Lesson 2, Volume 15—Sequelae of Respiratory Tract Exposures to Irritant Chemicals

By Dennis Shusterman, MD, MPH

Objectives

1. To familiarize the reader with the spectrum of acute irritant-related respiratory tract injury.
2. To highlight the most common persistent respiratory tract syndromes following such exposures.
3. To delineate potential secondary psychological consequences of irritant inhalations.
4. To provide practical guidance for the workup of episodic, exposure-related dyspnea occurring after irritant inhalation episodes

Key words

chemical irritants; chemical pneumonitis; irritant-associated vocal cord dysfunction; irritant-induced asthma; odor-triggered panic attacks; rhinosinusitis; tracheobronchitis

Abbreviations

BOOP = bronchiolitis obliterans organizing pneumonia; RADS = reactive airway dysfunction syndrome; VCD = vocal cord dysfunction

Inhalation of irritant chemicals—including gases, vapors, dusts, mists, and smokes—is a common presenting history in emergency and ambulatory care settings, and even more common in occupational medicine practices. Irritant exposures occur not only in industry (Table 1), but also in household settings, in which inappropriate mixing of cleaning products can give rise to potent irritant gases de novo.¹ Apart from the acute clinical presentation—which may range from transient conjunctival and nasal irritation at one extreme to life-threatening chemical pneumonitis at the other—there is the question of long-term sequelae of irritant inhalations. Interestingly, both biological and psychological mechanisms may be operative in the aftermath of such exposures, and the clinician's diagnostic acumen may be challenged in defining the pathology and in devising appropriate therapeutic strategies.

Anatomy and Pathophysiology

The word irritation has multiple meanings. In the context of inhalation injury, the word may be used to signify (1) chemically induced respiratory tract damage; (2) neurogenically mediated reflex changes in regional blood flow, mucus secretion, and airway caliber; and (3) the subjective sensation of airway irritation. After inhalation exposure, irritation usually occurs at multiple levels.

The respiratory tract is conventionally divided between upper and lower segments at the glottis. The upper airway is responsible for conditioning of inspired air and for sensory monitoring of the inspired environment, including odor (cranial nerve I) and irritation (cranial nerves V and IX).² The glottis at the border of the upper and lower airways is responsible for phonation and, like the bronchial epithelium distally, is innervated by vagus nerve (cranial nerve X). The lower airway is responsible for gas distribution and exchange, and may be the site of airway and/or parenchymal injury.

Irritant-triggered airway reflexes include cough and sneezing, alterations in respiratory pattern, and reflex bronchospasm and laryngospasm.^3-5 Other neurogenic reflexes, both parasympathetic and neuropeptide-mediated, include tearing, rhinorrhea, and bronchorrhea. Frank tissue damage involves release of autocoids from affected cells, variously resulting in cellular infiltration, alveolar and/or interstitial edema, hemorrhage, smooth muscle contraction, and mucus hypersecretion.⁶ Finally, repair mechanisms may alter airway structure and function in the aftermath of an airborne irritant exposure.

A differential impact on the upper and lower respiratory tract may occur during (and after) irritant exposure, depending upon both the patient's respiratory behavior (ie, nasal vs mouth breathing) and the physicochemical properties of the irritant involved. The nasal turbinates, whose normal function is to condition inspired air to body temperature and to achieve water vapor saturation, function as excellent "scrubbers" of water-soluble air pollutants. At the same time, the nasal cavity (as well as the cornea) is richly innervated with trigeminal nerve endings, which are responsive to a variety of chemical irritants. Thus, highly water-soluble pollutants—such as chlorine, sulfur dioxide, formaldehyde, and acrolein—may produce predominantly upper airway complaints early on (Fig 1), typically initiating escape or avoidance behavior. Photochemical oxidants such as ozone, on the other hand, tend to be of intermediate solubility, and stimulate tracheobronchial symptoms initially. Finally, poorly water-soluble pollutants—such as nitrogen oxides and phosgene—dissolve slowly in deep lung water (liberating a mixture of nitrous and nitric acids in the case of nitrogen oxides, and hydrochloric acid in the case of phosgene). If exposures are protracted, which they may be given these compounds' lack of acute irritancy, they may result in serious pathology (ie, chemical pneumonitis), at times with delayed onset. If exposures are very heavy, irritation and injury with inflammation can occur throughout the respiratory tract, even following inhalation of highly soluble materials.

