Rationale: Upper airway dysfunction may complicate asthma but has been largely ignored as an etiological factor. Diagnosis using endoscopic evaluation of vocal cord function is difficult to quantify, with limited clinical application.
Objectives: A novel imaging technique, dynamic 320-slice computerized tomography (CT), was used to examine laryngeal behavior in healthy individuals and individuals with asthma.
Methods: Vocal cord movement was imaged using 320-slice CT larynx. Healthy volunteers were studied to develop and validate an analysis algorithm for quantification of normal vocal cord function. Further studies were then conducted in 46 patients with difficult-to-treat asthma.
Measurements and Main Results: Vocal cord movement was quantified over the breathing cycle by CT using the ratio of vocal cord diameter to tracheal diameter. Normal limits were calculated, validated, and applied to evaluate difficult-to-treat asthma. Vocal cord movement was abnormal with excessive narrowing in 23 of 46 (50%) patients with asthma and severe in 9 (19%) patients (abnormal > 50% of inspiration or expiration time). Imaging also revealed that laryngeal dysfunction characterized the movement abnormality rather than isolated vocal cord dysfunction.
Conclusions: Noninvasive quantification of laryngeal movement was achieved using CT larynx. Significant numbers of patients with difficult-to-treat asthma had excessive narrowing of the vocal cords. This new approach has identified frequent upper airway dysfunction in asthma with potential implications for disease control and treatment.
Upper airway dysfunction may complicate asthma but has been largely ignored as an etiological factor in difficult-to-treat asthma. This is because endoscopic visualization is often not available and is difficult to quantify.
Dynamic 320-slice computerized tomography of the larynx was validated and applied to quantify vocal cord movement. Up to 50% of patients with difficult-to-treat asthma demonstrated abnormal laryngeal movement with excessive narrowing of the vocal cords. Upper airway dysfunction in asthma has implications for disease control and treatment.
Asthma is severe and difficult to treat in 5 to 20% of patients (1). Persistent symptoms lead to prescription of high-dose inhaled and oral corticosteroids, patients may require repeated hospital admission, and up to 60% of health care funding for asthma is used to manage severe disease (2). To date, limited advances have been made to improve treatment, and progress in this area has stalled.
Nonpharmacological approaches, such as optimization of medications and improved adherence, may help some patients, but a majority continue to experience ongoing symptoms. The lack of response to antiinflammatory agents has resulted in the identification of various corticosteroid-resistant phenotypes (3), but many patients with severe asthma do not fit unambiguously into these groups, suggesting that other etiologies may govern symptom expression and contribute to severity. We have therefore pursued an alternative approach and investigated whether difficult-to-treat asthma may be magnified in many patients with asthma by upper airway dysfunction.
A role of upper airway dysfunction complicating difficult-to-treat asthma has not been comprehensively investigated. Originally called vocal cord dysfunction (4–8), there are abundant anecdotal reports detailing vocal cord dysfunction masquerading as difficult-to-treat asthma (1, 4, 8–11). However, coexistent upper airway obstruction has largely been ignored as an etiological factor. The key reason is that clinicians have been unable to assemble the various components (symptomatic patients, immediate laryngoscopy, precise diagnostic criteria for diagnosis) required to confirm a diagnosis.
Dynamic 320-slice computerized tomography (CT) is a recent imaging technique that permits real-time viewing of tissue structure and movement over an anatomical width of 12 to 16 cm. It has several advantages over standard (64-slice) CT, allowing imaging of an entire organ to model dynamic processes such as airflow in the respiratory system. Initially developed for cardiac imaging, 320-slice CT also has potential to provide comprehensive and accurate images of laryngeal function during the phases of respiration. We have recently reported use of 320-slice CT larynx to detect upper airway dysfunction in patients with severe, symptomatic asthma (12) and in dynamic airway collapse (13). However, studies were limited in scope and did not define normal parameters for laryngeal movement in the context of this new imaging modality.
In the current studies, we hypothesized that laryngeal function may be abnormal in patients with asthma who have disease that is difficult to control with optimized medications. An algorithm was developed to quantify vocal cord movement detected by 320-slice CT larynx, normal function was defined, and the technique was then applied in a group of patients with difficult-to-treat asthma. Our findings indicate that vocal cord function is frequently abnormal in this patient group.
