Spirometry and provocation tests for vocal fold dysfunction diagnosis: a retrospective case series

DOI: https://doi.org/10.4414/smw.2018.14692

Background

Vocal cord dysfunction (VCD) is an upper airway disorder characterised by a paradoxical inspiratory closure of the vocal cords. It is an under-recognised cause of wheezing and unexplained refractory cough, often misdiagnosed as asthma [1–3]. Many labels have been used for VCD in recent decades, including false croup, Munchausen’s stridor, psychogenic stridor, hysterical stridor, factitious asthma, pseudo-asthma, emotional laryngeal wheezing, episodic laryngeal dyskinesia, irritable larynx syndrome, paradoxical vocal fold motion/movement [4–6] and, more recently, inducible laryngeal obstruction [7].

The prevalence of VCD in the general population is not known. It occurs in all age groups, frequently being reported in juvenile girls [8], and especially in athletic subjects [9]. A prospective evaluation of a military population with exertional dyspnoea revealed a diagnosis of VCD in 15% [10]. The prevalence of VCD in patients admitted to emergency services for breathlessness of acute onset varied between 2.5 and 22% depending on the study population, with a female predominance varying from 2:1 to 4:1 [11, 12]. VCD is related to a broad spectrum of underlying causes, including functional as well as organic conditions. Psychological disorders were initially believed to be the exclusive cause of VCD [13–15]. However, a role of various nonpsychological factors involving sensory mechanisms [16–18], such as gastro-oesophageal reflux [19], as well as upper respiratory tract conditions and infections (pharyngitis, laryngitis, rhinosinusitis), are progressively being recognised [20–25]. Paradoxical vocal fold movement has also been reported in the context of established neurological diseases, such as brain stem compression, severe cortical injury, nuclear or lower motor neurone injury movement disorders and neuroleptic abuse [24, 26].

The clinical presentation of VCD is that of airway obstruction with wheezing, inspiratory stridor, breathlessness and coughing, which are easy to confuse with symptoms of asthma [27, 28]. Cough as the sole presenting symptom raises the probability of extra-thoracic airway hyperresponsiveness (EAHR) [22, 29], which results in the same reduction of inspiratory flow as VCD, and therefore is difficult to distinguish from it [5, 22]. In general, the diagnosis is suspected in patients with atypical asthma presentation and refractory clinical course. Nevertheless, VCD and asthma can also present together, in half or more of the cases, as demonstrated in several series of asthmatic patients [2, 3, 30, 31].

The principal difficulty in recognising and diagnosing VCD is that laryngeal endoscopic observation or videolaryngostroboscopy are conclusive only during a symptomatic episode [31, 32]. Therefore, the sensitivity of these examinations is only moderate [33, 34]. To overcome this problem, some authors have tried to challenge VCD patients with exercise [9], or inhaled irritants such as methacholine [35], histamine [20, 22] and mannitol [34]. An alternative diagnostic approach might be based on the combination of a typical clinical history, eventually using standardised questionnaires [36–38], with less-specific tests [39], consisting of volume flow loops, mannitol challenge test (MCT), and the exercise challenge test (ECT).

The aim of this study was to present a case series of patients with a strong clinical suspicion of VCD based on medical history and findings obtained by laryngoscopy, spirometry and provocation tests consistent with VCD. The potential diagnostic usefulness of the latter two noninvasive tests was evaluated.

Materials and methods

Population

Patients were identified by the senior allergist in charge (PT) when presenting with a typical clinical history of VCD, and were included when at least one of the following three complementary tests was performed in order to confirm the diagnosis: laryngoscopy, spirometry and respiratory challenge tests. Patients were recruited in the last 10 years in the Allergy Unit of the Geneva University Hospital (HUG) and in the Centre des Allergies et de l’Asthme de la Terrassière, in Geneva between 2004 and 2013. Data were collected retrospectively from medical records in 2014. Approval was obtained by the local ethics committee (HUG; protocol n°13-166). This study was purely observational; therefore written consent was not required.

