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Jacobs Journal of Pulmonology

Inhalation Exposures and Vocal Cord DysfunctionStuart M. Brooks1*, MD 1University of South Florida, USA

*Corresponding author: Stuart M. Brooks, Emeritus Professor, Colleges of Public Health and Medicine, University of South Florida,

Tampa Florida, Email: [email protected]

Received: 09-02-2016

Accepted: 09-29-2016

Published: 09-30-2016

Copyright: © 2016 Stuart M. Brooks

Review article

Cite this article: Stuart M. Brooks. Inhalation Exposures and Vocal Cord Dysfunction. J J Pulmonol. 2016, 2(3): 034.

Introduction

Intrathoracic injuries such reactive airways dysfunction syn-drome (RADS), adult respiratory distress syndrome (ARDS), and/or bronchiolitis obliterans involve intrathoracic sites of the alveoli and bronchi/bronchioles [1]. In contrast, vocal cord dysfunction (VCD) occurs above the alveoli and bronchi within the larynx, an extrathoracic site [2].

While thousands of persons experience accidental inhalational exposures each year and seek medical care, the majority recov-ers and few persons die [3]. Most nonfatal inhalational expo-sures are the results of workplace accidents, the goings-on at home or hazardous situations in the community. Such example of the latter includes fires and explosions, volcanic eruptions, accidents involving trains or from over-turned trucks trans-porting chemicals [4]. Mass casualties from inhalation injuries result from chemical warfare, as in World War I or the Iran–Iraq War, and also, fatalities arise from conventional warfare or terrorist attacks comprising explosions, fires, and building destructions, as in the collapse of the World Trade Center on September 11, 2001 [5-7].

According to the study conducted by Henneberger et al, young male workers experience the highest rates of nonfatal inhala-tion injuries [8,9]. Common nonfatal causal inhalational expo-sures include: chlorine gas, bleach, fire smoke, minerals, ac-ids and ammonium compounds, plastics, paints, and solvents [10-14]. Exposure to carbon monoxide may not be the result of being trapped in a fire [9].

Dissimilarly, a high-level, massive inhalation exposure can be fatal. Nearly 25% of fatal inhalation exposures transpire when a worker is executing repair or maintenance-type jobs, about 10% happen during cleaning or washing activities. Repairing damaged structures or malfunctioning machines can be a dan-gerous if the damage or malfunctioning itself is the cause of a leak of harmful substances. Cleaning activities become hazard-ous when a worker is not properly equipped, trained or aware of the features of the job environment [15].

VCD After an Exposure

An inhalation exposure may masquerade as causing intratho-racic damage when in reality the ensuing respiratory entity

Abstract

An inhalation exposure can masquerade as causing intrathoracic damage when in actuality it produces vocal cord dysfunction (VCD), a clinical entity mutual to the larynx in absence of local laryngeal organic disease. With VCD, there is paradoxical (i.e., con-tradictory) vocal cord closure leading to extrathoracic upper airway flow obstruction. The VCD spectrum includes paradoxical vocal fold motion (PVFM), irritable larynx syndrome (ILS) and vocal cord dysfunction (VCD). Patients who develop VCD after an inhalation exposure usually portray sudden-onset coughing, dyspnea, augmented odor recognition and inspiratory wheezing with stridor. Spirometry and endoscopy during a VCD attack are beneficial for diagnosis. Spirometry shows flattening of the inspiratory loop of the flow-volume curve, and, endoscopy reveals the characteristic adduction (closure) of the anterior two-thirds of the vocal cords with posterior chinking that creates a diamond shape. The current paper mentions key fundamentals of VCD and discusses information on types of inhalation exposures leading to VCD. The paper proposes a distinct pathophysiologic mechanism for VCD following an inhalation exposure.

Keywords: RADS; Vocal Cord Dysfunction; Odorants; Irritants; Inhalation Injury; Asthma ; Speech Therapy

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[36,37]. During inspiration, the posterior cricoarytenoid mus-cle, which activates 40 to 100 milliseconds before the inspira-tory activation of the diaphragm, is the major muscle for vocal cord abduction [38]. The glottic opening is further controlled by the medullary respiratory center through the vagus nerve. Vocal cord adduction (i.e., closure) is mainly achieved through actions of the lateral cricoarytenoid muscle [39-41]. Adduction of the lateral cricoarytenoid muscle requires internal rotation of the arytenoid cartilages [34]. With normal tidal expiration, there is a decrease in the tonic activity of the laryngeal ab-ducting posterior cricoarytenoid muscles and greater contrac-tion of the adducting lateral cricoarytenoid muscles causing a 10–40% narrowing of the vocal cords [38]. The vocal cords slightly close (i.e., adduct) to roughly 10 to 40% of end-inspi-ration, but, there is continued adduction until approximately two thirds of the vital capacity is exhaled.

It is imperative to emphasize that a principal function of the larynx (and vocal cords) is/are to protect the lower airways and alveoli from aspiration by closing abruptly upon nerve stimulation, mechanical manipulation or under other circum-stances. The protective laryngeal closure reflex leads to up-per airway blockage, cessation of respiration and prevention of the entry of foreign matter into the lower airways [42,43]. Other purposes of the larynx include support of coughing, as-sisting in the Valsalva maneuver, regulating ventilation, acting as a sensory organ and of special importance, creating sounds (phonation). Different vocal fold movements are necessary for distinct laryngeal functions [35].