Normal volunteers and patients with asthma were recruited at Monash Medical Centre, a tertiary care hospital in Melbourne, Australia. Study protocols were reviewed and approved by the Monash Hospital human research ethics committee (projects 09254A and 09137Q) and written informed consent was obtained.
Fifteen healthy volunteers between 18 and 65 years of age were initially studied. Second and subsequently third healthy groups were recruited (n = 7 and n = 7) for repeat validation. The third group (an entirely new group) was recruited as older individuals with age, sex, and body mass index (BMI) comparable to the asthma group studied (see below). Two volunteers also had fiberoptic laryngoscopy assessment. Subjects were excluded if they had any prior history of chest or laryngeal disease, had any neurological disease, or were pregnant. Regular smokers and ex-smokers greater than 5 pack-years were excluded, but occasional smokers (< 2 pack-years) who had not smoked for at least 6 weeks were included. Their demographic characteristics are shown in Table 1.
|Initial Group (n = 15)||Validation Group I (n = 7)||Validation Group II (n = 7)|
|Age, yr, mean ± SD||36.07 ± 11.54||26.29 ± 7.50||56.14 ± 8.69|
|BMI, kg/m2, mean ± SD||24.93 ± 4.00||25.79 ± 4.91||35.40 ± 3.15|
|Ex-smoker (< 5 pack-years)||4||0||0|
|FEV1, % predicted||107.33 ± 10.67||98.71 ± 14.07||96.67 ± 14.67|
|BD response, % change||2.60 ± 2.44||1.86 ± 2.91||5.00 ± 1.67|
Forty-six patients with doctor-diagnosed asthma were recruited at random from a severe asthma clinic. Patients were older than 18 years of age, and individuals with chronic obstructive pulmonary disease or other lung disease, smoking history greater than 10 pack-years, vocal cord pathology (for example, laryngeal cancer), neurological disease, and pregnancy were excluded. Subjects had either: (1) difficult-to-treat asthma with chronic severe breathlessness, with lack of response to treatment with high-dose inhaled corticosteroid/long-acting β-agonist combinations, and requiring frequent courses of oral corticosteroids (n = 39), or (2) difficult-to-treat asthma with episodic severe breathlessness not responsive to optimized inhaled corticosteroid/long-acting β-agonist combinations (n = 7). There was a preponderance of female patients (36 female, 9 male; Table 2).
|Normal Laryngeal Function (n = 23)||Abnormal Laryngeal Function (n = 22)||Combined Group (n = 45)|
|Age, yr, mean ± SD||49.91 ± 16.9||59.64 ± 12.93||54.67 ± 15.71|
|BMI, kg/m2, mean ± SD||33.65 ± 7.29||36.02 ± 9.26||34.78 ± 8.27|
|Duration asthma, yr||18.8 ± 13.95||18.68 ± 20.45||18.74 ± 17.23|
|Asthma symptoms, ACT||11.7 ± 4.94||12 ± 6.47||11.84 ± 5.68|
|Asthma symptoms, ACQ||3.07 ± 1.24||3.21 ± 1.51||3.14 ± 1.36|
|Asthma severity, GINA||3 mild||4 mild||7 mild|
|6 moderate||6 moderate||12 moderate|
|14 severe||12 severe||26 severe|
|Refractory asthma, ATS||18/23||17/22||35/45|
|FEV1/FVC, %||81.45 ± 14.37||80.67 ± 17.08||81.07 ± 15.57|
|BD response, % change||7.64 ± 9.71||4.1 ± 6.84||5.91 ± 8.52|
|Oral CS ≤ 10 mg/d||21/23||15/22||36/45|
|Oral CS > 10 mg/d||4/23||2/22||6/45|
|Inhaled CS ≤ FP 500 mg/d||9/23||6/22||15/45|
|Inhaled CS > FP 500 mg/d||17/23||9/22||26/45|
|Other||1/23 (M)||3/22 (2 Tio, 1 T)||4/45|
Asthma was suspected on the basis of typical symptoms and a bronchodilator response greater than or equal to 12% and 200 ml to β-agonists (n = 32); this included a positive bronchial provocation test in two cases. Five of the 13 patients without a bronchodilator response had baseline FEV1 less than 80% predicted, and all 13 patients had at least one documented acute episode of asthma with wheezing requiring hospital emergency department admission and treatment with oral glucocorticosteroids. All patients had received the maximum recommended doses of high-dose inhaled corticosteroid/long-acting β-agonist combinations without clinical benefit. In some cases, inhaled corticosteroid doses had been reduced due to lack of perceived efficacy or adverse laryngeal effects, or inhalers had been replaced with oral corticosteroids.
