Occupational and environmental irritants play a role in the pathogenesis of chronic cough. An irritant is a non-corrosive chemical, which causes a reversible inflammatory change on living tissue by chemical action at the site of contact. The clinical and pathologic spectrum of chemically induced respiratory tract irritation ranges from neurogenically mediated alterations in regional blood flow, mucus secretion, and airway caliber to the initiation of cough. In an evolutionary perspective, two types of cough reflexes were created for different protective purposes, but each type used the same anatomic and physiologic neural and muscular structures. The mechanosensory type evolved as human ancestors adapted phonation over olfaction and the larynx moved in close proximity to the esophageal opening. The chemosensory type evolved to protect against an injured lung from a respiratory tract infection or after inhaling high levels of irritant gases and particulates that accumulated in confined quarters of early times. For this latter type of cough reflex, normally quiescent transient receptor potential (TRP) cation channels TRPV1(vanilloid) and TRPA1 (ankyrin) become activated or hyperactivated after lung injury, with lung inflammation, or in response to chemicals. Although animal and laboratory investigations support the possibility of human TRPpathies, further investigations are essential for the further elucidation of the role of TRP cationic channels in instigating chronic cough in humans.
The Occupational Safety and Health Administration defines an irritant as a chemical, which is not corrosive, but which causes a reversible inflammatory effect on living tissue by chemical action at the site of contact. Important physical features of an irritant exposure are its intensity (massive versus low-moderate concentrations); differences in the chemical constituents (eg, halogenated versus nonhalogenated gas); vapor pressure in reference to the atmosphere (high, so higher levels in air); solubility in aqueous solution (determines upper versus lower airway involvement); molecular state (vapor, gas fume, dust); and degree of chemical reactivity (highly reactive chemicals tend to be more irritating). Table 1 provides common irritants in various occupations and environments.
| Exposure | Agent or Process |
|---|---|
| Acids | Acetic, sulfuric, hydrochloric, hydrofluoric acid |
| Alkali | Bleach, calcium oxide, sodium hydroxide, World Trade Center dust |
| Gases | Chlorine, sulfur dioxide, ammonia, mustard, ozone, hydrogen sulfide, phosgene |
| Spraying | Spraying of paints and coatings |
| Explosion | Irritant gases, vapors and fume releases |
| Fire/pyrolysis | Combustion and pyrolysis products of fires, burning paint fumes, pyrolysis products of polyvinylchloride meat wrapping film |
| Confined spaces | Epichlorhydrin, acrolein, floor sealant, metal coating remover, biocides, fumigating aerosol, cleaning aerosol sprays, mixture of drain cleaning agents |
| Workplace | Glass bottle–making workers, popcorn-flavoring makers, second-hand tobacco smoke, chlorine gas puffs, pyrite dust explosion, locomotive and diesel exhaust, aerosols of metalworking fluids, aluminum smelter workers exposed to pot-room fumes, metal processing plant, pulp mill workers, shoe and leather workers exposed to the organic solvents, workers exposed to SO2 from apricot sulfurization, aldehydes including formaldehyde and glutaraldehyde, biologic dusts, tunnel construction workers, coke oven emissions, cleaning and disinfecting workers in the food industry, chili pepper pickers, cyanoacrylates |
Respiratory tract effects of irritants
The clinical and pathologic spectrum of chemically induced respiratory tract irritation ranges from neurogenically mediated alterations in regional blood flow, mucus secretion, and airway caliber to the initiation of cough. There may just be the complaint of annoyance or the sensation of chest discomfort, burning, or pain. “Somesthesis,” “chemesthesis,” and “chemical nociception” are terms that describe the chemically induced sensations caused by an irritant. The outcomes may depend on the location of the injury, especially following massive and high-level exposures. As such, there may be corneal damage; swelling of the tongue; persistent rhinitis; closure of the glottis and larynx; sudden-onset asthma (reactive airways dysfunction syndrome); acute respiratory distress syndrome; or persistent bronchiolar obstruction (bronchiolitis obliterans). Box 1 summarizes outcomes from repeated lower levels of irritant exposures.
Breathing pattern : apnea and slowed breathing rate
Upper airway : “pungency,” rhinitis, or nasal obstruction; stinging or burning of eyes and mucous membranes; corneal damage; eye lacrimation; tongue or glottal swelling with obstruction; vocal cord dysfunction
Trachea and bronchi : Somesthesis, chemesthesis, and chemical nociception; cough or phlegm; bronchospasm; decrease in forced expiratory volume in 1 second; increased nonspecific airway hyperresponsiveness; irritant-induced asthma from repeated exposures; reactive airways dysfunction syndrome from high-level single exposure
Alveolar : Acute respiratory distress syndrome, chemical pneumonitis
Bronchiolitis obliterans
Adjuvant or enhancement : to an allergen
Chronic obstructive pulmonary disease: industrial bronchitis
Persistent cough
Noninvasive changes : Alteration in exhaled breath nitric oxide or changes in induced sputum parameters
Allergen versus irritant
An allergen can cause an effect even in very low, nonirritating concentrations. In order for these effects to occur, there needs to be earlier repetitive exposures (usually for months or years) that bring about sensitization to the allergen. Allergy depends on this unique cellular sensitivity and involves immunologic mechanisms, unlike irritation. The irritant operates in a nonspecific manner to cause changes, whereas the allergen is distinctly different. The appreciation of irritation (ie, chemesthesis) affecting the eyes, nose, and throat is principally mediated by the trigeminal nerve (cranial nerve V). Pulmonary irritation is mainly under vagal (cranial nerve X) nerve control. Odor is detected by the olfactory nerve (cranial nerve I).