Lung defense against aspiration originates with the fetal glottic closure reflex, a protective strategy for preventing intrauter-ine aspiration of amniotic fluid into the tracheobronchial tree and lungs [43]. During in utero life, the human fetus regularly swallows amniotic fluid containing fetal lung fluid, fetal urine, debris from skin cells, and particulate matter [42-44]. By full-term gestation at 37 weeks, the fetus is capable of swallowing and circulating roughly 500 mL of amniotic fluid daily [43]. The fetal protective reflex of glottic closure is not eliminated after birth but continues during infancy and adulthood with coughing, requiring exhalation against a partially closed glot-tis to expel and clear secretions and materials from the lower airways. A closed glottis participates in the Valsalva maneuver [45]. There are vibrations of the vocal cords producing phona-tion to create language.

Understanding laryngeal and vocal cord basics may afford a better grasp of the control mechanisms regulating vocal cord closure and offer an improved foundation for VCD therapy. VCD encompasses the incorrect/abnormal adduction (clos-ing) of the vocal cords during inspiration and sometimes also during exhalation [2,19,46]. Laryngospasm, as seen with VCD, may represent a physiologic adaptation amplifying the sphinc-ter closure maneuver and/or the possible loss of an inhibito-ry laryngeal closure reflex [41,47-49]. Certain dynamic forc-es enhance the glottic closure reflex including the expiratory

is connected to extrathoracic vocal cord dysfunction (VCD), a clinical spectrum of entities mutual to the larynx in absence of local laryngeal organic disease [2,16]. With VCD, there is paradoxical (i.e., contradictory) vocal cord closure leading to extrathoracic air flow obstruction. Typically with VCD, the in-trathoracic site is not affected. Nonetheless, rapidly developing inspiratory dyspnea associated with VCD tends to be self-limit-ing and generally lasts 30 seconds to a few minutes, repetitive vocal cord closure materializes from one breath to the next. In some cases, dyspnea may last longer [17]. Patients por-tray inspiratory wheezing and stridor. A feeling in the respi-ratory tract is mostly in the neck or upper trachea [2,18,19]. Sometimes, there is difficulty in swallowing [20]. Frequently encountered terms for the VCD spectrum include paradoxical vocal fold motion (PVFM), irritable larynx syndrome (ILS) and vocal cord dysfunction (VCD) [2,21].

Epidemiology of VCD

There are no exact estimates as to the prevalence of VCD in adults [17,22]. The relatively low prevalence rate of VCD and the limited number of epidemiologic investigations incorpo-rating larger numbers of VCD patients hinder a better clinical understanding of the entity. Previous portrayals of VCD are limited to case reports and small series [19]. Perhaps, the true prevalence of VCD falls between 2.5% and 2.8% [17,23,24]. In-cidentally, VCD occurs more often in women than in men. Brug-man recounts a female to male ratio of 3: 1[25] while Morris observes a female to male ratio of 2: 1 [26].

Typically VCD develops in persons 20 to 40 years of age but the occurrence is higher among certain population groups. The prevalence of VCD is 22% for persons requiring repeated emer-gency room visits due to sudden-onset shortness of breath [27]. The condition is noted in about 10% of patients seeking evaluation of asthma unresponsive to aggressive therapy. VCD prevalence, as high as 14%, is detected among children and adolescents hospitalized because of asthma [28,29]. Roughly, 15% of US-American military recruits with suspected asthma exhibit VCD [30]. Almost 5% of US Olympic elite athletes show inspiratory stridor while exercising especially in cold, dry, am-bient environments [31,32]. Perkner and colleagues recognize laryngoscope-confirmed VCD, coined irritant-associated VCD, among a group of persons with purported RAD [33].

Vocal Cord Fundamentals

The larynx, positioned at the anterior upper portion of the neck in front of the pharynx and below the root of the tongue, contains two pyramidal laryngeal arytenoid cartilages at-tached to the folds of membranous tissue (also known as vocal cords or ‘voice reeds’) creating a vocal cord slit within the la-ryngeal glottis [34]. The vocal folds are only about 1/3 inch-es apart during normal respiration, but this width is doubled during forced respiration [35]. There is widening (abduction) of the vocal cords during normal quiet inspiratory breathing

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phase of breathing, reduced pCO2 concentration, increased pO2 levels, and, induction of a negative intrathoracic pressure [49]. An abrupt VCD attack may be associated with anxiety and panic leading to hyperventilation, there can be accompanying lowering of PCO2 (hypocapnia) and elevated airway and alve-olar PO2 [50,51]. The combination can prolong the duration of laryngospasm [49]. Central nervous system influences further impact on the glottic adductor reflex [52-54]. Shusterman and colleagues report on two cases of panic attacks with hyperven-tilation following exposure to chemical having both irritant and odorant properties that they stipulate as being “behavioral sensitization to an odorant” [51,55]. A central nervous system influence on VCD may be operative since laryngeal mucosal mechanoreceptors provide feedback to the central nervous system in humans during laryngeal movement and some of the laryngeal muscle functions are controlled by subcortical regions, especially the nucleus ambiguous [48]. Neuroimaging studies recognize different cortical systems for controlling la-ryngeal musculature. The laryngeal function of manipulating sound becomes an important driver of human evolution [56, 57]. Because vibrations of the two vocal cord edges create sounds, the voice is lost or altered during vocal cord spasm [58, 59].

