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Asma ocupacional separ_2006[1]
Asma ocupacional separ_2006[1]
Asma ocupacional separ_2006[1]
Asma ocupacional separ_2006[1]
Asma ocupacional separ_2006[1]
Asma ocupacional separ_2006[1]
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Asma ocupacional separ_2006[1]

  1. 1. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. RECOMMENDATIONS OF THE SPANISH SOCIETY OF PULMONOLOGY AND THORACIC SURGERY (SEPAR) 151.166 Guidelines for Occupational Asthma Ramon Orriols Martínez (coordinator),a Khalil Abu Shams,b Enrique Alday Figueroa,c María Jesús Cruz Carmona,a Juan Bautista Galdiz Iturri,d Isabel Isidro Montes,e Xavier Muñoz Gall,a Santiago Quirce Gancedo,f and Joaquín Sastre Domínguez.f Working Group of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR). a Servei de Pneumologia, Hospital Universitari Vall d’Hebron, Barcelona, Spain. b Sección de Neumología, Hospital Virgen del Camino, Pamplona, Navarra, Spain. c Servicio de Neumología, Instituto Nacional de Seguridad e Higiene en el Trabajo, Madrid, Spain. d Servicio de Neumología, Hospital de Cruces, Baracaldo, Vizcaya, Spain. e Servicio de Neumología Ocupacional, Instituto Nacional de Silicosis, Hospital Central de Asturias, Oviedo, Asturias, Spain. f Servicio de Alergia, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain. Introduction Classification Occupational asthma (OA) is the most common The following types of OA are distinguished occupational disease in industrialized countries and it is according to the pathogenesis of the disease1-4: estimated that approximately 15% of all adult asthma is 1. Immunologic OA or OA caused by hypersensitivity. occupational in origin. Correct diagnosis and early This requires a period of time for sensitization to the management are key factors affecting disease prognosis causative agent to develop, and therefore, there is a and socioeconomic consequences. The individual latent period between exposure and the appearance of patient is not the only one affected when measures are symptoms. The following subtypes are distinguished taken; the consequent changes in working conditions according to the substances responsible for causing the can also prevent the appearance of other cases at the disease: patient’s workplace or other sites. Thus, the benefits are important for the health of the workforce and also for – Immunologic OA caused by high molecular weight the economy, both of individual companies and of substances. This usually occurs via an immunologic society in general. mechanism involving immunoglobulin (Ig) E. Given the widespread importance of OA, the – Immunologic OA caused by low molecular weight scientific committee of the Spanish Society of substances. In this case, there is generally no clear Pulmonology and Thoracic Surgery (SEPAR) placed a involvement of IgE. group of highly experienced professionals from the 2. Nonimmunologic OA or irritant-induced OA. This SEPAR Working Groups on Occupational Respiratory type of OA occurs as a result of irritation or toxicity. Diseases (EROL) and Asthma under the supervision of Two subtypes can be distinguished: Dr Ramon Orriols Martínez to prepare these guidelines, which are intended to provide clear and concise advice – Reactive airways dysfunction syndrome (RADS). for the diagnosis and subsequent management of This is caused by single or multiple exposures to high patients with suspected OA. doses of an irritant. Its onset, however, is linked to a single exposure. It is also known as OA without a latent period, since the symptoms appear within 24 hours of Definition exposure. OA is a disease characterized by variable obstruction – OA caused by low doses of irritants. This occurs of airflow and/or airway hyperresponsiveness after repeated contact with low doses of the causative attributable to factors associated with the workplace agent. It is a condition of particular current relevance rather than to stimuli found outside that environment.1-4 but that is still under discussion.3-5 3. Other variants of OA. This category includes OA with special or distinctive characteristics: – Asthma-like disorders. These are due to exposure to plant-derived dust (grain, cotton, and other textile Correspondence: Dr. R. Orriols Martínez. fibers) and also to dust from confined animals. Servei de Pneumologia. Hospital Universitari Vall d’Hebron. Pg. Vall d’Hebron, 119-129. 08035 Barcelona. España. – Potroom asthma. This occurs in workers involved E-mail: rorriols@vhebron.net in the production of aluminium. Arch Bronconeumol. 2006;42(9):457-74 457
  2. 2. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. ORRIOLS MARTÍNEZ R ET AL. GUIDELINES FOR OCCUPATIONAL ASTHMA TABLE 1 High Molecular Weight Agents That Cause Immunologic Occupational Asthma Type Agent Product, Occupation, Industry Cereals Wheat, barley, rye, oats, maize, sunflower, Baker’s shop, bakery, cake shop, mill, transport, agriculture soya, etc Flowers Sunflowers, decorative flowers, etc Florist, greenhouse, gardener Seed or grain Coffee, castor-oil plant, pea, carob, soya, Oil industry, food processing industry, bakery, meat product sesame, fennel, etc industry, etc Rubber Acacia, tragacanth, gutta-percha, guar, Printing, rubber industry, dental hygienist, etc gum arabic, etc Enzymes Bacillus subtilis, trypsin, papain, pepsin, Bakery, pharmaceutical, plastics, and detergents industries, etc amylase Fungi Aspergillus, Cladosporium, Trichoderma Baking, agriculture, domestic tasks, technicians, saw mill species, etc workers, etc Animals Rat, guinea pig, rabbit, etc Laboratory workers Cow, pig, chicken, egg, lactalbumin, Farmers, dairy workers, butchers, cake shops, tanneries, etc casein, etc Beetle, locust, cockroach, cricket, fly, Museum, laboratory, fishing, agriculture, cosmetics, entomology, butterfly, silkworm, etc silkworm farms, etc Crustaceans, fish, coral, molluscs, etc Fisherman, fish farms, and feed, coral, and mother of pearl industries Others Latex, dust mites, henna Health care workers, production of gloves and condoms, etc, manipulation of grains, hairdressing TABLE 2 Low Molecular Weight Agents That Cause Immunologic Occupational Asthma Type Agent Product, Occupation, Industry Diisocyanates Toluene, methylene, and hexamethylene Polyurethane, plastic varnishes, insulation material, spray diisocyanates paints Acid anhydrides Phthalic acid, trimellitic acid anhydride, Plastics and resins, adhesives, chemical industry, flame hexahydrophthalic acid, tetrachlorophthalic acid, retardants pyromellitic