Allergen versus irritant
An allergen can cause an effect even in very low, nonirritating concentrations. In order for these effects to occur, there needs to be earlier repetitive exposures (usually for months or years) that bring about sensitization to the allergen. Allergy depends on this unique cellular sensitivity and involves immunologic mechanisms, unlike irritation. The irritant operates in a nonspecific manner to cause changes, whereas the allergen is distinctly different. The appreciation of irritation (ie, chemesthesis) affecting the eyes, nose, and throat is principally mediated by the trigeminal nerve (cranial nerve V). Pulmonary irritation is mainly under vagal (cranial nerve X) nerve control. Odor is detected by the olfactory nerve (cranial nerve I).
Role of odor
Some individuals report respiratory and other types of complaints, in some cases simulating asthma and often accompanied by coughing; the symptoms are professed to be caused by a low concentration of an irritant chemical recognized mainly by an odor. “Pungency” refers to a sharp, bitter, or biting taste but can also be used to describe an irritating odor. Unfortunately, the nose is not a sensitive discriminator for irritancy. Odor does not equate with toxicity. There may be magnitudes of differences between the detection concentration of an airborne odorant and the concentration causing pungency, irritation, or even significant toxicity.
There seems to be so-called exceptionally chemically “sensitive” persons in the general population, however, and their prevalence may be greater than appreciated. As many as 15% to 30% of individuals who participate in focused surveys claim to be very sensitive to chemicals in their environment. An administered telephone questionnaire to 4046 California subjects found that 15.9% reported being “allergic or unusually sensitive to everyday chemicals.” There was general homogeneity across race-ethnicity, geography, education, and marital status. Putting the study into perspective, a 15.9% prevalence of chemical sensitivity equates to approximately 4 million Californians. Meggs and colleagues defined “chemical sensitivity” as becoming ill after smelling chemical odors, such as perfume, pesticides, fresh paint, and cigarette smoke; new carpets; or automobile exhaust. The study by Bell and colleagues was even less precise. Their questionnaire queried about feeling ill from smelling multiple common environmental chemicals (eg, cacosmia). Kippen and colleagues expanded the scope of defining the exposures but did not clearly define the response. In this latter study, patients attending an environmental and occupational health clinic were administered a questionnaire asking about 122 common environmental substances, such as aerosol, deodorant, cigarette smoke, diesel exhaust, fabric softener, marker pens, new carpeting, colognes or perfumes, and recent dry-cleaned clothes that caused symptoms. Symptoms were defined as awareness of discomfort or bothersome change; many of the complaints were a response to odors. Although the clinical symptoms resemble asthma in some cases, all physiologic measurements including lung function testing, methacholine challenge, and skin prick tests were normal or negative. There is great controversy with those investigations using the very uncertain term chemical “sensitivity” to explain a “condition” based solely on self-reporting of symptoms and a perceived exposure recognized principally by an odor.
Several investigations report persons claiming increased sensitivity to odors and irritants and manifesting an enhanced cough reflex as defined by capsaicin challenge testing. The interpretation of these studies is limited by the small subject population size, lack of customary standards for administration of cough challenges, and virtually no assessment of environmental or occupational exposures. Overall, qualitative estimates of chemical sensitivity based solely on reports of illness caused by odors have little validity. This latter conclusion is likely one of the major reasons why there is such controversy over the diagnosis of multiple chemical sensitivity. The latter is a condition, perception, or circumstance where subjects complain of many symptoms following what seems to be an innocuous exposure; few if any show any objective laboratory findings.
Occupational, environmental, and irritant-induced cough
Groneberg and associates emphasized the role of occupational factors in the pathogenesis of chronic cough. Blanc and colleagues reported that chili pepper workers continually exposed to capsaicin report chronic cough. Gordon and colleagues investigated workers making glass bottles who were chronically exposed to a variety of irritants including hydrochloric acid aerosol. Symptomatic bottle workers reported a higher prevalence of nose and throat irritation complaints and cough. In a laboratory setting, greater cough sensitivity to citric acid and capsaicin aerosols was observed in symptomatic workers. The latent interval between starting work and first developing symptoms was typically 4 years. A persisting postinfectious cough occurs after viral and bacterial infections and is associated with disruption of epithelial integrity and widespread inflammation of the upper or lower airways.