Olfaction

Perhaps 15-30% of the general population claims increased sensitivity to odorant chemicals in their environment [60]. “Sensory hyperreactivity” is a term used to describe persons who complain of upper and lower airway symptoms induced by scents and inhaled chemicals like perfumes, flowers, col-ored paints, cigarette smoke and automobile exhaust fumes [61, 62]. Supposedly, these individual do not suffer from VCD but show increase cough sensitivity by capsaicin challenge testing, poorer quality of life scores and no increased sensitiv-ity to methacholine challenge [63-65].

The nose possesses sensory innervations from the olfactory nerve [i.e., cranial nerve I] for odor perception and irritant per-ception derived from the trigeminal nerve [i.e., cranial nerve V] [66] Stimulation of the nasal trigeminal nerve leads to a nasal sensory irritation response with an avoidance behavior [51, 67-71]. Odorant-alerting nasal receptor properties can height-en the sensitivity of laryngeal reflexes [72]. Irritation of the nasal mucosal may induce the glottic reflex [73, 74]. Clinical studies suggest there is enhanced irritant SENSITIVITY in the presence of odorants [53, 75]. An odorant cue may trigger a conditioned physiologic response (i.e., vocal cord adduction), which is further influenced by central nervous psychological contributions [51, 68, 76]. Presumably, certain odors can trig-ger a VCD attack [53, 77-79].

Irritable Larynx Syndrome

Among some susceptible persons, the irritable larynx syn-drome emerges when the brainstem laryngeal-controlled neu-

ronal networks are maintained in a perpetual hyperexcitable state reacting inappropriately to sensory stimulation [21]. The mechanism to explain the altered central nervous system change has not been adequately established.

Gastroesophageal Reflux Disorder (GERD), Post-Nasal Drainage (PND) and VCD

There remains controversy as to the role of GERD and PND in the pathogenesis of VCD [21, 80-83]. There are reports in the pediatric literature that gastroesophageal reflux (GER) leads to laryngospasm and sudden death in infants [84]. Research findings suggest that the pathogenesis of reflux esophagitis may be cytokine-mediated rather from a chemical injury due to stomach acid [85]. Postnasal drip associated with rhinosi-nusitis has been linked to airway hyperresponsiveness [22, 86]. A high prevalence of rhinosinusitis in patients with vocal cord dysfunction and case reports of resolution of vocal cord dysfunction symptoms with treatment suggest that rhinosi-nusitis may play a role in some patients [87].

Reactive Airways Dysfunction Syndrome (RADS)

VCD following an inhalation exposure can mistakenly be diag-nosed as RADS. The latter is a designation that labels the pa-tient who, without prior respiratory complaints, acutely and without latency or immunological sensitization develops an intrathoracic airway syndrome within 24-hours after inhaling a single high-level, massive irritant gas, vapor or fume expo-sure [88, 89]. The patient with RADS is typified by asthma-type complaints and persistent airway hyperresponsiveness [90]. Generally, it is not possible to quantify the magnitude of the inhalation exposure since most cases of RADS are associated with an unanticipated explosion and accidental release of irri-tant(s) under pressure, when the ventilation exchange rate is reduced in an enclosed environs such as the person in a con-fined space, or, from the smoke and pyrolytic emissions pro-duced by a fire [91]. There is absent voice change and no ex-aggerated response to odorants and scents in RADS but often occur in VCD after an inhalation exposure-type event. As a final point, there is the obvious failure of therapeutic improvement following aggressive prescribing of asthma medications in VCD [92, 93].

Laryngomalacia

There are three clinical presentations of laryngomalacia. First, childhood laryngomalacia, a common congenital cause of stri-dor in infancy and very young children, reportedly is the result of delayed maturation of the laryngeal cartilage leading to la-ryngeal collapse and upper airway obstruction during inspira-tion [94]. Typically, the childhood form becomes symptomatic within two-three months of life, and, stridor becomes audibly louder over the first year. There may be feeding difficulties in toddlers and sleep apnea in children [94]. Fortunately, the ma-jority of childhood laryngomalacia resolve spontaneously. Less

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appearing during deployment is claimed the result of anxiety/stress, exercise or combination of factors [111]. Smith and col-leagues report that 23% veterans deployed to Iraq and Afghan-istan exhibit a higher rate of newly reported respiratory symp-toms than do veterans who are not deployed [112]. Advocates claim there is an increased risk for developing new-onset asth-ma among U.S. military personnel, especially those deployed to Iraq and Afghanistan [113, 114]. The “Iraq/Afghanistan War Lung Injury” is conveyed as a moniker for a respiratory illness-es connected to deployment in the Iraq/Afghanistan geograph-ical region [114]. Various deployment-related exposures are espoused as causing new military respiratory complaints in-cluding inhaling small particulate matter arising from blowing sand and dust, presumed toxic matter emitted in smoke from burn pits used for waste disposal, noxious emissions and fires emanating from oil fields and petrochemical sites, pollutants discharged from vehicular traffic, short-term intense cigarette smoking by military personnel, recruits’ poor sanitation and living in close quarters, and, possible discharges of heavy met-al-containing condensates arising from metals smelting and battery manufacturing facilities [115-120]. Arising disruptive military situations may include increase in physical demands, lack of sleep, excessive stress, ongoing emotional turmoil, ne-cessity of wearing personal respiratory protective equipment and perhaps the difficulty delivering asthma medications to the battlefield. Obviously, “deployment” is falsely equated as being an exposure but, in reality, embodies a time spent in a diverse foreign environment containing potentially danger-ous exposures [121]. Military investigations by countries oth-er than the United States are enlightening because of the re-ported greater prevalence of under-diagnosed asthma among the military population, the occurrence allows recruits with undiagnosed asthma to enter military service [122-130]. Per-sons with asthma, who considered themselves “normal” and report no symptoms, may demonstrate sub-clinical physiolog-ic abnormalities that may become clinically overt following an irritant gas, vapor or even fine particulate exposure [122, 123]. Undiagnosed asthmatics, perhaps asthma in remission, recruits with exercise/cold induced bronchospasm or soldiers having asymptomatic nonspecific airway hyperresponsiveness may show distinct pathological airway changes if they were in-vestigated prior to the occurrence of the exposure [124-130].