Baseline demographic characteristics, asthma history, and details of exacerbations and medications were obtained. Respiratory and asthma symptoms were assessed using the asthma control test (14) and asthma control questionnaire (15). Characteristics of the group are shown in Table 2.
No treatment for asthma was taken on the day of study. Patients received identical instructions through an automated intercom system and were instructed to breathe normally (“as they do at home”) and not to swallow at any stage. To ensure relaxed breathing a practice run was done before CT was commenced. Studies were performed using the Toshiba Aquilion-One CT (Toshiba Medical Systems, Tokyo, Japan) with 320-slice detector. Parameters were 80 kVp, 300 to 350 mA, and gantry rotation 0.35 seconds. Images were therefore generated every 0.35 seconds over the duration of the respiratory cycle (beginning of inspiration to the beginning of inspiration of the next breath). Radiation doses were in a range of approximately 0.8 to 2 mSv depending on the amount of soft tissue in the neck of a particular individual.
Integrated CT software programs were used to obtain continuous dynamic axial, sagittal, and coronal multiplanar images of the larynx. Images were reconstructed at 0.35 s/frame and included dynamic three-dimensional laryngeal airway views. Luminal (lateral) diameters at the level of the vocal cords and first tracheal ring were measured on coronal views using electronic calipers. The ratio of vocal cord diameter to tracheal diameter (referred to as RATIO) was used for analyses. Changes in tracheal diameter during the breathing cycle were minimal (data not shown), and the RATIO (rather than absolute measurements) was used to control for airway size of individual subjects. Analyses were conducted by a radiologist (K.K.L.) blinded to the study groups.
Lung function testing was performed as detailed in the online supplement.
Laryngeal behavior was evaluated in two normal volunteers to benchmark vocal cord movement detected by dynamic CT against endoscopy. Methods are detailed in the online supplement.
An algorithm for analysis and to benchmark normal vocal cord movement was initially established. This was done in healthy volunteers, with the initial data used to ascertain the range of normal vocal cord movement. Additional validation of the algorithm was then conducted in two separate groups of healthy volunteers. The algorithm was finally used to examine laryngeal function in patients with difficult-to-treat asthma. A detailed description of the methodology can be viewed in the online supplement.
Briefly, a normal curve for RATIO (as defined above) was generated by integration of multiple measurements obtained during a breathing cycle. Figure 1A shows the evolution of RATIO over real time in 15 subjects over one breathing cycle. Times were standardized to 1 unit of inspiration and 1 unit of expiration and a cubic spline interpolation performed (with 101 interpolating points for each stage). Figure 1B shows the smoothed evolution of the RATIO over the two standardized units of time for each subject. These smoothed curves constituted the collective response measure for the 15 subjects. Next, the mean for 15 subjects was computed (Figure 1C). SDs within each phase of respiration were pooled, resulting in SDs of 0.1123 for inspiration and of 0.1379 for expiration (Figure 1D). There was no influence of age or sex on the algorithm. Because excessive vocal cord narrowing was of primary interest and in the light of the above-noted findings, a conservative 1.5 SDs below the mean was defined as the lower limit of normal. Figure E1 in the online supplement demonstrates analysis of individual vocal cord function using this algorithm in 15 healthy subjects.
Two additional groups of healthy participants (n = 7 and n = 7) were studied to validate measurements. For each participant and each phase of respiration data were entered in an in-house computerized program (HAMZACT) that generated a time-RATIO curve during both inspiration and expiration. It also calculated the proportion of time RATIO was reduced below the lower limit of normal (i.e., lower than 1.5 SDs under the mean). The measurement algorithm was then finally applied to CT measurements obtained in 46 patients with asthma.