Clinical parameters

Patient characterisation included age and gender; reason for consulting (asthma, cough, dyspnoea, dysphonia, or referral for VCD suspicion); triggering symptoms (anxiety, physical exertion, irritant inhalation, gastro-oesophageal reflux disease, rhinosinusitis), clinical symptoms and disease pattern (inspiratory or expiratory dyspnoea, cough, hoarseness, rhinosinusitis, gastro-oesophageal reflux disease [GORD], atopy, suspicion of asthma, rapid onset [<3 minutes] and resolution [<5 minutes] of symptoms, and β₂-antagonist responsiveness). Atopy was defined by the presence of at least one positive skin prick test for common aeroallergens, one positive specific IgE, or a positive Phadiatop test. Suspicion of asthma was based on recurrent attacks of breathlessness and wheezing associated with either a diminished FEV/FVC ratio (80% or less at age 20–39, 75% or less at age 40–59, and 70% or less at age 60–79), or a positive response to β₂-antagonists an increase in FEV₁ of 200 ml or greater and 12% or greater from baseline) [40].

Spirometry

Spirometry (EasyOne™, Zurich, Switzerland) was performed to measure forced vital capacity (FVC) and forced expiratory volume in the first second (FEV₁) using the American Thoracic Society criteria [41]. Spirometry was performed until two comparable values of FEV₁ within 100 ml were obtained. The higher of the two values was recorded and the percentage of predicted values was calculated. We added a measure that pinpoints EAHR on the flow volume-loop: the forced expiratory flow over the forced inspiratory flow at 50% of inspiration ratio (FEF₅₀/FIF₅₀). In addition, we described three typical morphological aspects of the inspiratory flow curve that can be related to laryngeal hyper-reactivity: the flattened aspect, the notched aspect and the steep slope aspect of the second part of the inspiratory curve. If the inspiratory curve was not U-shaped and did not belong to one of these three typical morphological patterns, we referred to it as undefined pathological aspect [11, 12, 42]. In contrast to the measurement of FEV₁ [41], inspiratory measures such as FIF₅₀ and FEF₅₀/FIF₅₀ ratio are not yet standardised. We performed a minimum of three expiratory/inspiratory volume-flow loops and accepted it as abnormal if at least one of the three inspiratory curves had ≥1 of the typical morphologies described.

Exercise challenge test

Briefly, the ECT was performed according to the ATS guidelines for exercise challenge testing [41] by using an electronically braked cycle ergometer. Work rate (Watts) was adjusted in increments. Speed was chosen to produce 4–6 minutes of exercise at near-maximum levels (i.e. Borg effort scale 17–20/20) with a total duration of exercise of 8 min. Spirometry was performed before exercise and then serially at 2, 5, 10 and 15 min after cessation of exercise. A positive response to ECT was defined by a fall in FEV₁ of ≥15% after challenge, a positive ECT for VCD as a ≥20% fall in FIF₅₀ from baseline.

Mannitol challenge test

The MCT was performed according to the protocol by Anderson et al [42]. Briefly, doses of 0 (empty capsule acting as a placebo), 5, 10, 20, 40, 80 and 160 mg of mannitol were administered via an inhaler device (Pharmaxis Ltd., Frenchs Forrest, NSW, Australia). After the inhalation, the patients were told to hold their breath for 5 seconds. Two FEV₁ manoeuvres were performed 60 seconds after each dose and the highest FEV₁ measurement was recorded. The value measured after the 0 mg capsule was taken as the pre-challenge FEV₁ and was used to calculate the percentage decrease in FEV₁ in response to mannitol challenge. The challenge was stopped when a 15% fall in FEV₁ was documented or a cumulative dose of 635 mg had been administered. The dose of mannitol to cause a 15% fall in FEV₁ was calculated by linear interpolation of the relationship between the percent fall in FEV₁ at the end of the MCT and the cumulative dose of mannitol required (in mg) to provoke this fall. Response to the MCT was considered positive when a fall in FEV₁ of ≥15% occurred after a cumulative mannitol dose of 635 mg or less. We also measured FIF₅₀ and the drop of FIF₅₀ from baseline, to document extra-thoracic hyper-reactivity. A positive MCT for VCD was defined as a ≥20% fall in FIF₅₀ from baseline.

Hypertonic saline challenge tests

Spirometry was performed before hypertonic saline exposure (NaCl 6%), and then serially at 2, 5, 10 and 15 minutes after exposure. A positive test was defined by a fall in FEV₁ of ≥15% after challenge, a positive test for VCD as a ≥ 20% fall in FIF₅₀ from baseline.

Statistical analysis

Data were analysed using R software (Vienna, Austria, version 3.1.1). Continuous outcomes (i.e. age) were reported with mean and standard deviation. Binary outcomes were reported with absolute values and percentages with their corresponding confidence intervals. Sample size was reported for each binary outcome of interest, because of the significant rate of missing values.