Swimming Pools and Swimmers:

Swimming has been associated with asthma and respiratory disorders [10, 104, 105, 131-136]. Reportedly, chlorine gas induces VCD [137, 138]. Over time some children and ado-lescents, who repeatedly swim and are exposed to chlorine additives used for water disinfection, can develop asthmatic symptoms [131, 133]. Exposure relationships between total chloramine levels and development of acute irritation of eyes and upper airway symptoms, but not development of bronchi-al hyperresponsiveness, have been recognized among swim-ming pool lifeguards [132].

than 15% of the cases require surgical intervention [95]. A late-onset childhood laryngomalacia can present after the age of 2 years. Second, laryngomalacia appearing in an older in-dividual is usually associated with a neuromuscular condition recognizable during laryngoscopy [94, 96]. Unlike pediatric laryngomalacia, adult laryngomalacia is less likely to resolve with conservative management and often requires surgical intervention [96]. A third type of laryngomalacia simulating VCD is exercise-induced laryngomalacia. It is characterized by exercise-provoked breathlessness, stridor and wheezing un-responsive to prophylactic treatment with inhaled aerosol be-ta-adrenergic medications or disodium Cromoglycate [97-99].

Athletes and Exercise

Reportedly, exercise-induced asthma and exercise-induced bronchoconstriction are common findings among Olympic athletes [100]. However, the mere association of exercise and airway obstruction is not sufficient to establish the diagnosis of asthma [101]. Cases of VCD can occur only during exercise among the elite or intense-training athletes [31, 100, 102]. About 8% of athletes screened for asthma at the 2004 Olympics suffered from VCD [103]. VCD prevalence reaches up to 3-5% of athletes [32, 103]. Swimmers, runners, and cold-air athletes are considered at greatest risk [104-106]. A common clinical pattern is an athlete reporting episodes of dyspnea or short-ness of breath during exercise but medications prescribed to relieve symptoms are ineffective [102]. Continued symptoms, coupled with the failure of medications and the athlete’s in-ability to finish allotted “fitness” drills, increases the emotional stress. Unlike asthma, symptoms of VCD usually spontaneously resolve within five minutes after cessation of exercise [32]. Re-ported common psychological experiences of failing athletes include: physical exhaustion, emotional exhaustion, devaluat-ing sport, feelings of isolation, reduced ability for accomplish-ment with loss of confidence, questioning their athletic identi-ty, development of or worsening personal mood, reduction in determination, emergence of denial and fear, and perception of unfairness [103]. McFadden reported on seven elite athletes with vocal cord dysfunction who presented with acute dyspnea during sporting competitions [101]. These patients underwent bronchoprovocation using isocapnic hyperventilation of frigid air, methacholine challenge testing, and direct laryngoscopy. Bronchoprovocation documents variable extrathoracic airway obstruction characteristic of vocal cord dysfunction.

It is important to exclude exercise-induced laryngomalacia in young adults. Often, there are few differences between sub-jects with exercise-induced VCD and persons with exercise-in-duced laryngomalacia. The two entities are so similar that a controversy remains as to whether exercise-induced VCD and exercise-induced laryngomalacia in young adults are distinct syndromes [99].

Military Deployment and Asthma:

Military deployment, its self, becomes an issue [107-110]. VCD

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Dissolved chlorine in water kills bacteria though a chemical re-action not by way of generating toxic chlorine gas [11, 12, 139]. Chlorine, when dissolved in the water, is not readily available as a massive chlorine gas air exposure capable of causing an in-halation injury such as RADS [140]. Conceivably in an enclosed space within a shed, addition of muriatic acid to hypochlorite may generate chlorine gas but not in a massive quantity with-in the surrounding swimming pool area. Disinfection of public swimming pools generates “free chlorine” by adding sodium hypochlorite (liquid bleach), calcium hypochlorite or chlorine gas. Chlorine when dissolved in water yields dissolved chlo-rine (Cl2), and by reversible reactions, hydrochloric acid and hypochlorous acid: Cl2 + H2O ⇌ HCl + HClO. In the swimming pool, the water’s chlorine solution breaks down into hypo-chlorous acid (HOCl) and hypochlorite ion (OCl-) disinfecting microorganisms by breaking-down lipids contained in the cell walls and oxidizing internal cellular enzymes and structures. Hypochlorous acid oxidizes organisms in several seconds, hy-pochlorite ion takes up to 30 minutes. The water present in public swimming pools contains organic precursors derived from tap water used to fill the pools, there are also swimmers’ constituents such as ingredients of sweat, urine, skin particles, hair, microorganisms, cosmetics and other personal care prod-ucts. Free chlorine in the water reacts with various precursors to create disinfection by-products such as inorganic chlora-mines, organic chloramines, haloacetonitriles and various or-ganic compounds.