dianhydride Metals Platinum salts, cobalt sulfate, chromium sulphate Platinum refinery, polishers, silver and chrome-containing and chromium salts, potassium dichromate, paints, tanners, emery polish tungsten carbide Antibiotics Penicillin, spiramycin, tetracycline Pharmaceutical industry Amines Piperazine, ethanolamine, dimethyl Chemical industry, spray paints, ski manufacture, polishes, propanolamine, ethylene diamine, photography, rubber, solder, cables aliphatic amines, aminoethanolamine, hexamethylene tetramycin Woods Red cedar, rosin Woods, electronic solder Miscellaneous Glutaraldehyde, persulfate salts, cyanoacrylate, Nursing/endoscopy, hairdressing, orthopedics, glues, paper factors methylmethacrylate, polyethylene, chloramine, packaging, plastic bags, sterilizer in food and pharmaceutical polypropylene industries TABLE 3Causes Agents That Cause Nonimmunologic Occupational Asthma More than 300 agents have been implicated in the Type Agent Product, Occupation, Industrydevelopment of OA (Tables 1-3). A complete list ofthose agents can be found in certain research articles Bleach Chlorine Cleaning, paper, sewage treatment, bleachand reviews6-13 and webpages.14-16 industry, etc Smoke Fire-related products Emergency servicesPrevalence and Incidence Gases Products derived Metalwork from metal Notable discrepancies are found in the data on galvanizationprevalence and incidence currently available in the Other products Resins, hydrochloric Chemical, cleaning, andmedical literature. Differences in the design of acid, sodium health industriesepidemiologic studies, the definition of OA, the study hydroxide, acetic acidpopulation, and the country in which the study was458 Arch Bronconeumol. 2006;42(9):457-74
  3. 3. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. ORRIOLS MARTÍNEZ R ET AL. GUIDELINES FOR OCCUPATIONAL ASTHMA performed account for some of the discrepancies and HLA-DQBI*0603 and HLA-DQBI*0302 alleles and a the consequent difficulty in making comparisons. Some decrease in the DQBI*050134 allele has been of the data can be found in a recent review article.4 It observed.34 Other authors have reaffirmed that HLA has been reported that 4% to 58% of all cases of asthma class II alleles contribute to the susceptibility of may be occupational in origin. A recent review of the the individual to suffer from asthma caused by low literature estimated a mean value of 15%.17 molecular weight substances.35 However, the associations Immunologic OA caused by high molecular weight are not sufficient to generate preventative substances is the most common form. The prevalence of recommendations. Genes of the glutathione S-transferase the disease varies depending on the causative agent and and N-acetyltransferase superfamilies also appear to be it has been shown to occur in 4% to 12% of animal involved in OA, especially that caused by isocyanates.4 laboratory workers, 79% of bakers, and 1% to 7% of health care workers exposed to latex.18 The prevalence Causative agent. The high molecular weight substances of OA caused by sensitization to low molecular weight that are able to generate sensitization are proteins that substances is less clear, although some authors estimate behave as complete antigens.36 In addition, there is it at around 40% of all cases of OA.7 The agents most evidence that some of those proteins have enzymatic frequently implicated in the disease in industrialized activity that could aid antigen penetration.37 In contrast countries have generally been the isocyanates, which to the allergenic proteins, the low molecular weight cause asthma in 2% to 10% of workers.7 In British substances that are able to cause OA are generally Colombia, Canada, where the wood industry is very incomplete antigens (haptens) that must combine with extensive, another agent, cedar wood, is more common other molecules to trigger an immune response.36 These and is responsible for causing asthma in 10% of agents are known to be highly reactive and capable of workers.19 Other substances such as glutaraldehyde, binding certain specific sites on proteins in the airway.38 cleaning products, and persulfates are emerging as In the case of RADS, it is reasonable to assume that the disease-causing agents in workers involved in the health higher or lower irritant capacity of an agent would be care, cleaning, and hairdressing industries.20-22 RADS is involved in the pathogenesis of the disease.8 estimated to occur in 36% of cases referred to hospital for assessment of OA.23-26 In addition, 11% to 15% of Type of exposure. The level of exposure appears to be the all work-related asthma is reported to be caused by main determinant in the development of OA caused by irritants.27-29 agents that act through IgE-mediated mechanisms, such Monitoring through the use of registries allows the as the majority of high molecular weight substances but incidence of OA to be estimated. Such programs have also certain low molecular weight substances such as been developed in many different countries. In Spain, platinum salts and acid anhydrides.39,40 The risk of the registry started in 2002 in Asturias, Catalonia, and developing OA is highest just after the first year of Navarre obtained respective incidences of 48.4, 77.2, exposure to the causative agent and if symptoms of and 75.8 cases per million inhabitants per year. Given occupational rhinoconjunctivitis appear prior to bronchial that the registries are still in their initial stages, symptoms.4 Evidence also exists supporting an comparisons with the incidences of 92 and 22 cases per interaction between irritants and sensitizing agents. million inhabitants per year reported from registries in Smoking has been linked to an increase in sensitization Canada19 and the United Kingdom,30 respectively, should to tetrachlorophthalic anhydride and platinum salts,41 and only be made with caution. Results for prevalence and exposure to ozone may potentiate the development incidence in different countries are available in a recent of bronchial hyperresponsiveness to hexachloroplatinate.42 article.4 In addition to the causative agent itself, the intensity of the exposure also appears to be an important determinant in the appearance of RADS.8 Pathogenesis Genetic predisposition. Atopy is a risk factor for asthma Pathophysiology (Table 4) induced by high molecular weight substances.31 For instance, OA in health care workers exposed to latex is IgE-dependent mechanisms. Most high molecular weight more common in atopic than nonatopic individuals.32 