Results

Ninety patients with typical history of VCD were identified and 84 who had undergone laryngoscopy, spirometry or respiratory challenge test were included: 62 (74%) females and 22 (26%) males. The median age was 51 ± 18 years old. The reasons for consulting, reported for all patients, comprised asthma (18%), cough (19%), dyspnoea (23%), combined cough and dyspnoea (10%), dysphonia (7%), and referral for VCD suspicion (21%) (table 1). VCD triggers, evaluated in 53/70 patients, consisted of anxiety (23%), physical exertion (48%), irritants inhalation (16%), GORD (26%), and rhinosinusitis (20%) (table 2). Note that multiple triggers could be found on the same patient.

Associated symptoms and disease pattern were sometimes partially reported (table 3). The major associated symptom was dyspnoea (91%), with 78% being inspiratory. Other associated symptoms were cough (90%), hoarseness (70%) and rhinosinusitis (60%). The principal comorbidities were GORD (56%), atopy (54%) and asthma (45%). During an acute period, rapid onset (75%) and resolution (52%) of symptoms was frequent. Response to β₂-antagonists occurred in 53% of cases.

Thirty-six patients underwent laryngoscopy, which was positive in three (table 4). Provocation tests were performed in 37 patients and were positive in 68%, of which 81% were MCTs, 50% were ECTs and 43% with various irritant triggers. The only test performed with hypertonic saline was also positive. Spirometry was conducted in 76 patients and was positive in 84%. The inspiratory volume-flow loop was notched in 36% of cases, flattened in 42%, had a steep slope in 2%, and had multiple undefined pathological patterns in 10%. FEF₅₀/FIF₅₀ ratio was >1 in 54% of cases. For the 73 patients presenting at least one complementary examination positive, contribution to the diagnosis was obtained by spirometry alone in 45 cases, by provocation tests alone in 6 cases, and by any combination of spirometry, provocation tests and laryngoscopy in 23 cases.

Discussion

The current study describes a large case series of patients presenting with a strong clinical suspicion of VCD, a condition for which a sensitive or specific complementary examination does not yet exist. Our findings provide additional information on VCD patient characteristics and indicate the potential usefulness of noninvasive diagnostic tools.

VCD characteristics and triggers

The observed female-to-male ratio of 3:1 was previously reported [11, 43], but we found a median age of 54 years, which is much older than usually reported [8]. This higher age can be partly explained by a referral bias, since paediatric and adolescent patients are rarely seen in our clinics. The second possible explanation is that nowadays, VCD diagnosis is more frequently thought of in older age groups.

VCD triggers include inhaled irritants, physical exertion, acid reflux, upper respiratory tract infection [44], cold air, laughing and anxiety, all causing EAHR. Interestingly, a Brazilian cohort of patients suffering from allergic rhinitis reported a VCD prevalence of 28.5% following nasal provocation test with the house dust mite allergen Dermatophagoides pteronyssinus [45]. Allergens could therefore represent another potential trigger in a specific VCD subgroup. We found an atopy prevalence of 54% in our cohort. In comparison, the atopy prevalence in the general population is 32.3% [43]. This difference might be explained either by potential associations between atopy and VCD ± asthma, or by a potential referral bias (patients were screened in allergy and asthma centres). Pulmonary symptoms were the reason for consulting in a high proportion of our case series (see table 1). This might also be the result of a potential referral bias, for example compared to patients presenting predominantly with dysphonia who preferentially consult with ear nose and throat (ENT) specialists.

VCD and asthma overlap

Most of the symptoms associated with VCD are not specific for this disease (see table 3) with the exception of rapid symptom onset and disappearance, which partially explains the difficulties in making a correct diagnosis. A recent validated tool, the Newcastle laryngeal hypersensitivity questionnaire [36–38], can differentiate VCD patients from healthy controls, but differentiating VCD from other respiratory conditions such as chronic cough remains challenging [46]. The prevalence of comorbidities such as asthma, rhinitis, and GORD was similar to previously reported findings [30]. Rhinosinusitis (60%) and GORD (56%) are direct contributors to extra-thoracic hyperreactivity, by either direct laryngeal deposition of mucus and its proinflammatory mediators, or acid irritation. We found a prevalence of asthma suspicion in 32/80 patients (45%), and a relatively high proportion of β₂-agonist responders (26/49 patients, 55%). A similar prevalence of asthma of 55% has been previously reported in a case series of 95 patients with laryngoscopically diagnosed VCD [30]. One can argue that we recruited patients suffering from asthma but not VCD. However, the potential coexistence of asthma and VCD and the overlap in their clinical presentation account for the diagnostic difficulties and delays in identifying VCD.