Cleaning Materials

Studies, conducted in several countries, report higher risks for asthma among professional cleaners using cleaning agents [141-148]. These compounds may initiate acute VCD. Clean-ing agents are of use in eliminating dirt and dust, removing various stains and eradicating malodors. Cleaning agents typically consist of liquids, powders, sprays or granules. The agents may be solvent-based or solvent-containing. A chemi-cal may be mixed as a water solution and can have an acidic, alkaline or neutral pH depending on the intended use. Janitors and cleaners show a high average annual rate of work-related asthma [149]. Professional cleaners may experience repeated exposures to chemicals, such as bleach and aerosol disinfec-tants. NHANES III data specifies that “cleaners” demonstrate the fourth highest odds ratio for work-related wheeze among 28 occupational categories [150]. The European Community Respiratory Health Survey (ECRHS), investigating 15,000 par-ticipants (20-44 years old) in 26 areas in 12 industrialized na-tions, concludes cleaners display the fourth highest odds ratio for asthma among 29 occupational groups.

World Trade Center Illnesses

On September 11, 2001, radical Islamic terrorist operatives of Al-Qaida and Osama Bin Laden, commandeer four US com-mercial airplanes and initiate an attack on the United States. The destruction and collapse of the World Trade Center (WTC) towers results in nearly 3,000 deaths. An intense, short-term

exposure to inorganic dust, pyrolysis products and other respi-rable materials places an estimated 250,000 to 400,000 people in the vicinity of the WTC collapse at future health risk [151]. Firefighters and other rescue workers are exposed to the high levels of the dust and other particulate materials especially during the first few days after the WTC collapse [152]. Later, there is measurement of the specific content of the dust [153]. The alkaline composition of the dust (pH values between 8.2 and 11.8) consists of silicon, aluminum, calcium, magnesium, sodium, gypsum, concrete, particulates (0.4 to 2 percent of par-ticulates are respirable), aggregates of calcium, organic carbon materials, aluminum hydroxides and metals [151, 153, 154]. Following the WTC collapse, there are descriptions of respira-tory illnesses among rescue workers including “World Trade Center cough”, persistent hyperreactivity, reactive airways dys-function syndrome [RADS] and acute eosinophilic pneumonia [154-156]. VCD appeared to be part of the spectrum of airway disorders caused by occupational exposures at the WTC disas-ter site [157].

Ozone

Ozone forms in the lower atmosphere by photochemical re-action of nitrogen oxides and volatile organic compounds. In the ozone layer, ozone filters out sunlight wavelengths from about 200 nm UV rays to 315 nm, with ozone peak absorp-tion at about 250 nm. Concentrations of ozone in the indoor environment vary from 0.05 ppm in tightly sealed buildings to 0.85 ppm in buildings with very high air exchange rates [158]. Ozone concentrations may vary between 2 and 40 ppb added to the indoor environment based on outdoor-to-indoor transport [159]. Reportedly, individuals living in cities with high ozone levels have more than a 30% increased risk of dying from lung disease [160]. Ozone manifest prominent respiratory irritation properties but with variability in individual responses [161]. Ozone causes respiratory complaints among pulp mill and bleachery workers [162, 163]. A summary of ozone response include cough and chest pain worsened by deep inspiration and declines in forced vital capacity (FVC) and forced expira-tory volume in one second (FEV1) on repeat testing [164]. The mechanism to explain the fall in FVC and FEV1 is believed due to stimulation of airway “irritant” receptors and contraction of alveolar duct smooth muscle causing involuntary inhibition of full inspiration [165]. Young individuals are more responsive to ozone exposures than older persons [166]. An increased risk of asthma is significantly associated with increased am-bient concentrations of ozone exposure in men. There are changes in the breathing pattern with an increase in respira-tory rate and tidal ventilation presumably because there are bronchial sensory C-fibers stimulation and vagally-induced changes in breathing pattern [167]. There is a tolerance, ad-aptation or attenuation of the pulmonary responses occurring after repeated ozone exposures [168]. Ozone exposure causes lung inflammation with increased numbers of neutrophils, in-creased protein content and release of pro-inflammatory cyto-kines [169-172]. Transiently, ozone will increase nonspecific

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http://www.ncbi.nlm.nih.gov/pubmed/12573988

bronchial hyperresponsiveness to methacholine challenge in both normal and asthmatic subjects. Finally among asthmatics, ozone exposure enhances the response to allergen challenge. An increased risk of asthma was significantly associated with increased ambient concentrations of ozone exposure in men [173]. VCD has not been described after ozone exposures. Pre-sumably, ozone can instigate VCD due to its odor and irritancy but there are no case reports incriminating this agent.

Meat Wrapper’s Asthma

In 1973, three workers employed as meat wrappers develop re-spiratory symptoms after exposure to fumes of polyvinyl chlo-ride [PVC] film cut with a hot wire [174]. The entity becomes known as “Meat Wrapper’s Asthma”. Subsequently, there are a number of other reports with diverse symptoms, including rhinorrhea, cough, and tightness of the chest, sore throat, ex-haustion, wheezing, and throat soreness. A supposition is the cause of meat wrapper’s asthma relates to the emissions from thermally activated price labels. Subsequent investigations do not confirm that major adverse airways conditions affect meat wrappers. The designation of “asthma” is a misnomer [175, 176]. Polyvinyl chloride [PVC] emission products have irritant properties but no case report of VCD incriminates the emis-sion.