substances that cause OA are animal- or vegetable- The same is true of workers exposed to laboratory derived proteins or glycoproteins that act via a animals or detergents.18 The phenotype of individuals mechanism involving IgE. These proteins behave as with OA appears to be generated through the complete antigens that stimulate the production of IgE. involvement of genes of the major histocompatibility Nevertheless, some low molecular weight substances (eg, complex on chromosome 6p coding for class II human acid anhydrides and platinum salts) can function as leukocyte antigen (HLA) molecules.4 In the case of haptens and combine with carrier proteins to form a isocyanates, an association has been described between hapten-protein complex that will also stimulate IgE this disease and the HLA-DQBQ0503 allele and production. When these substances are inhaled they bind protection in the presence of the HLA-DBQ0501 allele. the specific IgE found on the surface of mast cells and The marker for susceptibility is the substitution of the basophils, triggering a sequence of cellular events that aspartate residue at position 57 of HLA-DBQ.33 In the leads to the release of preformed or de novo synthesized case of asthma caused by red cedar, an increase in the mediators and the recruitment and activation of Arch Bronconeumol. 2006;42(9):457-74 459
  4. 4. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. ORRIOLS MARTÍNEZ R ET AL. GUIDELINES FOR OCCUPATIONAL ASTHMA TABLE 4 Types of Occupational Asthma According to the Mechanism Involved and the Principal Characteristics* Immunologic OA Nonimmunologic OA Characteristics IgE-Mediated Non-IgE-Mediated RADS Clinical Interval between onset of exposure and symptoms Long Shorter Short (<24 h) (latency) Typical response to bronchial challenge Immediate, dual Late, dual, atypical Not determined Epidemiologic Prevalence in exposed population <5% >5% Unknown Predisposing factors Atopy, smoking Inconclusive Inconclusive Histopathologic Epithelial desquamation ++ ++ +++ Subepithelial fibrosis ++ ++ +++ Basement membrane thickening ++ ++ ++ Eosinophils +++ +++ +/– Lymphocytes ++ ++ +/–* OA indicates occupational asthma; Ig, immunoglobulin; RADS, reactive airways dysfunction syndrome.inflammatory cells that ultimately provoke an changes in vascular permeability but would alsoinflammatory reaction in the airways characteristic of provoke an increase in mucosal secretion that wouldasthma.36 contribute to the chronic inflammation seen in biopsy material. During the process of recovery theIgE-independent mechanisms. Most low molecular inflammation would be resolved, leading to recovery ofweight substances that cause OA act via a mechanism the epithelium, inhibition of neuronal activity, andthat, while probably immunologic, does not involve improvement of vascular integrity. However, completeIgE.36 Specific IgG and IgG4 antibodies appear to be recovery would not always be achieved and sequelae ofassociated more with the level of exposure than with the the inflammatory response would persist in the form ofdisease itself.43 It is possible that cellular or delayed hyperreactivity and bronchial obstruction.hypersensitivity is involved in these cases.44 CD4lymphocytes play a supporting role in the production of Diagnosis and Treatment of ImmunologicIgE by B lymphocytes and may also induce Occupational Asthmainflammation by secreting interleukin (IL) 5. IL-5 is apotent stimulator and activator of eosinophils and is the Diagnosis of immunologic OA requires a series ofmain cytokine involved in the recruitment and activation steps (Figure).40,50of eosinophils during delayed asthmatic responses.45Increased numbers of activated T lymphocytes (which Clinical Historyexpress the receptor for IL-2), activated eosinophils, andmast cells have been observed in bronchial biopsies A clinical history is essential for the diagnosis offrom patients with OA caused by low molecular weight OA. The patient should be questioned not only aboutsubstances.46,47 the existence of bronchial symptoms but also about In addition, those substances can have nasal symptoms and symptoms of the eyes, skin, andnonimmunologic proinflammatory effects. If they bind upper airways. Those symptoms often precede theglutathione, they cause intracellular glutathione appearance of asthma, particularly when highdeficiency, which can reduce defense against oxidizing molecular weight antigens are involved. Prior toagents.48 In fact, it has been reported that exposure to entering the symptomatic period of the disease there isisocyanates is associated with elevated intracellular normally a highly variable period of time that can lastconcentrations of peroxide.49 Damage to cells of the from a few weeks to a number of years. Therefore,bronchial mucosa caused by such a process could diagnosis should not be ruled out by a worker havingamplify or initiate a response to low molecular weight performed the same job for years without presentingsubstances. symptoms. Sudden-onset asthma in an adult with no history of respiratory or allergic disease may be causeIrritation or toxicity. The mechanisms underlying for suspicion of OA. It is important to be able to linkRADS deserve special mention.8 The massive initial asymptomatic periods with absence of exposure andepithelial lesion would probably be followed by direct symptomatic periods with exposure. Sometimes theactivation of sensory nerves that would give rise to patient will spontaneously report the presence ofneurogenic inflammation. This would not only induce symptoms minutes after exposure to the causative460 Arch Bronconeumol. 2006;42(9):457-74