The potential association of asthma and VCD could widen the concept of “united airway disease” to a new global rhino-laryngo-bronchial respiratory entity including laryngeal hypersensitivity [47, 48]. In the future, the recognition of a high prevalence of asthma associated to VCD could lead to significant changes in current asthma guidelines with potentially an important reduction in the morbidity of a subgroup of patients.

Implications for clinical practice

Diagnosis of VCD not only requires a high level of suspicion, but also access to specialised ENT testing such as laryngoscopy or videolaryngostroboscopy. Albeit laryngoscopy is the historical gold standard [5], it can fail to demonstrate VCD because of the paroxysmal nature of this condition. Indeed, in our case series, laryngoscopy was positive in only 3/36 patients (8%), reflecting a low sensitivity outside an acute episode. Provocation manoeuvres may increase the sensitivity of the laryngoscopy, especially when adequate triggers are applied [49, 50]. Laryngoscopy remains of great importance in the management of recalcitrant VCD cases, in order to differentiate between supraglottic and infraglottic obstructions. Indeed, supraglottic obstruction might be effectively managed by endoscopic supraglottoplasty [51], and laryngomalacia might coexist in cases of infraglottic obstruction [52].

Various bronchial provocation tests using hypertonic saline, methacholine, histamine, effort or other irritants have been proposed to investigate both classical bronchial hyperreactivity and EAHR. The rationale for the use of these provocation tests is laryngeal sensory neuropathy; characterised by hypersensitivity to many specific or nonspecific triggers. These provocation tests act as laryngeal irritants and prompt extrathoracic symptoms such as cough, dyspnoea and dysphonia. The recognition of laryngeal dysfunction has led to an emerging concept, which is now called the irritable larynx syndrome [53]. The most promising provocation test is the MCT, which was positive in 17/21 (81%) of our patients. MCT is simple to implement for an allergy or respiratory physician, takes less than 30 minutes and can be performed outside an acute attack. In our clinical practice, an MCT is performed when history does not reveal a specific trigger. ECT and irritant respiratory challenges tests were performed when the related VCD stimulus was revealed by the clinical history, and were positive in one half of the cases.

Spirometry was completed in 76 patients and results were consistent with VCD in 84% of the cases. Previous studies have reported conflicting results on abnormal inspiratory loops in patients with a confirmed diagnosis of VCD, the incidences ranging from 23 to 100% [54], as well as a limited usefulness of spirometry to predict the diagnosis of VCD [55]. We found a surprisingly high prevalence of positive spirometry for VCD (84%). This unexpected finding has to be confirmed by future studies with confirmed diagnosis of VCD, eventually in combination with trigger provocation manoeuvres in order to get results during an acute attack.

A proper diagnostic test for VCD is imperative, because this condition requires specific therapeutic modalities. Furthermore, it is important to identify and manage VCD triggers. The first line of treatment includes diet and lifestyle adaptations, proton pump inhibitors, intranasal corticosteroids, and if feasible avoidance of inhaled irritants. The cornerstone of specific VCD treatment is based on speech therapy, to provide instructions in techniques of throat relaxation as well as cough and throat clearing avoidance. We found a prevalence of anxiety of 21%. Psychological interventions such as psychotherapy, behavioural therapy, biofeedback or hypnosis may be required for some patients [14, 56, 57].

Limitations and implications for further research

Our study has significant limitations including the retrospective design, the potential inherent selection bias, a moderate sample size, missing values, the absence of a control group and foremost, the absence of a robust gold-standard test to confirm the diagnosis. Sensitivity and specificity analysis were therefore not feasible. However, we consider our results as relevant and representative of the current clinical practice, since a validated diagnostic algorithm is not yet established [7]. Practically, the diagnosis of VCD was based on a combination of low-weighted clinical arguments including VCD symptoms, trigger factors, associated conditions and easy-to-perform and noninvasive diagnostic tests. We observed surprisingly high proportions of atopy, positive mannitol provocation testing and specific disease patterns on spirometry. Even if our results did not lead to clear clinical recommendations, they could be useful in paving the way for future prospective case-control studies, which should focus on sensitivity analysis for the various noninvasive diagnostic tools presented here, applied either separately or, more interestingly, in combination. Future studies focusing on VCD and on its association with allergies and asthma would be of great interest.