Cotton and Textiles

An occupational airways disorder results from exposure to the dust of cotton, flax, jute, sisal or soft hemp. Traditionally, byssi-nosis, also called “brown lung disease” or “Monday fever”, is an occupational lung disease caused by exposure to cotton dust in inadequately ventilated working environments [177, 178]. Byssinosis commonly occurs in workers who are employed in yarn and fabric manufacture industries. The entity byssi-nosis varies clinically from acute dyspnea and chest tightness on one or more days of a workweek (i.e., acute byssinosis) to possibly a chronic and permanent obstructive airways disease [179, 180]. Kobayashi reports on an asymptomatic 66-year-old man, who inhales cotton fiber for 50 years, with subsequent development of an interstitial lung disease [181]. For cotton, the prevalence of the symptoms is associated with the magni-tude of the dust level, and especially, the coarse protein parti-cles rather than the mineral or cellulose portion of the cotton. The exact role of cigarette smoking for the chronic form of the disease is unclear. Atopy seems to be a risk factor for the bron-choconstrictive response to cotton dust. Mechanisms to ex-plain byssinosis include a nonspecific effect of cotton dust on the airways leading to direct mediator release from the mast cells, an endotoxin-like action of the dust from gram-negative bacterial (mainly Enterobacter) contamination of the cotton, and remotely, an allergic mechanism. As a rule, it is believed that cotton dust directly causes the disease although there is still support for a mechanism related to endotoxins arising from the cell walls of gram-negative bacteria growing on the cotton. Vegetable fibers, while not described as causing VCD,

are potential etiologic agents.

Red-Tide Toxin

A natural phenomenon, occurring occurs in the Gulf of Mex-ico and mainly along the west coast of Florida, is related to the blooms of the unicellular marine alga Ptychodiscus brevis. Red tide is reported to produce asthma-like symptoms in hu-mans and contraction in vitro of canine airway smooth muscle preparations [182]. There are no known cases of VCD attribut-able to red-tide toxin.

Conferring the Diagnosis of VCD

Clinical: Three clinical tip-offs for the diagnosis of VCD after an inhalation exposure embrace: (1) dysphonia and voice change, (2) heightened vocal cord/larynx sensitivity to odorants and scents, and, (3) unresponsiveness to aggressive asthma/RADS treatment regimens [19, 68]. In more than 50% of cases, asthma and VCD are present in the same patient [19]. Unlike asthmatics, VCD patients rarely are awakened from sleep by attacks. Asthma-type treatments do not correct the clinical ex-pression of VCD even with more aggressive therapy. Patients diagnosed with VCD can receive treatment with asthma and/or anaphylaxis medications such as aerosol bronchodilators, Epi-Pen injections and oral or parenteral corticosteroids. Re-peated Emergency Department visits and/or hospitalizations can be part of the clinical picture of VCD. Rarely, intubation or tracheotomy are treatment-recommendations for patients [22].

Analyzing features of the inhalation exposure such as concen-tration levels, chemical’s physical properties (i.e., vapor pres-sure, pH and irritancy) and inhalation exposure duration can be illuminating. Careful examination of exposure and clinical parameters will help distinguish the likelihood of a serious ad-verse respiratory outcome. With an intrathoracic injury, it is biologically unlikely, if not impossible, for there to be absence of accompanying physical signs of eyes, nose, throat (ENT) and/or upper airways damage such as corneal injury, marked conjunctivitis, swelling of the tongue, nasal burning/inflam-mation, unrelenting rhinitis, closure of the vocal cords and/or inflammation of the larynx. When the intrathoracic site is af-fected, then the eyes, nose, throat (ENT) and/or upper airways sites cannot be spared.

The physical examination is typically normal for most patients with VCD between attacks. In contrast, there are findings of stridor, inspiratory wheezing, apprehension, voice change and coughing during an acute attack of laryngospasm. As part of the physical examination, observe for stigmata of posterior na-sal drainage and/or gastro-esophagus reflux disease (GERD) as contributive to vocal cord hyperreactivity.

Spirometry: The most important clue is derived during an acute symptomatic VCD attack. Lung volume testing in an as-ymptomatic patient experiencing only VCD reveals normal to-

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tal lung capacity (TLC) without lung hyperinflation, such as is characteristically observed in chronic asthma. Also, the chest x-rays will not exhibit evidence of lung hyperinflation. Never the less, spirometry will clinch the diagnosis during an acute attack. The most significant diagnostic element is seen in the flow-volume curve. The spirometer used for testing must pro-vide a visual flow-volume tracing. Both the inspiratory and ex-piratory flow-volume loops are scrutinized. In VCD, it is typical for the expiratory loop to be normal. Characteristically, the in-spiratory loop of the flow-volume curve in a patient with VCD will be truncated or show flattening as displayed in Figure1 [183]. Unfortunately, an abnormal inspiratory flow loop may merely be the result of poor patient effort. Therefore, at least three spirometric tracings are necessary, with two of the three loops showing at least 5% consistency. Patients with pure VCD do not have a bronchodilator response and in many instanc-es seem to have difficulty performing consistent spirometric tracings.

Figure 1. Example of a flow-volume loop in a normal subject (A) and in a patient with VCD (B). Note the blunting and flattening of the inspiratory loop of the flow-volume curve (arrow). Also, note reduced FEV1 in proportion to FVC so FEV1/FVC% is >70% in B. During VCD symptoms, an abrupt drop and rise in the expiratory flow volume loop may be observed in the absence of coughing. (Adapted from (22)).