  5. 5. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. ORRIOLS MARTÍNEZ R ET AL. GUIDELINES FOR OCCUPATIONAL ASTHMA agent. In other cases, however, the symptoms are noted in the evening or only during the night. In those cases, Indicative Clinical History it is less likely that patients will associate the symptoms with their daytime activities. In general, Skin Prick Tests and/or improvements are observed at the weekend or during Analysis of Specific holidays, but this is not always the case. In fact, this Serum IgE association is more common at the onset of clinical (If Possible) symptoms, since as the symptoms progress they often become more persistent and recurrent and this can Bronchodilator Test and/or Measurement prevent the patient from associating their asthma with of Nonspecific Bronchial Hyperreactivity work. Nevertheless, questions about the improvement of asthma symptoms during the weekend and especially during holidays display a greater diagnostic Negative Positive yield than those relating to the worsening of symptoms at work.51 Sometimes, as occurs with red cedar and isocyanates, the symptoms continue for months or Patient Continues Patient Has Patient Continues years after exposure is discontinued.52 Furthermore, in to Work Stopped Work to Work some industries the chemical and operational processes are complex and cause the release of substances that Specific Bronchial Provocation remain completely unnoticed. For this reason, one of Test in a Specialized Laboratory the keys to the diagnosis of OA is a year by year work history and awareness of the products found in the Positive Negative workplace that can cause asthma. It is useful to review the safety information provided with the products used by the worker and determine whether the causative Return agent thought to be involved has been previously to Work linked to asthma of occupational origin. A clinical history indicative of OA is not sufficient to establish Bronchial Provocation at Work* the diagnosis, since the opinion of the physician only and/or in the Laboratory coincides with a true diagnosis of OA in slightly more than half of suspected cases.53 Positive Negative Physical Examination, Chest Radiography, Standard No Asthma Occupational Asthma Nonoccupational Workup, and Lung Function Testing Asthma Physical examination, chest radiography, standard Figure. Diagnostic algorithm for immunologic occupational asthma. Ig workup, and lung function testing do not differ in OA indicates immunoglobulin. *May require measurement of exposure. from those performed in any other asthmatic patient. However, they should be used because, firstly, they allow a diagnosis of asthma to be made, and secondly, Immunologic Tests they allow OA to be differentiated from other work- related conditions with which the disease can be The results of immunologic tests can indicate confused. It must be taken into account that often when exposure and sensitization but by themselves are unable patients attend the clinic they are completely to confirm a diagnosis of OA. A positive test does not asymptomatic and only report a sensation of dyspnea always imply the existence of clinical signs. To prevent or tightness in the chest, sometimes without wheezing erroneous interpretations, the sensitivity and specificity or other symptoms. A test to reveal nonspecific of each of the antigens used must be known when any bronchial hyperreactivity, such as the methacholine or such tests are performed, since various substances can histamine test, is necessary when the bronchodilator give rise to false positive or negative reactions. Either in test is negative due to the absence of bronchial vivo (prick test) or in vitro (analysis of specific IgE obstruction at that time. This test, along with clinical antibodies) techniques can be used. Sometimes allergen assessment by the physician, is a useful approach to extracts have to be prepared in the laboratory due to a diagnosis of bronchial asthma in patients whose lack of commercial availability. In general, high history, physical examination, or lung function are molecular weight substances display a high sensitivity indicative of atopy.54 In addition, if the methacholine or and in some cases the absence of a reaction allows the histamine test is negative, the existence of OA can be possibility that the substance with which the test was ruled out in practice, so long as the test is performed performed is responsible for the symptoms of the when the patient is working, since airway patient to be ruled out.58 Most low molecular weight hyperresponsiveness can normalize following a substances are irritants and, therefore, prick tests are not variable period without exposure to the causative appropriate. Likewise, if there is no clear IgE mediated substance.55-57 immunologic mechanism, this antibody cannot be Arch Bronconeumol. 2006;42(9):457-74 461
  6. 6. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. ORRIOLS MARTÍNEZ R ET AL. GUIDELINES FOR OCCUPATIONAL ASTHMAdetected, and if it can be, low sensitivity means that it is the course of the week with recovery at the weekend; c)almost always of very little use. Only some low week-by-week deterioration with recovery only after atmolecular weight substances, such as isocyanates, least 3 days away from work; and d) maximalappear to display a good specificity.59 When a positive deterioration on Monday with recovery over the courseresult is obtained, the possibility of an accurate of the week. Sometimes different patterns can also bediagnosis of OA should once again be considered in observed, such as periodic reductions when the workercase of uncertainty or when a diagnosis of OA has is exposed to a specific substance only occasionallypreviously been rejected. over the course of the day or only on particular days. However, as with other respiratory function tests, experience and correct interpretation of the data canBronchial Provocation in the Workplace draw attention to manipulations or tricks on the part of Bronchial provocation can confirm clinical suspicion individuals seeking work or financial advantages.of bronchial asthma caused by an agent that is present Nowadays, however, apparatus is available in which thein the workplace or produced by work activities. The use of a computer program allows the information to bemeasurement relates the occupation to the disease but stored and prevents it being manipulated.64does not indicate which specific substance or agent isinvolved.60 However, if it is known that in that particular Specific Bronchial Provocation Testoccupation a product is used that is commonly linked toOA, or if evidence of sensitization of the patient to a Although specific bronchial provocation tests areparticular agent can be obtained through immunologic considered the gold standard for diagnosis of OA, intests, diagnosis of OA caused by that agent is highly most cases they cannot be considered for routinelikely. The test must be performed during or after a diagnosis.4 They may be indicated in the followingperiod of time in which the patient is working and situations: a) when there is a new agent that may be aduring or after another period in which the individual is possible cause of asthma; b) to identify the causativenot. Those periods must generally be at least 2 weeks agent from among various substances to which a workerlong and interference in the test due to factors such as is exposed; c) when