion of the expulsive mechanism already at threshold level, thus allowing the achievement of expiratory flow velocities high enough to warrant effective airway clearing or removal of inhaled foreign bodies, providing a substantial safety factor. As already suggested (28, 42), further needs of airway clearing in real life may be coped with by small, additional recruitment of motor units in the contracting muscles and, perhaps more efficiently, by increasing the number of cough efforts.
It is well documented that humans can sense and evaluate respiratory changes (42–45); however, little is known about sensations evoked by inhalation of tussigenic agents. Recently, it has been reported that a sense of an urge to cough occurs before cough is produced in normal adults challenged with capsaicin (42, 45). In a previous study performed in adult humans, we have shown that inhalation of threshold or near-threshold fog and capsaicin concentrations evokes a variety of respiratory sensations, including the urge to cough, that are qualitatively similar with both tussigenic agents (42) and occur before cough. We have previously demonstrated (30, 42) that, in adults, inhalation of fog concentrations of threshold intensity for the cough reflex also causes, before cough, an increase in A possible methodologic limitation of the present study is that the intensity of the fog stimulus was varied in an ascending way, thus predisposing the subjects to always expect the next stimulus to be greater than the previous one. This anticipatory bias could have affected both the assessment of cough threshold and the measures of respiratory sensations. To overcome this, an obvious alternative would be to administer fog concentrations in random order. However, it has been demonstrated that fog-induced cough is subjected to a high degree of adaptation (46). Thus, administration of a suprathreshold fog stimulus is likely to prevent coughing in response to a subsequent weaker stimulus, even if the latter would have sufficed if administered in reverse order. With this in mind, we believed that the use of progressively increasing fog concentrations would minimize the risk of adaptation and result in a more reliable assessment of cough threshold. Whether adaptation also interferes with the perception of an urge to cough during fog challenges remains to be ascertained.
There is strong evidence supporting the view that these patients lack normal respiratory sensations in some specific circumstances. For instance, they do not report "air hunger" during breath-holding and CO2 rebreathing (20, 24), but they can experience roughly the same level of shortness of breath as that of age-matched normal subjects during heavy exercise (20). The present results provide evidence that children with CCHS do not perceive the sensations or display the ventilatory adjustments that are typically elicited by inhalation of fog concentrations of threshold intensity for the cough reflex (30, 42). Because the onset of sensations consistently precedes the increases in In conclusion, the present study demonstrates that the investigated afferent and motor components of RC are normal in children with CCHS with a mild (3) respiratory phenotype. Nonetheless, the results also demonstrate that these patients present a deficit in their awareness of airway irritation and urge to cough, and in the ventilatory adjustments induced by tussigenic fog concentrations. The present results cannot be extrapolated to children with CCHS of all ages and with a broader range of PHOX2B genotypes. Conceivably, a more complete understanding of cough mechanisms and associated sensations in CCHS would require investigation of cough and respiratory sensations in more severely affected patients with CCHS. In addition, useful information on cough mechanisms in the disease and on the impact of PHOX2B gene on cough control might derive from investigations on the effects of other inhaled irritants, such as capsaicin, which may evoke cough via sensory pathways other than those activated by fog (47), as well as from studies on the pharmacologic control of cough by antitussive agents.
The authors are grateful to the children who participated in this study and to their dedicated families. They thank Dr. Isabella Ceccherini for valuable suggestions and for performing the genetic testing.
Supported by grants from the Ministero dell'Università e della Ricerca of Italy. Originally Published in Press as DOI: 10.1164/rccm.200612-1870OC on August 2, 2007 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form December 22, 2006; accepted in final form July 30, 2007
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ABSTRACT
AT A GLANCE COMMENTARY
25 mm/s) recordings of the flow signal during MVC, we measured for each voluntary effort the duration of the cough compressive phase (i.e., the time period during which the inspired air is compressed within the lungs against a closed glottis) (