Conclusions

VCD remains an underdiagnosed condition despite being increasingly recognised. For the important proportion of VCD patients presenting with a false-negative laryngoscopy or videofluoroscopy, a combination of clinical history and less invasive diagnostic tools, especially provocation tests and spirometry, might contribute to a better diagnostic approach to VCD. Atopy could play a role in VCD. Future case-control studies using a reproducible diagnostic scoring or assessment system for this condition are needed in order to draw firm clinical recommendations.

References

1 Goldberg BJ , Kaplan MS . Non-asthmatic respiratory symptomatology. Curr Opin Pulm Med. 2000;6(1):26–30. Published online December 23, 1999. doi:.https://doi.org/10.1097/00063198-200001000-00006  

2 Jain S , Bandi V , Officer T , Wolley M , Guntupalli KK . Role of vocal cord function and dysfunction in patients presenting with symptoms of acute asthma exacerbation. J Asthma. 2006;43(3):207–12. Published online June 07, 2006. doi:.https://doi.org/10.1080/02770900600566892  

3 King CS , Moores LK . Clinical asthma syndromes and important asthma mimics. Respir Care. 2008;53(5):568–80, discussion 580–2. Published online April 23, 2008.  

4 Bahrainwala AH , Simon MR . Wheezing and vocal cord dysfunction mimicking asthma. Curr Opin Pulm Med. 2001;7(1):8–13. Published online January 05, 2001. doi:.https://doi.org/10.1097/00063198-200101000-00002  

5 Christopher KL , Wood RP, 2nd , Eckert RC , Blager FB , Raney RA , Souhrada JF . Vocal-cord dysfunction presenting as asthma. N Engl J Med. 1983;308(26):1566–70. Published online June 30, 1983. doi:.https://doi.org/10.1056/NEJM198306303082605  

6 Roger G , Denoyelle F , Garabedian EN . Dysfonction laryngée épisodique [Episodic laryngeal dysfunction]. Arch Pediatr. 2001;8(Suppl 3):650–4. Published online October 31, 2001. Article in French. doi:.https://doi.org/10.1016/S0929-693X(01)80022-1  

7 Halvorsen T , Walsted ES , Bucca C , Bush A , Cantarella G , Friedrich G , et al. Inducible laryngeal obstruction: an official joint European Respiratory Society and European Laryngological Society statement. Eur Respir J. 2017;50(3):1602221. Published online September 11, 2017. doi:.https://doi.org/10.1183/13993003.02221-2016  

8 Powell DM , Karanfilov BI , Beechler KB , Treole K , Trudeau MD , Forrest LA . Paradoxical vocal cord dysfunction in juveniles. Arch Otolaryngol Head Neck Surg. 2000;126(1):29–34. Published online January 11, 2000. doi:.https://doi.org/10.1001/archotol.126.1.29  

9 Wilson JJ , Wilson EM . Practical management: vocal cord dysfunction in athletes. Clin J Sport Med. 2006;16(4):357–60. Published online July 22, 2006. doi:.https://doi.org/10.1097/00042752-200607000-00014  

10 Morris MJ , Deal LE , Bean DR , Grbach VX , Morgan JA . Vocal cord dysfunction in patients with exertional dyspnea. Chest. 1999;116(6):1676–82. Published online December 14, 1999. doi:.https://doi.org/10.1378/chest.116.6.1676  

11 Hoyte FC . Vocal cord dysfunction. Immunol Allergy Clin North Am. 2013;33(1):1–22. doi:.https://doi.org/10.1016/j.iac.2012.10.010  

12 Ibrahim WH , Gheriani HA , Almohamed AA , Raza T . Paradoxical vocal cord motion disorder: past, present and future. Postgrad Med J. 2007;83(977):164–72. Published online March 09, 2007. doi:.https://doi.org/10.1136/pgmj.2006.052522  

13 Fritz GK , Fritsch S , Hagino O . Somatoform disorders in children and adolescents: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry. 1997;36(10):1329–38. Published online October 23, 1997. doi:.https://doi.org/10.1097/00004583-199710000-00014  

14 Husein OF , Husein TN , Gardner R , Chiang T , Larson DG , Obert K , et al. Formal psychological testing in patients with paradoxical vocal fold dysfunction. Laryngoscope. 2008;118(4):740–7. Published online January 10, 2008. doi:.https://doi.org/10.1097/MLG.0b013e31815ed13a  