Figure 1. Water solubility and site of initial impact of airborne irritants. Adapted from the US Department of Health and Human Services.²⁴

Spectrum of Inhalation Injury

Inhalation injuries may produce a variety of acute outcomes, including transient mucous membrane irritation, rhinosinusitis, laryngitis, tracheobronchitis, bronchospasm, and chemical pneumonitis. Subacutely and chronically, such exposures may result in a variety of syndromes, including irritant-induced rhinitis, irritant-associated vocal cord dysfunction (VCD), irritant-induced asthma, and bronchiolitis obliterans. In addition to the above, exposed individuals may exhibit episodic hyperventilation/autonomic activation (ie, panic) when confronted again (at lower odorant concentrations) with the original irritant agent responsible for the inhalation injury.

Rhinosinusitis

Acute rhinitis is perhaps the most common outcome after irritant exposures, although it is often underemphasized in reviews of the subject. Rhinitis is often accompanied by conjunctivitis, less often by sinusitis. Symptoms include nasal (and eye) irritation, rhinorrhea, tearing, and nasal congestion. Similar symptoms may be precipitated by nonspecific physical stimuli such as cold, dry air, particularly in susceptible individuals with so-called vasomotor rhinitis. Treatment, in general, consists of removal from exposure, with the expectation that symptoms will be self-limited.

Controversy surrounds the entity of persistent, postexposure "irritant-induced rhinitis." Patterning the diagnosis on that of "irritant-induced asthma"(reactive airway dysfunction syndrome⁷ [RADS]; see below), Meggs⁸ proposed the acronym RUDS (reactive upper airway dysfunction syndrome) to describe acute-onset, subacute, or chronic-duration rhinitis, the onset of which coincides with a one-time, high-level irritant exposure. Symptoms may include nasal hyperesthesia, nasal congestion, headache, and associated systemic complaints.⁸ Nasal biopsy studies among chlorine-exposed workers have been reported to show desquamation of epithelial cells, defective epithelial tight junctions, and lymphocytic infiltrates.⁹ However, pathology alone does not define reactive upper airway dysfunction syndrome, and difficulties with this analogy include the lack of strict diagnostic criteria, as well as the high population prevalence of individuals with pre-existing rhinitis who would be excluded if the RADS analogy were adhered to strictly. Presumably, what sets these patients apart from those with irritant rhinitis in general is the persistence of nasal inflammation (and symptoms) after removal from the initiating exposure. Empirically, therapy can include the use of intranasal steroids if removal from exposure does not lead to prompt resolution of symptoms.

Irritant Laryngitis and Irritant-Associated VCD

Acute exposure to high-level irritants can produce inflammation of the larynx. At its extreme, this is represented by laryngeal edema, such as may occur following smoke inhalation, in which both chemical and thermal injuries occur. Such cases can be life-threatening, and are cause for close medical observation and, at times, early endotracheal intubation. Chronically, both tracheomalacia and subglottic strictures have been described in severe cases, particularly those requiring prolonged intubation.¹⁰

Chemical irritant exposures alone have also produced documented cases of acute laryngitis.¹¹ Again, the majority of such cases would be expected to show symptomatic resolution over a period of days to weeks after removal from exposure. Of particular interest, however, is an entity of persistent "laryngeal dysfunction" associated with patient-perceived intermittent irritant exposures such as cigarette smoke, perfumes, cleaning products, and new paint. In most but not all cases, individuals give an antecedent history of an acute irritant exposure affecting the upper airway. The diagnosis of irritant-associated VCD has been proposed for such individuals.¹²

VCD more broadly refers to a condition in which inappropriate adduction of the vocal cords occurs during the respiratory cycle, particularly during inspiration. Symptoms variably include intermittent hoarseness, stridor, cough, globus, and "wheeze" (laryngeal in origin). Individuals may carry diagnoses of asthma but they lack standard spirometric evidence of variable airflow obstruction or nonspecific airway hyperresponsiveness. In addition to irritant exposures, patients may give a history of factors associated with laryngeal inflammation, including gastroesophageal reflux disease, chronic rhinosinusitis with postnasal drip, and poor vocal hygiene (vocal strain and excessive throat-clearing).¹³ Pulmonary function testing may be useful, in that truncation of the inspiratory limb of the flow-volume loop may be present during symptomatic episodes. Other diagnostic procedures include acoustic analysis of vocalization, flexible rhinolaryngoscopy with direct observation of the vocal cords during respiration and vocalization, and such specialized techniques as electroglottography and acoustic pharyngometry. Competing diagnoses (besides asthma) include laryngeal dystonia (with or without spasmodic dysphonia), vocal cord paralysis, and psychogenic processes (such as conversion disorder). Therapy for VCD, regardless of reported environmental triggers, involves voice training, at times employing videolaryngoscopy as a biofeedback tool. Adjunctive psychotherapy may also be of assistance in the management of some cases.