severe asthmatic reactions mayuse of bronchodilators, presence of exacerbations, etc, occur when the individual returns to work; and d) whenshould be prevented. In some cases, such as when it is diagnosis is still doubtful after other tests have beensuspected that irritant concentrations of particular performed.substances are reached in the workplace, it may be Exposure to the agent can be performed in 2 ways,necessary to measure the concentrations of the agent always in specialized clinics65:under suspicion. Measurement of the changes between2 periods can be performed in various ways. The 1. Via nebulization when the agents are soluble andmethod that is most widely used and probably possesses the immunologic mechanism is mediated by IgE.the greatest diagnostic efficiency is serial monitoring of Antigen solutions are administered as aerosols atpeak expiratory flow (PEF) during periods of exposure increasing concentrations. The concentration at whichand lack of exposure, although serial monitoring of the technique is initiated is calculated using a formulaforced expiratory volume in 1 second (FEV1) during based on the PC20 (mg/mL) for methacholine and theboth periods or periodic monitoring of FEV1 or lowest concentration that generates a positive responsenonspecific bronchial hyperreactivity at the end of each in skin prick tests. Forced spirometry is performedperiod can also be useful.61 In any case, they are not 10 minutes after each nebulization. The test result isincompatible with each other and sometimes a method positive if there is a reduction in FEV1 of at least 20%.such as testing of nonspecific bronchial hyperreactivity The results are expressed as the PC20 of the allergen, orcan reinforce the diagnosis obtained using another as the PD20 of the allergen if a dosimeter is used. If themethod such as serial monitoring of PEF.60 Although result is negative a higher concentration is administered.there is some lack of consensus regarding what During the 24 hours following inhalation it is importantrepresents a significant change, a difference of more to monitor FEV1 every hour to identify delayedthan 20% in PEF or FEV1, or a reduction of at least 3 responses.fold in the concentration of agent that causes a 2. In a challenge chamber, when the agents arereduction of at least 20% in FEV1 (PC20) between the 2 insoluble. The test involves exposure of the patient to aperiods would be considered definitively positive.4,60,62 nonirritant concentration of the suspected causativeIt is noteworthy that qualitative visual analysis of serial agent. For this reason, means of measuring thePEF recordings by an expert has a very high sensitivity concentration of those agents should be available ifand specificity, the highest among the different systems possible. The length of exposure varies according to thementioned.61 Serial PEF recordings must nevertheless agent and the characteristics of the patient. The testbe performed according to a method.60 Measurement results are positive if there is a greater than 20%4 times per day is usually acceptable for most patients.63 reduction in FEV1, or a positive response or significantUsing that method, 4 types of response have been decrease in the PC20 compared with that performedidentified: a) deterioration during the working day, such prior to exposure.56,57 If the test is negative, exposure isthat on returning the following day the patient has repeated for a longer period of time or with a highercompletely recovered; b) progressive deterioration over concentration of the product on successive days.462 Arch Bronconeumol. 2006;42(9):457-74
  7. 7. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. ORRIOLS MARTÍNEZ R ET AL. GUIDELINES FOR OCCUPATIONAL ASTHMA When non-water-soluble dust is used, it can be Diagnosis and Treatment of Nonimmunologic passed from one tray to another mixed with lactose to Occupational Asthma produce a cloud of dust. The use of lactose alone allows Reactive Airways Dysfunction Syndrome a placebo test to be performed.21 Drug-inhalation devices that employ capsules containing a specific Even though cases had already been described, the amount of dust have also been used.66 term RADS was not used until 1985, when Brooks et When gases or fumes are tested, the methods used to al23 described a series of 10 patients. The diagnostic generate a given concentration can be classified as static criteria for RADS established by those authors continue or dynamic (continuous flow).65,67,68 In the static to be used3,4,25,75: systems, a known quantity of gas is mixed with another of air to produce a given concentration. In dynamic 1. Absence of prior respiratory symptoms systems, the airflow and the addition of gas is 2. Exposure to a gas, smoke, or vapor present at high controlled to produce a specific dilution. These systems concentrations and with irritant qualities offer a continuous flow and allow rapid and predictable 3. Onset of symptoms within the first 24 hours of changes in the concentration to be made, favoring good exposure and persistence for at least 3 months mixture and minimizing loss through adsorption to the 4. Symptoms similar to asthma with cough, walls of the chamber. wheezing, and dyspnea As an alternative or to avoid the use of a challenge 5. Objective evidence of bronchial asthma chamber, some hospitals have developed equipment for 6. Other types of lung disease ruled out closed-circuit exposure, which in theory offers greater control over exposure and makes it safer for health care RADS occurs through direct toxic mechanisms. personnel.68 Destruction of the respiratory epithelium and inflammation have been demonstrated to take place during the acute phase and with collagen regeneration Treatment and Prognosis and proliferation in subsequent phases. Once exposure In most cases of immunologic OA it appears to be has occurred, only treatment appears able to influence obligatory to recommend discontinuation of exposure to the course and prognosis of the disease. Reports of the processes or substances responsible.4,69 Wherever experience with a small number of cases have indicated possible, the solution lies in a change of work situation. that early treatment with high doses of corticosteroids If that is not possible and the worker continues to be can improve prognosis.76,77 However, many patients exposed, the safety procedures of the company should with RADS continue to present symptoms of bronchial be assessed and exposure should be avoided as far as irritation and hyperreactivity