Laryngoscopy/Endoscopy: Some clinicians consider endo-scopic examination with direct visualization of the vocal folds via flexible, transnasal fiber-optic laryngoscopy during an acute attack as the gold standard for diagnosis of VCD [2,17]. However, the endoscopic examination of a patient with VCD is frequently normal when the patient is symptom-free. But during an acute attack of VCD, there is an observation of the adduction (closure) of the anterior two-thirds of the vocal cords with posterior chinking that creates a diamond shape (Figure 2). Usually, this appearance presents during inspira-tion but may persist into expiration. Vocal cord closure may oc-cur only during inspiration, during both phases of respiration, or during expiration alone. There may also be mucus stranding across the cords [46]. During the endoscopic/laryngoscopic examination, patients should be instructed to perform vari-

ous maneuvers including sniff, sequential phonation, normal breathing, panting and repetitive deep breaths in order to fully evaluate vocal cord movement [26, 46].

Figure 2. Classic vocal cord dysfunction with a) early paradoxical adduction of the vocal folds.” (b) Complete closure of the vocal folds with formation of a “posterior chink (Adapted from (18)).

Provocation Testing: Provocation will insure correctness of VCD diagnosis. Therefore, one often can elicit vocal cords clo-sure by accomplishing a provocation test using aerosolized methacholine, administering inhaled mannitol powder, per-forming strenuous exercise on a treadmill or bicycle ergome-ter, breathing in refrigerated cold air, or, inhaling odorants/ir-ritants, such as perfume or cleaning agents containing chlorine or ammonia for VCD induction [18].

Suggested Pathogenesis of VCD

There are leanings towards attributing VCD as a psychological illness, a factitious entity, a hysterical neurosis or some type of conversion disorder [25, 29, 46, 184-186]. VCD is men-tioned as a form of somatoform disorder with “a loss of or al-teration in physical functioning” that “cannot be explained by any physical disorder adapted or known pathophysiological mechanism” [184]. It has been claimed that unnamed stress-ors or an unidentified disturbance in both patient and family play significant roles in VCD pathogenesis [18, 29, 187, 188]. Currently, the exact etiology of VCD remains unknown with no bio-chemical, physiologic or structural abnormalities known to be consequential.

An alternative explanation is relevant for VCD that follows an inhalation exposure. In such a case, an arousal of a self “pro-tective” mechanism attempts to protect the lower lungs from a potentially “dangerous” inhalation agent. Thus, the condition following an inhalation exposure can be coined Glottis Awak-ening Protection Syndrome (GAPS). GAPS requires a “suscep-tible patient”. But “susceptible” does not necessarily pertain to a hysterical or abnormal psychological persona. Rather, the “susceptible” person may simply have a unique personal-ity or mental makeup. This “susceptible” individual may be a member of the general population [189]. Accordingly, VCD fol-lowing a perceived or actual inhalation event captures a sub-

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29

FIGURES

Figure 1. Example of a flow-volume loop in a normal subject (A) and in a patient with VCD (B). Note the

blunting and flattening of the inspiratory loop of the flow-volume curve (arrow). Also, note reduced FEV1 in

proportion to FVC so FEV1/FVC% is >70% in B. During VCD symptoms, an abrupt drop and rise in the expiratory

flow volume loop may be observed in the absence of coughing. (Adapted from (22)).

Figure 2. Classic vocal cord dysfunction with a) early paradoxical adduction of the vocal folds.” (b) Complete

closure of the vocal folds with formation of a “posterior chink (Adapted from (18)).

EXPIRATION

INSPIRATION

VCD does not require treatment by a physician, but rather the patient needs a cessation of the asthma medications and con-sultation and management by a speech therapist.

Treatment & Management of VCD

From the outset, it is indispensable to negate the patient’s perception that the physician is saying “it’s all in your head,” a common reaction when a physician or health care provider considers psychological factors playing a prominent role in the patient’s VCD development. Such a patient may perceive being responsible for their own illness or accused of imagining their symptoms. The fear of being dismissed as a deeply troubled person only heightens psychological insecurity. A patient may benefit by viewing a videotape of their laryngoscopic examina-tion that documents the pathologic vocal cord movement.

The cornerstone and most appropriate treatment of VCD is speech therapy [46, 92]. Phonatory function tests, videostro-boscopy and laryngeal image analysis are tests available for VCD analysis [58, 59]. Videostroboscopy is particularly bene-ficial since a steel scope containing a tiny camera and strobe light is placed in the patient’s mouth. The camera is angled to allow a clear and painless view of the patient’s throat enabling a videotape of vocal cord movement and vibration in slow mo-tion. The camera projects a moving image of the vocal cords, frame by frame, onto the television monitor. These images can be retrieved instantly as a video recording or as a still photo. Figure 3 shows a patient undergoing videostroboscopy.

Figure 3. A patient undergoing videostroboscopy.

Because relaxation of the neck and throat is vital for the main-tenance of VCD-related speech therapy, attaining effective re-laxation betters the patient’s therapeutic success. Employing biofeedback teaches the patient to better recognize correlation between their throat-related tension and autonomic hyper-arousal. A chief goal is to decrease laryngeal muscle tone by focusing on the expiratory rather than the inspiratory phase of respiration [46]. One relaxation maneuver is for the patient

set of individuals in the general population who possess per-sonality “susceptibility” rather than a preexisting psychiatric illness. An odorant cue triggers VCD through the coordinated actions involving the nasal odorant receptors, the trigeminal nerve, aryepiglottic junctions, arytenoid cartilages, epiglottis, laryngeal adductor muscles and false and true vocal cords. The odorant(s) sensitize nasal receptors to augment the sensitivity of the laryngeal reflex [72]. Laryngeal sensory and motor in-nervations become over-excitable and hyperresponsive [72].