World Trade Center cough
A prototype for irritant-induced cough is epitomized by the events of September 11, 2001, when terrorist operatives of Al-Qaida’s Osama Bin Laden commandeered four United States commercial airplanes and initiated an attack on the United States. Two of the planes were flown into the World Trade Center (WTC) towers causing their collapse. The destruction and collapse of the towers generated an intense, short-term exposure to inorganic dust, pyrolysis products, and other respirable materials. Nearly 3000 people died and an estimated 250,000 to 400,000 people in the vicinity of the WTC collapse were exposed to dust, debris, smoke, and chemicals. Firefighters and other rescue workers were exposed to high levels of the dust and other particulate materials, especially during the first few days after the WTC collapse. The specific content of the dust was later measured by the United States Geological Survey, who collected dust samples from various WTC areas and from steel girder coatings of the WTC debris. The leachate solutions of the dust showed alkaline pH values between 8.2 and 11.8, likely a result of the dissolution of concrete, glass fibers, gypsum, and other material in the dust. Following the WTC collapse, several respiratory illnesses were described among rescue workers, including what has been called “World Trade Center cough.” There were other reports of conditions with persistent airway hyperreactivity, claimed reactive airways dysfunction syndrome, and acute eosinophilic pneumonia. A high prevalence of rhinitis-sinusitis and gastroesophageal reflux disorder was also noted.
WTC cough presented as a persistent cough that developed after exposure to the WTC site and was accompanied by respiratory symptoms severe enough to require medical leave for at least 4 weeks. WTC cough was more common in firefighters relegated to the highest exposure categories who reported to the WTC site on the morning of the collapse (<24 hours); a moderate level of exposure was selected for firefighters arriving within 2 days; and low exposure was designated for firefighters arriving between 3 and 7 days after the collapse. No exposure was appropriated for firefighters if they were not at the site during at least 2 weeks of the rescue operation. Within 24 hours after exposure, those firefighters with WTC cough reported having a productive cough with black-gray–colored sputum that was “infiltrated with pebbles or particles.” Nonspecific airway hyperreactivity was noted in about 25% of the tested firefighters with high levels of exposure, whether or not they had WTC cough.
Evolution of irritant-induced cough
Over millions of years, primitive animals and then humans evolved adaptations that created a physiologic or biochemical advantage over disease or adaptations to protect against noxious environmental hazards. An evolutionary process resulted in the cough reflex, one of the most important human defensive adaptations; cough became a common symptom of various lung diseases. Over millions of years, two types of human cough reflexes evolved to become adapted for different protective purposes. Presumably, both types use the same muscles and nerves to elicit a precisely timed, multifaceted, neuromuscular phenomenon distinguished by the concurrent and sequential coordination of muscular activity of the diaphragm; muscle groups of the chest wall, neck, and abdomen; and the laryngeal abductor and adductor muscles. Fig. 1 summarizes information of two different types of cough reflexes.
Supposedly, one type of cough reflex evolved to prevent the harmful effects of the aspiration of gastric content into the lungs because the larynx moved in close proximity to the opening of the esophagus as human ancestors adapted phonation over olfaction beginning less than 10 million years ago. This mechanosensory-type reflex, transduced mainly by laryngeal and tracheal Aδ fibers, generates immediate expiratory efforts, often referred to as the “expiration reflex.”
The second type of cough reflex is transmitted by unmyelinated sensory vagal C-fibers that occupy a dense neuronal plexus beneath the airway epithelium. This type of cough was likely adapted by prehistoric humans who began living closely together in larger social groups, in poorly ventilated enclosures, and in close proximity to nonprimate animals. There was the possibility of contracting a contagious respiratory tract or parasitic infection or being exposed to gaseous-particulate irritant emanations that produced airway and distal lung inflammation or damage. This second type of cough reflex relied on primordial ionic channels, inherited from some ancient predecessor living hundreds of millions of years before, to create a chemosensory-type of cough reflex. This cough response is analogous to the induced pain following tissue injury, and it is controlled by the identical transient receptor potential vanilloid cation channel (TRPV1). The airways do not normally manifest nociceptive pain from a stimulus but the only consistent response that capsaicin and inflammation provoke in healthy human airways is cough.
The polymodal TRPV1 receptor acts both as a receptor in the traditional sense that it binds to high-affinity specific ligands and also is an ion channel. TRPV1 is responsive to capsaicin (“capsaicin receptor”) and inflammatory products ( Fig. 2 ). TRPA1, referred to as the “irritant receptor,” is an excitatory ion channel expressed by a subpopulation of unmyelinated afferent C fiber nociceptors that are possibly linked to TRPV1 and contribute to the transduction of the noxious stimuli. TRPA1 has been found to be activated by a number of irritant chemicals including capsaicin; mustard oil (ie, isothiocyanate); acrolein; allicin; wasabi and horseradish; cinnamon oil; menthol; acrolein; formalin; diallyl disulfide; garlic (ie, 2-propenyl 2-propene thiosulfinate, allyl isothiocyanate, diallyl sulfides, ajoene, dithiines, and 4-hydroxy-2-nonea); and tetrahydrocannabinol.