years after exposure. possible through protection of the airways. In such Consequently, once stabilized following the acute cases, the effectiveness of the intervention must be phase, patients should be treated as asthmatics. On the demonstrated on a regular basis through respiratory other hand, since they do not display any greater function tests.51 Limitation of contact through the use of susceptibility than other asthmatic patients to protective masks in animal care facilities and the reexposure to nonirritant doses of the causative agent, pharmaceutical industry has been associated with a they can return to work so long as preventative certain improvement in clinical condition and measures remove the possibility of contact with respiratory function.70,71 A beneficial effect has also products at irritant concentrations.8,26 been observed with the use of inhaled bronchodilators and antiinflammatory drugs in this type of patient.72 Occupational Asthma Caused by Low Doses of Irritants Discontinuation of exposure to the causative agent is associated with an improvement in symptoms and lung The appearance of cases with symptoms of asthma function that does not normally exceed 50% in affected following repeated exposure to moderate or low individuals. Lung function is only normalized and concentrations of irritants is currently of particular nonspecific bronchial hyperreactivity stopped in around interest. In 1989, Tarlo and Broder,24 upon introducing 25% of individuals. In general, the prognosis of a given the term “irritant-induced asthma,” already included patient in whom contact with the causative agent is workers who developed asthma following single or removed depends on the severity of the condition when multiple exposure to the irritant, even if exposure was at diagnosis was established. On the other hand, if low concentrations. Chan-Yeung et al78 also described exposure to the causative agent continues, it almost cases of asthma with those characteristics. The terms always leads to clinical and functional deterioration of “low-dose RADS” and “delayed RADS” were later the patient.69,72 proposed.8,79 However, it was not clearly demonstrated Following diagnosis of OA, available information in those case series that multiple moderate-intensity indicates that from a socioeconomic perspective there is exposure could cause asthma, and furthermore, other a substantial deterioration if the patient stops work, studies have demonstrated that repeated moderate since the system of support appears to be insufficient in inhalation of an irritant is not associated with Western countries. In fact, a third of workers do not persistence of airway hyperresponsiveness, whereas discontinue exposure to the causative agent following such persistence is observed with exposure to higher diagnosis to avoid adverse financial consequences.4,73,74 concentrations, even in the case of single exposure.80,81 Arch Bronconeumol. 2006;42(9):457-74 463
  8. 8. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. ORRIOLS MARTÍNEZ R ET AL. GUIDELINES FOR OCCUPATIONAL ASTHMAAs admitted by Tarlo,5 there is currently a genuine of byssinosis cannot be ruled out in patients who do notdebate regarding the existence of asthma produced by exhibit acute or chronic changes in lung function;low or moderate doses of irritants.3,4 Further studies will likewise, the presence of such changes is insufficient tobe necessary to clearly establish and characterize the establish a diagnosis.87condition. Asthma caused by exposure to grain dust. Asthma caused by exposure to dust from cereal grain occursOther Variants of Occupational Asthma mainly in workers involved with grain silos, mills, or bakeries but is also seen in agricultural workers.88 TheAsthma-Like Syndromes specific cause is unknown but could be a component Asthma-like syndromes can present certain of the cereal, of parasitic fungi such as smut or rust,differential characteristics: systemic symptoms are of saprophytes such as Aspergillus species, ofpresent, the severity of the symptoms decreases over the organisms such as weevils or mites, or of gram-course of the week, changes in expiratory flow as a negative bacteria.result of exposure are less pronounced, airway The reported prevalence varies markedly in differenthyperresponsiveness is not so notable or persistent, and studies. The asthma is often mild and the individual’sneutrophilic inflammation is present in the airways.1,4 work is not affected. In close to 50% of cases the symptoms improve or disappear spontaneously, Byssinosis. Byssinosis develops in textile-industry suggesting a process of desensitization in someworkers exposed to dust from cotton, flax, hemp, jute, cases.and pita thread.82 The main agent responsible forbyssinosis seems to be a high concentration of Asthma in livestock workers. A higher rate ofendotoxin from gram-negative bacilli present in the air, nonatopic asthma has been demonstrated in farmalthough this is not certain.83 In Europe and the United workers who are exposed to livestock, particularly birds,States of America, the prevalence of the condition in cattle, and pigs. This type of asthma is associated withindividuals working in areas of production that generate exposure to endotoxins, fungal spores, and ammonia.89-91the most dust has decreased from 50% to around 3%. Indeveloping countries the prevalence remains high at Asthma in aluminium potroom workers. Asthma isaround 30% to 50%.82,83 produced in aluminium foundry workers during Byssinosis in its classical form is characterized by production of the metal from an aluminium oxide suchthe appearance of a set of systemic and respiratory as corundum, in electrolytic cells. In this variant ofsymptoms, generally following more than 10 years of OA, increased airway hyperresponsiveness is notexposure. Fever, asthenia, loss of appetite, tightness in normally observed upon exposure and variousthe chest, dyspnea, and cough are characteristic immunologic and nonimmunologic mechanisms may besymptoms on the first day of the working week involved. Although excessive concentrations of fluoride(following absence from the textile plant for 48 hours). have been implicated, the cause remains to beThe symptoms diminish during the following working elucidated.4,92days despite continued exposure. As the diseaseprogresses, the symptoms also begin to present later in Differential Diagnosisthe week, although with less intensity, and eventuallythey appear every day of the week, including the Work-Aggravated Asthmaweekend. The onset