15 Nagai A , Yamaguchi E , Sakamoto K , Takahashi E . Functional upper airway obstruction. Psychogenic pharyngeal constriction. Chest. 1992;101(5):1460–1. Published online May 01, 1992. doi:.https://doi.org/10.1378/chest.101.5.1460  

16 Cukier-Blaj S , Bewley A , Aviv JE , Murry T . Paradoxical vocal fold motion: a sensory-motor laryngeal disorder. Laryngoscope. 2008;118(2):367–70. Published online November 15, 2007. doi:.https://doi.org/10.1097/MLG.0b013e31815988b0  

17 Millqvist E , Bende M , Löwhagen O . Sensory hyperreactivity--a possible mechanism underlying cough and asthma-like symptoms. Allergy. 1998;53(12):1208–12. Published online February 04, 1999. doi:.https://doi.org/10.1111/j.1398-9995.1998.tb03843.x  

18 Ternesten-Hasséus E , Farbrot A , Löwhagen O , Millqvist E . Sensitivity to methacholine and capsaicin in patients with unclear respiratory symptoms. Allergy. 2002;57(6):501–7. Published online May 25, 2002. doi:.https://doi.org/10.1034/j.1398-9995.2002.23380.x  

19 Rolla G , Colagrande P , Magnano M , Debernardi V , Dutto L , Delpiano L , et al. Extrathoracic airway dysfunction in cough associated with gastroesophageal reflux. J Allergy Clin Immunol. 1998;102(2):204–9. Published online September 02, 1998. doi:.https://doi.org/10.1016/S0091-6749(98)70087-9  

20 Bucca C , Rolla G , Brussino L , De Rose V , Bugiani M . Are asthma-like symptoms due to bronchial or extrathoracic airway dysfunction? Lancet. 1995;346(8978):791–5. Published online September 23, 1995. doi:.https://doi.org/10.1016/S0140-6736(95)91617-2  

21 Bucca C , Rolla G , Scappaticci E , Baldi S , Caria E , Oliva A . Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms. Allergy. 1991;46(2):147–53. Published online February 01, 1991. doi:.https://doi.org/10.1111/j.1398-9995.1991.tb00559.x  

22 Bucca C , Rolla G , Scappaticci E , Chiampo F , Bugiani M , Magnano M , et al. Extrathoracic and intrathoracic airway responsiveness in sinusitis. J Allergy Clin Immunol. 1995;95(1):52–9. Published online January 01, 1995. doi:.https://doi.org/10.1016/S0091-6749(95)70152-4  

23 Carney IK , Gibson PG , Murree-Allen K , Saltos N , Olson LG , Hensley MJ . A systematic evaluation of mechanisms in chronic cough. Am J Respir Crit Care Med. 1997;156(1):211–6. Published online July 01, 1997. doi:.https://doi.org/10.1164/ajrccm.156.1.9605044  

24 Maschka DA , Bauman NM , McCray PB, Jr , Hoffman HT , Karnell MP , Smith RJ . A classification scheme for paradoxical vocal cord motion. Laryngoscope. 1997;107(11):1429–35. Published online November 22, 1997. doi:.https://doi.org/10.1097/00005537-199711000-00002  

25 Rolla G , Colagrande P , Scappaticci E , Bottomicca F , Magnano M , Brussino L , et al. Damage of the pharyngeal mucosa and hyperresponsiveness of airway in sinusitis. J Allergy Clin Immunol. 1997;100(1):52–7. Published online July 01, 1997. doi:.https://doi.org/10.1016/S0091-6749(97)70194-5  

26 Hicks M , Brugman SM , Katial R . Vocal cord dysfunction/paradoxical vocal fold motion. Prim Care. 2008;35(1):81–103, vii. Published online January 22, 2008. doi:.https://doi.org/10.1016/j.pop.2007.09.005  

27 Murray DM , Lawler PG . All that wheezes is not asthma. Paradoxical vocal cord movement presenting as severe acute asthma requiring ventilatory support. Anaesthesia. 1998;53(10):1006–11. Published online January 20, 1999. doi:.https://doi.org/10.1046/j.1365-2044.1998.00577.x  

28 Vertigan AE , Theodoros DG , Gibson PG , Winkworth AL . The relationship between chronic cough and paradoxical vocal fold movement: a review of the literature. J Voice. 2006;20(3):466–80. Published online November 09, 2005. doi:.https://doi.org/10.1016/j.jvoice.2005.08.001  