RATIO obtained from measurements of vocal cord lateral diameter (coronal views) was compared with RATIO of the vocal cord lumen area (obtained in axial views). RATIO and lumen area RATIO were measured and calculated in 15 patients and the extent of agreement was calculated.
Logistic regression was used to find predictors of abnormal vocal cord movement in asthma. Individual features included in the analysis were age, sex, BMI, FEV1, asthma severity, and duration of asthma. Univariate analysis was initially done with the intention of identifying factors to include in multivariate analyses. Agreement between vocal cord lateral diameter and vocal cord lumen area was examined using Pearson correlation and Bland-Altman analysis. Asthma symptom scores were compared using paired t tests. Significance was accepted if P was less than or equal to 0.05.
Laryngoscopy is the gold standard against which other imaging techniques have been judged. We therefore compared video images obtained by endoscopy to virtual images generated by 320-slice CT larynx in two healthy volunteers. Endoscopic images were practically identical to CT, confirming our previous findings (12). Endoscopic and virtual endoscopy images generated by CT can be viewed in the online supplement (Figure E2).
We next determined the parameters of normal vocal cord movement as quantified by 320-slice CT larynx. There were notable differences in vocal cord behavior during inspiration and expiration as detailed in Methods. However, it was possible to elucidate lower limits of normal for vocal cord function and this was then validated in a second group of seven healthy participants. All subjects in this group remained above the lower limit of normal for both inspiration and expiration (Figure 2). Additional validation was subsequently done in seven additional healthy individuals with age, sex, and BMI comparable to the group with asthma (Table 1). Again, all subjects in this group had vocal cord movements that remained above the lower limit of normal during both inspiration and expiration (data not shown).
To assess vocal cord function in patients with asthma, 46 patients with difficult-to-treat asthma were studied (Table 2). This was done applying the analysis algorithm as detailed above to all cases and defining abnormal vocal cord movement as below the predefined lower limit of normal (1.5 SD under the predicted mean). Vocal cord movement was abnormal during either inspiration or expiration in 23 (50%) of 46 patients with asthma (Figure E3). Representative examples of movement abnormality observed in asthma are demonstrated in Figure 3. An illustration of abnormal vocal cord function in asthma demonstrated by three-dimensional volume-rendered coronal reconstruction can also be viewed as an online video segment (Cine E1). RATIO was abnormal during inspiration only in five cases (12%), expiration only in three cases (8%), and in both phases of respiration in 15 patients (30%). Abnormal vocal cord movement was detected in 18 of 32 cases (56%) with a bronchodilator response greater than or equal to 12% indicative of asthma.
RATIO was abnormal for 50.5 ± 39.1% of inspiration time and/or 50.2 ± 29.8% of expiration time. The duration of abnormality (i.e., percentage time that RATIO was below lower limit of normal) during inspiration and expiration is demonstrated in Figure E4. Prolonged motion abnormality was noted in nine (19%) cases where the lower limit of normal was exceeded for more than 50% of inspiration time or expiration time.
RATIO calculated using measurements of vocal cord diameter and RATIO calculated using measurements of vocal cord area were closely correlated (R2 > 0.8; data not shown). Considerable variation in the pattern and dispersion of abnormal vocal cord movement was observed, but the group was too small to investigate whether this finding may be associated with individual patient or spirometric characteristics.
CT images generated by this method made it possible to view overall laryngeal function rather than predominantly vocal cord movement as typically visualized by endoscopy (Figure 4B, Cine E1). Contraction of the entire larynx and supraglottal areas with airway narrowing (and at times almost complete closure) was frequently observed. Vocal cord movement abnormality could be intermittent, as demonstrated in an individual with asthma who had an initial normal study followed by evidence of vocal cord narrowing at a subsequent study conducted during a period of severe breathlessness (Figures 3H, 3I, 4A, and 4B). Detailed studies of breath-to-breath variation in RATIO were precluded by radiation exposure, but in patients who “ran over,” the shape of the time-RATIO curve was virtually identical to the initial cycle.
Clinical patient characteristics or spirometric changes may predict abnormal vocal cord movement. However, univariate analysis did not identify any factors predictive of abnormality, including age, sex, BMI, FEV1, asthma severity, or duration of asthma. Inspection of expiratory flow-volume curves as well as inspiratory flow-volume loops for individual patients also could not distinguish patients with abnormal vocal cord movement.