While the personality “susceptibility” is difficult to depict, con-ceivably it is epitomized by a high achieving individual striving for external validation. Possibly, the person is overly health conscious and holds a strong self-protection attitude. Possibly, the “susceptible” person finds it difficult to express emotion. There is an unfailing level of stress, maybe free-floating anx-iety, poorly defined nuances for secondary gains and even a tendency for a caretaking role [18, 189].

The anatomy of VCD development after an inhalation expo-sure may be as follows. First, under the guise of the preexist-ing “susceptible” personality, the person experiences an actual or perceived inhalation exposure, professed to be a traumat-ic event. Sometimes, there is only the experience of an inap-propriate or incorrect situation where a hazardess condition may be present. Second, the “susceptible” personality (alone or with help) interprets the supposed inhalation exposure as being a “toxic” chemical. There is learned knowledge about the exposure constituent(s), perhaps there is information of the potential of causing an adverse clinical consequence when present in very high concentrations. Third, a subsequent “ex-posure” is recognized by the presence of an odor. Fourth, the “susceptible” personality evokes the fetal protective glottic clo-sure mechanism instigated by an odorant stimulus. Finally, the odorant causes acute vocal cord spasm because the patient’s aim is to “protect” the lungs from inhaling a perceived “toxic” constituent. The condition may be as others have elucidated [33, 51, 52, 67]. The odorant recognition may be accompanied by anxiety, panic and/or fear of personal harm ([50, 51]. Panic and anxiety are associated with hyperventilation leading to re-duced arterial PCO2 and elevated alveolar PO2. The combina-tion worsens the laryngeal spasm. The “susceptible” individ-ual seeks care by a physician or health care professional in an Urgent Care Facility or Emergency Department for treatment/management of symptoms due to vocal cord spasm. Because the clinical picture simulates asthma, the consulted pulmonary specialist or emergency care provider institute asthma medi-cations. The health care providers mistakenly opine the diag-nosis of reactive airways dysfunction syndrome (RADS) and/or asthma. The clinical label continues on average of about 5 years until the medical condition is more correctly diagnosed as VCD.

How and why the “susceptible” person reverts to a glottic re-tort, formerly active during fetal development for protecting the lung against aspiration, is not clear. Such an individual with

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to count numbers silently during exhalation, thus preventing breath holding or shallow breathing. There is a prerequisite for achieving efficacious abdominal breathing. To do so, the patient’s hand is placed on their abdomen in order to feel it ex-pand during inspiration and fall with expiration. The tongue is situated on the floor of the mouth, with the lips gently closed. The jaw is relaxed. Exhalation is completed by maintaining a soothing “s.” sound. Patients are coached to practice the tech-nique several times a day without stridor or chest tightness [46].

Another approach during an acute VCD attack is a breathing technique consisting of three steps. First, as soon as the pa-tient feels an acute VCD attack is eminent then slowly breathe in through their nose. Certainly do not breathe in through the mouth. Second, exhale quickly out the mouth with pursed lips. Finally, continue slow nasal inhalation and quick mouth exha-lation with pursed lips until the episode passes. Why does the method for the acute VCD attack work? For some reason, nasal breathing reinforces the brain to keep the vocal cords apart when inhaling. Quick inhalation through the mouth seems to do the opposite. Terminate oral hyperventilation, which may aggravate vocal cords closure. Slow breathing helps keep the vocal cords apart.

If speech therapy is unsuccessful in controlling VCD symptoms during an acute attack, then helium—oxygen mixture (70% helium, 30% oxygen) can be incorporated during breathing. Helium, a light gas that more easily passes through areas of high airflow turbulence, relieves dyspnea and/or partially or completely ablates the acute VCD attack [46].

Possibly, psychological and psychiatric management can in-clude behavioral, psychodynamic and/or pharmacological treatment modalities [19]. Marital or family counseling may be beneficial. Biofeedback with relaxation training is of value for patients whose intensity of anxiety contributes to VCD symp-tomatology. For patients with a significant mood or anxiety disorder, antidepressant or anxiolytic treatment can be added to treatment.

In rare case of severe VCD where the patient develops signifi-cant hypoxia during an acute VCD attack and is unresponsive to appropriate speech, psychological and medical therapy, tra-cheostomy can be an alternative modality [46]. Other more radical treatments include sectioning of the laryngeal nerve and paralysis of the ipsilateral vocal cord [46]. Anticholiner-gics may be a helpful adjunct in patients with exercise-induced vocal cord dysfunction. In a series of six patients receiving pre-treatment with inhaled ipratropium (Atrovent), all patients re-ported improvement of symptoms [190].

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ASTHMA VCD

Onset Minutes Seconds

Duration Variable, minutes, hours or days Short, seconds to a few minutes

Dyspnea Development Usually expiration Usually inspiration

Response to odorant Occasionally Frequent

Auscultation Expiratory & inspiratory wheezing Inspiratory wheezing/stridor

Affected Site Lower respiratory tract Neck and/or throat

Spirometry Reduced FEV1/FVC% & airflow

obstruction

Flattening of inspiratory loop of flow-

volume loop

Endoscopy Bronchial mucosal erythema,

edema and secretion

Vocal cord anterior 2/3 adduction with

posterior chinking

Bronchodilator therapy Effective Ineffective

Triggers Irritants, allergens, exertion Odorants, exercise, cold air, irritants,

stress

Coughing Persistent Recurrent

Table 1. Typical Clinical Manifestations for Asthma And VCD. (MODIFIED FROM (17))

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