Tracheobronchitis and Irritant-Induced Asthma

Acute chemical tracheobronchitis is marked by substernal burning pain, dyspnea, tachypnea, and productive sputum, with variable degrees of acute airflow obstruction. Most cases are self-limited, but others may herald more long-term effects, including persistent bronchial hyperresponsiveness (ie, irritant-induced asthma or RADS) and, more rarely, the development of bronchiectasis, bronchiolitis obliterans, or bronchiolitis obliterans organizing pneumonia (BOOP).

Acute exposure to inhaled irritants may result in the development of bronchial hyperresponsiveness on an apparently de novo basis. This condition has been variously termed RADS,⁷ irritant-induced asthma,¹⁴ and occupational asthma without latency.¹⁵ Controversies exist as to the role of atopy and/or pre-existing subclinical bronchial hyperresponsiveness in the genesis of RADS, as well as the ability of subacute, moderate-level exposures, (as opposed to acute, high-level exposures) to elicit characteristic symptoms. These, as well as issues pertaining to pathophysiology and pathology, have been reviewed elsewhere.¹⁶

The case definition of RADS, as originally proposed by Brooks et al,⁷ includes (1) appearance of asthma-like symptoms (wheezing, dyspnea, cough, chest tightness, sputum production) after a one-time, high-level irritant exposure; (2) onset of lower respiratory tract symptoms within 24 h of exposure; (3) duration of symptoms > 3 months; (4) a documented absence of prior chronic respiratory tract conditions; and (5) nonspecific bronchial hyperresponsiveness (eg, abnormal methacholine challenge test). Routine spirometry may be normal, or may show obstruction with variable reversibility.¹⁷

RADS patients often report intolerance of workplace chemicals, cigarette smoke, perfumes, household cleaning products, and other airborne irritants, as well as symptoms provoked by exercise in cold environments. The severity of symptoms may not always conform to the degree of hyperresponsiveness documented by methacholine challenge, but some hyperresponsiveness must be present, as noted above, to establish the diagnosis. Therapy, to date, has been largely empirical, although one published case report showed rebound of an improvement in bronchial responsiveness when inhaled steroid therapy was interrupted.¹⁸ Absent a randomized clinical trial of topical steroid therapy in RADS (which is unlikely to occur in the near future), inhaled steroids should be considered as probably beneficial, and the condition should be approached overall with a stepwise approach to pharmacologic therapy, as in standard adult asthma.

Bronchiolitis Obliterans and BOOP

Bronchiolitis obliterans and, even more rarely, BOOP are rare complications of irritant inhalation injury. The agent most often implicated in such cases is nitrogen dioxide (eg, in silo-filler's disease), but ammonia, fly ash, hydrogen bromide, sulfur dioxide, and zinc chloride smoke bombs have all been associated in case reports.¹⁶ Irritant-related bronchiolitis obliterans is characterized clinically by an acute exposure incident of moderate to high severity (with development of tracheobronchitis or chemical pneumonitis), a period of partial resolution, and then clinical deterioration 2 to 4 weeks later. Patients typically present with fever, chills, and cough, and may have a normal chest radiograph or, if BOOP is present, diffuse alveolar opacities may be evident on chest radiograph.¹⁹ A detailed discussion of the pathophysiologic and clinical differences between bronchiolitis obliterans and BOOP are beyond the scope of this review. There are no systematic data addressing whether outcomes vary for chemically induced bronchioloitis obliterans or BOOP as opposed to idiopathic cases.

Chemical Pneumonitis

Other than laryngospasm or laryngeal edema, chemical pneumonitis is the irritant-related response most likely to constitute an acute life-threatening emergency. Similar to other causes of ARDS, chemical pneumonitis involves the breakdown of the alveolar-capillary barrier, with extravasation of plasma into the pulmonary interstitium and airspace, noncardiogenic pulmonary edema, and development of an acute gas exchange defect. It is important to note that the syndrome can evolve over a number of hours following severe exposure, requiring appropriate follow-up observation after acute irritant inhalation. Acid-base abnormalities, cardiac arrhythmias, and multisystem failure may ensue, as in ARDS due to other causes. Management should not differ from that for ARDS generally. Although steroids are often used empirically in chemical irritant lung injury, this has never been studied in a controlled fashion.²⁰

Virtually any airborne irritant, given sufficient concentration and duration of exposure, is capable of inducing severe lower respiratory tract injury. However, certain chemical agents are more frequently seen in this role. Cadmium oxide fume, for one, appears to have a special predilection for producing diffuse lung injury through direct cell toxicity. Likewise, nitrogen oxides and phosgene, because of their poor acute warning properties, are also associated with this outcome.