Novel 320-slice CT provided explicit dynamic images of the larynx and characterized function during the respiratory cycle. The technique identified abnormal laryngeal movement in a significant number of patients with difficult-to-treat asthma and these unexpected findings suggest that sizable numbers of patients with chronic asthma may have coexistent upper airway dysfunction. Our findings should stimulate further studies of laryngeal function and its relationship to difficult-to-treat asthma and remind clinicians to consider, investigate, and treat putative laryngeal dysfunction in this group.
Asthma is a disease with high prevalence, and reported rates approach 10% in adults and 30% in children (16). Patients with severe asthma experience relentless breathlessness, often sudden and unexpected, despite optimal treatment. Treating physicians are prompted to increase antiinflammatory therapies, leading to high doses of inhaled and oral corticosteroid prescription with attendant side effects. Morbidity is excessive in difficult-to-treat asthma, patients are regularly admitted to hospital, and consequently up to 60% of health care funding allocated to asthma may be consumed by this group (2). In clinical practice, patients with severe asthma represent a substantial number of patients who require chronic respiratory care, and treatment is challenging, with limited options.
Surprisingly, upper airway dysfunction mimicking resistant asthma or coexisting with asthma has not been comprehensively investigated, and despite numerous reports detailing upper airway dysfunction masquerading as difficult-to-treat asthma, it has been largely ignored as an alternative or coexisting diagnosis. The primary reason is that operational problems have made it problematic to investigate and confirm vocal cord dysfunction; because patients may be relatively asymptomatic at examination, immediate laryngoscopy is often not available, and diagnostic criteria are imprecise. Laryngoscopy is also poorly tolerated in many patients with asthma with acute symptoms (17). However, accurate diagnosis and treatment of upper airway dysfunction can improve morbidity, reducing medical use, curtailing inappropriate treatment with high-dose corticosteroids, and preventing intubation (7, 11).
To date, studies to quantify normal and abnormal laryngeal and vocal cord activities in humans have been limited, and most current knowledge in the field derives from studies conducted in the 1970s (18, 19). Studies by Collett and coworkers in the early 1980s used radiological techniques to evaluate laryngeal function in healthy volunteers and patients with asthma (20). Evidence was found suggesting aberrant laryngeal behavior in asthma, but investigation was restricted by the amount of radiation required and limited patient numbers. Recently dynamic 320-slice CT has permitted real-time viewing of organ function by scanning a Z-axis “volume” over time without table movement. This allows seamless imaging of heart and brain function over time (21–23), and there is no need to stitch together images from multiple gantry rotations. This makes it possible to achieve volumetric three-dimensional reconstruction of dynamic processes such as blood flow in the heart and airflow in the respiratory system. Finally, increased numbers of detectors with faster acquisition times translate into high levels of anatomical resolution with less radiation exposure. Crucially, radiation doses to the larynx in studies reported here, as well as in previous investigations (12), were within safe limits (1–2 mSv).
In the current studies, high-speed 320-slice CT larynx was used to define normal vocal cord function and to quantify analysis. We demonstrate that normal vocal cord movement can be quantified by the ratio of vocal cord diameter to tracheal diameter (RATIO); a normal curve was generated by integration of multiple measurements obtained during a breathing cycle. Studies in 15 healthy subjects determined the lower limits (curve) of normal, and these putative limits were then validated in two groups of healthy volunteers, one group specifically matched with the asthma group for age, sex, and BMI.
We next applied the technique in a random group of patients with difficult-to-treat asthma, a subgroup at risk of laryngeal dysfunction (4, 7, 8). These studies yielded unexpected results. Fifty percent of patients had vocal cord movements that fell below normal limits (during either inspiration or expiration or both) as predefined. In up to 20% of patients the abnormality was prolonged (> 50% of inspiration or expiration below critical level), and in some patients virtual closure of the vocal cords was observed. Regression analysis did not identify any disease or phenotypic features associated with abnormality. Our findings represent the first demonstration of laryngeal dysfunction in a large proportion of patients diagnosed and managed as difficult-to-treat asthma.