of symptoms during a shift canoccur either at the beginning of the shift (60%) or The term work-aggravated asthma refers to theduring the second half (40%). Those symptoms are situation in which there is evidence of worsening ofaccompanied by lung function abnormalities, such as preexisting asthma as a consequence of environmentalthe following: exposure in the workplace. Although it manifests as an increase in the frequency and/or severity of asthma 1. Reduced FEV1 at the end of the working day symptoms and/or an increase in the medication required(compared with the value obtained prior to beginning to control the disease during working days, diagnosiswork); the reduction is more marked on the first day of should be performed on the basis of changes inwork83 bronchial diameter, the degree of bronchial 2. Presence of nonspecific bronchial hyperresponsiveness hyperresponsiveness, or the extent of inflammation of(78% of cases of byssinosis, 38% of workers with the airway in relation to workplace exposure.75respiratory symptoms not associated with byssinosis, However, demonstrating such changes in a patientand 17% of asthmatic workers83,84) with asthma prior to workplace exposure is not always 3. Long-term reduction in spirometry values85,86 easy. As a consequence, some authors have suggested that work-aggravated asthma be distinguished from The main determining factor in the diagnosis is the symptoms of asthma aggravated by work. The secondpatient’s history, in particular confirmation that entity appears to be much more common than the first,symptoms typically appear or display the greatest although few publications have looked at itsseverity on the first working day of the week. Diagnosis pathogenesis, treatment, and course.93464 Arch Bronconeumol. 2006;42(9):457-74
  9. 9. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. ORRIOLS MARTÍNEZ R ET AL. GUIDELINES FOR OCCUPATIONAL ASTHMA Eosinophilic Bronchitis functional restriction, diffuse radiographic abnormalities, lymphocytosis in bronchoalveolar Eosinophilic bronchitis causes chronic cough, lavage, granulomatous pathologic reactions, and/or expectoration, dyspnea, and on rare occasions, positive alveolar response to specific challenge test.103 wheezing. Its main characteristic is the presence of a large number of eosinophils in sputum and the absence of variable airflow obstruction and/or bronchial Vocal Cord Dysfunction hyperresponsiveness.94,95 It should be noted that cases of Vocal cord dysfunction is characterized by eosinophilic bronchitis have been described associated paradoxical vocal cord adduction during inhalation. with exposure to certain workplace-related substances.96 This anomalous adduction causes airflow obstruction In such cases, and in the absence of recognizable that can be manifested as stridor, wheezing, tightness of bronchial hyperresponsiveness, diagnosis is provided the chest, dyspnea, and/or cough.106 Differential when significant reproducible changes in the number of diagnosis with asthma is difficult and it is possible that eosinophils in sputum are seen to be associated with many patients with vocal cord dysfunction are workplace exposure. misdiagnosed and treated as if they were suffering from Some authors have classified eosinophilic bronchitis asthma. The disease is suspected if flattening of the as a variant of OA3,4; however, the condition clearly inspiratory flow profile is seen in forced spirometry. does not fulfill the criteria that define bronchial asthma. Diagnosis is confirmed by fiberoptic bronchoscopy on observation of anomalous adduction of the vocal cords Bronchiolitis during inhalation. The term bronchiolitis applies to various diseases Although the condition has been associated with involving inflammation of the bronchioles. The various psychiatric disorders, it has recently been symptoms will depend on the underlying disease, proposed that certain types of workplace exposure, although the majority of patients present cough, especially to irritants, can cause vocal cord dyspnea, tightness of the chest, and occasionally, dysfunction.107 Distinguishing this condition is expectoration and/or wheezing.97,98 important, since the treatment is radically different from As an occupational disease, constrictive bronchiolitis that prescribed for asthma. Patients with vocal cord has been associated with the inhalation of various dysfunction can benefit from educational treatment agents found in the workplace, such as nitrogen aimed at training the muscles that cause the laryngeal dioxide, sulfur dioxide, ammonia, or hydrochloric acid, dysfunction. Inhaled or systemic corticosteroids and and more recently it has been described in workers in a bronchodilators have not been proven to be of benefit. popcorn factory, probably due to exposure to diacetyl, an organic chemical used in the preparation of that Multiple Chemical Sensitivities Syndrome product.99 Inhalation of asbestos, iron oxide, aluminium oxide, Multiple chemical sensitivities syndrome is a talc, mica, silica, silicates, and carbon can cause condition acquired following a documented toxic bronchiolitis secondary to inhalation of mineral dust. exposure and is usually characterized by recurrent The condition is characterized by inflammation of the symptoms that affect multiple organ systems.108 Those respiratory bronchioles and occasionally of the alveoli, symptoms appear in response to exposure to unrelated leading to airflow obstruction. These changes can occur chemical compounds at doses lower than those known in the absence of concomitant pneumoconiosis. to be toxic in the general population. The following Finally, lymphocytic bronchiolitis has recently been criteria are used to establish diagnosis: a) the symptoms described in workers in the nylon industry.100 are reproduced with repeated chemical exposure; b) the disease is chronic; c) a low level of exposure causes the syndrome; d) the symptoms improve or disappear when Hypersensitivity Pneumonitis the triggers are removed; e) the symptoms occur in Hypersensitivity pneumonitis is a lung disease that response to multiple chemically unrelated substances; f) occurs as a result of inhalation of antigens to which the the symptoms affect multiple organ systems; and g) not patient has been previously sensitized. Many of those all of the symptoms can be explained by a multiorgan antigens may be present in the workplace and cause disease. occupational disease.101-103 It is important to distinguish The symptoms reported by the patients are highly this