Secondary Psychological Morbidity

Acute inhalation exposures are generally unanticipated events, and carry with them the aura of escape and emergency response. In short, they are situations of "fight or flight." Autonomic activation, anxiety, and hyperventilation (panic) is an intrinsic (unconditioned) response to such situations. Prior to the overexposure, the chemical agent involved may have been experienced as relatively benign, and sensory cues of exposure (most notably, odor) as inoffensive and not alarm-provoking. However, subsequent to an irritant overexposure, patients may find themselves unexpectedly dyspneic, lightheaded, and "spacey" when they encounter the odor of the chemical agent involved. In short, the chemical's odor may have acquired a new signal value (ie, that of a conditioned stimulus) for autonomic activation or panic (Fig 2).²¹

Figure 2. Respondent conditioning model for odor-triggered autonomic activation (panic) after irritant overexposure. UCS = unconditioned stimulus; CS = conditioned stimulus. Reproduced with permission from Shusterman and Dager.²⁴

Odor-triggering panic attacks are not limited to individuals with antecedent irritant overexposures. One report describes a series of cases of solvent-exposed workers whose first panic attack occurred at work, but who subsequently came to experience panic attacks triggered by specific odors away from the workplace.²² The author speculated that, under the narcotic influence of a solvent agent, an individual's threshold for panic may be lowered. Once having experienced their first panic attack, such individuals may show persistent alteration of their threshold for panic, perhaps by a process resembling neurologic kindling. Panic attacks may eventually occur without specific triggers, possibly fulfilling the diagnostic criteria for panic disorder.²³ Regardless of the inciting event (ie, traumatic/irritant vs nontraumatic/narcotic), absent effective intervention, such individuals may go on to show triggering of panic attacks by an ever-widening array of odors (stimulus generalization).²¹ Potential interventions include environmental controls (to the extent warranted by existing standards), cognitive-behavioral intervention, and pharmacologic therapy.²³

Differential Diagnosis Issues

A subset of the diagnoses mentioned above can produce an easily confused clinical presentation. As noted in Figure 3, occupational asthma, irritant-associated VCD, and odor-triggered panic attacks all present with episodic, exposure-related dyspnea. Inciting airborne exposures may be at a low concentration level (ie, a concentration adequate to produce odor sensation, but not irritant sensation), potentially adding to the confusion. The key to the differential diagnosis rests, at least initially, on the occupational history. Important historical points include careful identification of symptom triggers, a precise description of episodic dyspnea ("Do you have trouble getting air in or out?"), the presence or absence of laryngeal symptoms (throat pressure, hoarseness, stridor), and coincident symptoms of hyperventilation and/or autonomic activation (lightheadedness, palpitations, diaphoresis, nausea, diarrhea, sensation of depersonalization and/or derealization, feeling of loss of control, sense of impending doom). A complete workup may require the assistance of a speech pathologist or otolaryngologist who is equipped to observe for paradoxical vocal cord movement, as well as the services of a mental health professional who is aware of occupational psychological issues.

Figure 3. Potential diagnostic overlap between irritant-induced asthma, irritant-associated VCD, and odor-triggered panic attacks. All three conditions may present with episodic, exposure-triggered dyspnea.

Summary

Respiratory tract exposures to irritant chemicals result in varying outcomes, from sensory irritation and annoyance at one extreme to fatal laryngospasm or chemical pneumonitis at the other. Between the two extremes of severity, several outcomes may be associated with long-term morbidity, including irritantinduced asthma, irritant-associated VCD, bronchiolitis obliterans, and secondary behavioral outcomes (odor-triggered panic attacks). Primary prevention of exposure is the key to preventing serious morbidity and mortality. Failing primary prevention, early recognition of irritant-related syndromes and appropriate intervention can significantly improve outcomes in many cases. An openness to integrating psychosocial and biological explanations may assist in the proper evaluation and treatment of such cases.

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