A valid question is whether the patients under study could all have vocal cord dysfunction and whether they did indeed have asthma. Although asthma can be closely mimicked by abnormal vocal cord movement, the majority of our patients had persuasive evidence of asthma. Significant bronchodilator responses were demonstrable in more than 70% of cases, and another five patients had abnormal spirometry consistent with severe asthma. More than 80% of cases would therefore meet current definitions of asthma (24).
What do these findings mean? It seems feasible that a few patients had isolated classical vocal cord dysfunction (4). Others may have less severe forme fruste variants of the same condition with fluctuating laryngeal obstruction. However, on the basis of the clinical findings in our study, we would argue that the majority of subjects had sufficient grounds to support a diagnosis of asthma. This suggests in turn that abnormal vocal cord movement may represent a coexisting condition—rather than an alternative diagnosis—in this group. It tallies with the impression of many clinicians that patients with difficult-to-treat asthma have coexistent laryngeal dysfunction. Mechanistically, it raises the possibility that asthma and laryngeal dysfunction are interrelated conditions with “laryngeal hyperresponsiveness” as an intrinsic and unsuspected characteristic of asthma itself. Conceivably, intermittent upper airway obstruction in addition to lower airway obstruction may influence symptom expression and contribute to resistance against generally highly effective antiinflammatory corticosteroid treatments. Nonetheless, although we demonstrated a strong association between laryngeal dysfunction and difficult-to-treat asthma, laryngeal dysfunction as a direct cause of asthma symptoms and difficult-to-treat asthma remains to be verified. This may be achievable through interventions such a vocal cord retraining and other strategies (25, 26).
An interesting aspect of comprehensive imaging achieved by CT larynx is that the extent of laryngeal involvement in vocal cord movement dysfunction appears much greater than previously believed. Dynamic images provide vivid evidence of almost total occlusion of the entire larynx and supraglottal area in some cases. This suggests that early designation of the condition as vocal cord dysfunction is probably a misnomer based on the limited anatomical and functional views gained from visual inspection of the vocal cords during endoscopy. This observation has implications for the pathogenesis and treatment of the condition. Clearly the causes of dysfunction may not be simply related to isolated vocal cord abnormality but rather involve the entire larynx, an organ with a bountiful supply of muscle groups and nerves. Treatment is likely to be more effective if therapeutic strategies target the larynx as a whole.
Several questions remain. As noted, vocal movement abnormality remains to be proven as a direct cause of difficult-to-treat asthma, and the prevalence in other asthma severity populations requires investigation. Radiation concerns precluded studies to examine the duration and consistency of abnormal movement over several breathing cycles. Movement abnormality may also occur intermittently, and investigations to provoke and identify laryngeal dysfunction will be a significant advance. Some studies have suggested that upper airway involvement in asthma may be detectable by inspection of flow-volume loops (27, 28), but we were unable to confirm this observation. This possibility deserves further investigation using newer techniques such as impulse oscillometry. Finally, specific patient characteristics and other disease factors predictive of laryngeal dysfunction could not be comprehensively evaluated in the current studies and remain to be elucidated.
In summary, CT imaging of the larynx permitted noninvasive quantification of vocal cord movement and detection of vocal cord narrowing in asthma. This novel approach has potential to detect unsuspected, coexisting upper airway dysfunction in asthma with potential practical implications for treatment, disease control, and quality of life.
The authors thank all patients who participated in studies. Expert clinical support was provided by Joanne McKenzie and Simon Joosten. Anita Rodda assisted in preparation of the manuscript. The authors also thank Peter McLaughlin, Xun Li, Michael Ho, Stephen Stuckey, and Dee Nandurkar for helpful discussions and support. The analysis program used to assess vocal cord function by means of CT larynx (HAMZACT) will be made available free of charge to other researchers.
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Supported by Monash Medical Centre and Respiratory and Sleep Medicine, Monash Medical Centre, Melbourne, Australia.
Author contributions: P.G.B., G.H., P.H., K.H., and K.K.L. conceived studies. Studies were conducted and data collection was done by K.L., K.K.L., M.C., N.V., and D.P. All authors contributed to data analysis, drafting the manuscript, and approved the final version.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201010-1604OC on March 31, 2010