29 Murry T , Tabaee A , Aviv JE . Respiratory retraining of refractory cough and laryngopharyngeal reflux in patients with paradoxical vocal fold movement disorder. Laryngoscope. 2004;114(8):1341–5. Published online July 29, 2004. doi:.https://doi.org/10.1097/00005537-200408000-00005  

30 Newman KB , Mason UG, 3rd , Schmaling KB . Clinical features of vocal cord dysfunction. Am J Respir Crit Care Med. 1995;152(4):1382–6. Published online October 01, 1995. doi:.https://doi.org/10.1164/ajrccm.152.4.7551399  

31 Parsons JP , Benninger C , Hawley MP , Philips G , Forrest LA , Mastronarde JG . Vocal cord dysfunction: beyond severe asthma. Respir Med. 2010;104(4):504–9. Published online December 08, 2009. doi:.https://doi.org/10.1016/j.rmed.2009.11.004  

32 Treole K , Trudeau MD , Forrest LA . Endoscopic and stroboscopic description of adults with paradoxical vocal fold dysfunction. J Voice. 1999;13(1):143–52. Published online May 01, 1999. doi:.https://doi.org/10.1016/S0892-1997(99)80068-X  

33 Marcinow AM , Thompson J , Forrest LA , deSilva BW . Irritant-Induced Paradoxical Vocal Fold Motion Disorder: Diagnosis and Management. Otolaryngol Head Neck Surg. 2015;153(6):996–1000. Published online August 27, 2015. doi:.https://doi.org/10.1177/0194599815600144  

34 Tay TR , Hoy R , Richards AL , Paddle P , Hew M . Inhaled Mannitol as a Laryngeal and Bronchial Provocation Test. J Voice. 2017;31(2):247.e19–23. Published online August 28, 2016. doi:.https://doi.org/10.1016/j.jvoice.2016.08.003  

35 Guss J , Mirza N . Methacholine challenge testing in the diagnosis of paradoxical vocal fold motion. Laryngoscope. 2006;116(9):1558–61. Published online September 07, 2006. doi:.https://doi.org/10.1097/01.mlg.0000228007.74561.33  

36 Fowler SJ , Thurston A , Chesworth B , Cheng V , Constantinou P , Vyas A , et al. The VCDQ--a Questionnaire for symptom monitoring in vocal cord dysfunction. Clin Exp Allergy. 2015;45(9):1406–11. Published online April 14, 2015. doi:.https://doi.org/10.1111/cea.12550  

37 Pinto LHE , Aun MV , Cukier-Blaj S , Stelmach R , Cukier A , Kalil J , et al. Vocal cord dysfunction diagnosis may be improved by a screening check list. Allergol Int. 2016;65(2):180–5. Published online December 17, 2015. doi:.https://doi.org/10.1016/j.alit.2015.11.001  

38 Vertigan AE , Bone SL , Gibson PG . Development and validation of the Newcastle laryngeal hypersensitivity questionnaire. Cough. 2014;10(1):1. Published online February 21, 2014. doi:.https://doi.org/10.1186/1745-9974-10-1  

39 Andrianopoulos MV , Gallivan GJ , Gallivan KH . PVCM, PVCD, EPL, and irritable larynx syndrome: what are we talking about and how do we treat it? J Voice. 2000;14(4):607–18. Published online December 29, 2000. doi:.https://doi.org/10.1016/S0892-1997(00)80016-8  

40 McCracken JL , Veeranki SP , Ameredes BT , Calhoun WJ . Diagnosis and Management of Asthma in Adults: A Review. JAMA. 2017;318(3):279–90. Published online July 19, 2017. doi:.. Article corrected in: JAMA. 2017;318(16):1615. doi:https://doi.org/10.1001/jama.2017.8372  

41 American Thoracic Society. Standardization of Spirometry, 1994 Update. Am J Respir Crit Care Med. 1995;152(3):1107–36. Published online September 01, 1995. doi:.https://doi.org/10.1164/ajrccm.152.3.7663792  

42 Anderson SD , Brannan J , Spring J , Spalding N , Rodwell LT , Chan K , et al. A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med. 1997;156(3):758–65. Published online October 06, 1997. doi:.https://doi.org/10.1164/ajrccm.156.3.9701113  

43 Wüthrich B , Schindler C , Leuenberger P , Ackermann-Liebrich U ; Swiss Study on Air Pollution and Lung Diseases in Adults. Prevalence of atopy and pollinosis in the adult population of Switzerland (SAPALDIA study). Int Arch Allergy Immunol. 1995;106(2):149–56. Published online February 01, 1995. doi:.https://doi.org/10.1159/000236836  

44 Taramarcaz P , Grissell TV , Borgas T , Gibson PG . Transient postviral vocal cord dysfunction. J Allergy Clin Immunol. 2004;114(6):1471–2. Published online December 04, 2004. doi:.https://doi.org/10.1016/j.jaci.2004.08.038  

45 Olivier CE , Argentão DG , Lima RP , da Silva MD , dos Santos RA . The nasal provocation test combined with spirometry establishes paradoxical vocal fold motion in allergic subjects. Allergy Asthma Proc. 2013;34(5):453–8. doi:.https://doi.org/10.2500/aap.2013.34.3681  

46 Hartley NA , Petty BE , Johnson B , Thibeault SL . Comparative analysis of clinical profile: Chronic cough vs paradoxical vocal fold motion. Respir Med. 2015;109(12):1516–20. Published online October 29, 2015. doi:.https://doi.org/10.1016/j.rmed.2015.10.007  

47 Ayres JG , Mansur AH . Vocal cord dysfunction and severe asthma: considering the total airway. Am J Respir Crit Care Med. 2011;184(1):2–3. Published online July 09, 2011. doi:.https://doi.org/10.1164/rccm.201103-0582ED  

48 Taramarcaz P , Gibson PG . The effectiveness of intranasal corticosteroids in combined allergic rhinitis and asthma syndrome. Clin Exp Allergy. 2004;34(12):1883–9. Published online January 25, 2005. doi:.https://doi.org/10.1111/j.1365-2222.2004.02130.x  

49 Taverne J , Ramon P , Fournier C , Fry S , Wallaert B . Diagnostic de la dysfonction des cordes vocales à l’exercice dans l’asthme sévère [Exercise-induced vocal cord dysfunction in asthma: a new diagnostic method]. Presse Med. 2014;43(12):e393–400. Article in French. Published online December 03, 2014. doi:.https://doi.org/10.1016/j.lpm.2014.05.017  

50 Forrest LA , Husein T , Husein O . Paradoxical vocal cord motion: classification and treatment. Laryngoscope. 2012;122(4):844–53. Published online March 22, 2012. doi:.https://doi.org/10.1002/lary.23176  

51 Liyanagedera S , McLeod R , Elhassan HA . Exercise induced laryngeal obstruction: a review of diagnosis and management. Eur Arch Otorhinolaryngol. 2017;274(4):1781–9. Published online October 13, 2016. doi:.https://doi.org/10.1007/s00405-016-4338-1  

52 Røksund OD , Heimdal JH , Clemm H , Vollsæter M , Halvorsen T . Exercise inducible laryngeal obstruction: diagnostics and management. Paediatr Respir Rev. 2017;21:86–94. Published online August 06, 2016. doi:.https://doi.org/10.1016/j.prrv.2016.07.003  

53 Vertigan AE , Bone SL , Gibson PG . Laryngeal sensory dysfunction in laryngeal hypersensitivity syndrome. Respirology. 2013;18(6):948–56. Published online April 27, 2013. doi:.https://doi.org/10.1111/resp.12103  

54 Murry T , Cukier-Blaj S , Kelleher A , Malki KH . Laryngeal and respiratory patterns in patients with paradoxical vocal fold motion. Respir Med. 2011;105(12):1891–5. Published online September 13, 2011. doi:.https://doi.org/10.1016/j.rmed.2011.08.023  

55 Watson MA , King CS , Holley AB , Greenburg DL , Mikita JA . Clinical and lung-function variables associated with vocal cord dysfunction. Respir Care. 2009;54(4):467–73. Published online March 31, 2009.  

56 Guglani L , Atkinson S , Hosanagar A , Guglani L . A systematic review of psychological interventions for adult and pediatric patients with vocal cord dysfunction. Front Pediatr. 2014;2:82. Published online August 26, 2014. doi:.https://doi.org/10.3389/fped.2014.00082  

57 Seifert E , Kollbrunner J . Vocal cord dysfunction: dealing with aggressivity. Swiss Med Wkly. 2007;137(7-8):127–9. Published online March 21, 2007. doi:.https://doi.org/10.4414/smw.2007.11843