condition from OA, taking into account that both variable, although the most frequent are neurologic, the causative agents and the clinical symptoms may on digestive, and respiratory. In relation to the respiratory occasions be the same. Thus, it is known that an system, patients usually report cough, dyspnea, appreciable percentage of patients with hypersensitivity tightness of the chest, and presternal pain during pneumonitis present wheezing, airway inhalation. Clinical examination is usually normal, as hyperresponsiveness, and a normal chest are the various complementary tests, including tests of radiograph.104,105 Nevertheless, the diagnosis of lung function and bronchial hyperresponsiveness. hypersensitivity pneumonitis, unlike asthma, is The agents most commonly implicated in this suspected and/or confirmed in the presence of systemic syndrome are petrochemical-derived products, symptoms, reduced diffusing capacity with or without pesticides, synthetic fragrances, cleaning products, Arch Bronconeumol. 2006;42(9):457-74 465
  10. 10. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. ORRIOLS MARTÍNEZ R ET AL. GUIDELINES FOR OCCUPATIONAL ASTHMApaints, and detergents. It is important to note that the causative agent. Otherwise, it is difficult, andsymptoms can occur in response to a wide variety of sometimes impossible, to identify the agent. It mustagents, commonly leading to a substantial reduction in be remembered that a specific agent normallypatient quality of life. Since there is no specific requires a particular type of sampling in order totreatment for this syndrome, many authors favor then use the appropriate analytic technique. The webencouraging patients to carry on with their lives as pages of various organizations publish samplingnormally as possible, including the work activities that methods and analytic techniques for a variety ofhave caused the disease, and to learn to live with the chemicals.110-112symptoms, since to date it has not been demonstratedthat this leads to deterioration of any organ in Sampling Techniquesparticular. Sampling involves collecting a sample of air to be taken to the laboratory, where the agent it contains isEnvironmental Monitoring of Chemical Agents identified and characterized, or alternatively passing a The measurement of possible causative agents of OA volume of air through a support that retains thein the environment may be important for a number of contaminants of interest.reasons109: a) it is sometimes necessary to confirm a Sampling of gases is performed in plastic, Teflon, ordiagnosis of OA in the laboratory or workplace; b) aluminium bags into which air is pumped. The flow andmonitoring should be used to ensure that exposure to time of use of the pump allow the concentration of thehigh concentrations of certain agents is prevented to agent studied to be calculated. Sampling in bags isguard against the development of OA in the workforce; limited to stable gases that do not react with theand c) since workers who have developed OA should material of the bag and that are not absorbed by it.not continue to be exposed to the causative agent, it Sampling of volatile organic components is usuallymay sometimes be necessary to monitor the agent undertaken through adsorption on a solid such asfollowing introduction of safety measures or workplace activated charcoal or silica gel. This can be performedchanges. actively through the use of a pump or passively as a However, it is important to bear in mind that result of diffusion by simple exposure of the support tomeasurements of possible causative agents should not the agent present in the air.be considered in isolation and should form part of the If the substance is in the form of an aerosol, dust, orgeneral principles of industrial safety. Within this smoke, it can be captured using filters or membranesprocess, the following elements are often necessary: made of materials such as Teflon, cellulose, polyvinyl chloride, or glass fiber. The filter is located in a plastic 1. Diagram of the processing or flow of the primary container connected to a pump that passes room airmaterials until the final product is obtained. This through the filter.involves exhaustive monitoring of the primary materialfrom the moment it enters the company and as it passes Analytic Techniquesthrough the processes that alter it and may involve otherchemicals that could lead to the appearance of Various analytic techniques exist, such as gasintermediate substances or other byproducts before the chromatography, high performance liquidfinal product or products are obtained. chromatography, atomic absorption, ultraviolet, and/or 2. Inventory and identification of substances that may infrared spectrophotometry, spectrometry, ionbe present in the working environment. In addition to chromatography, and mass spectrometry.our own knowledge of a possible agent’s presence in a It should be noted that industrial hygiene equipmentworking environment, we should look at manufacturer’s has now been developed that collects andsafety data sheets, which nearly always provide the simultaneously carries out analysis of air for variousnecessary information on the substances used. The chemical substances such as isocyanate monomers,possibility should also be considered that it is not one of anhydrides, and formaldehyde. Such equipment shouldthe substances normally present in the production be used with caution in the workplace due to theprocess but rather a substance produced by an possibility of interference from the environmentalanomalous industrial process or a substance that does conditions and other contaminants.not form part of the process but for one reason or Various organizations, such as the Spanish nationalanother is used, sometimes temporarily, in the occupational safety commission (Instituto Nacional decompany; such substances may include cleaning Seguridad e Higiene en el Trabajo) have establishedproducts, coolants, paints, fuels, etc. limits for exposure to protect workers from the toxic 3. Assessment of the aggregation state of the agent as effects of chemical contaminants.113 These limitsa dust, aerosol, gas, or vapor, since this can affect its appear to be inadequate either for prevention ofinteraction with the body and the way in which it must immunologic OA or for protection of workers whobe analyzed. have already developed the disease. However, they may be sufficient to protect a worker who has suffered Prior to sampling and analysis it is usually RADS and waited a sufficient period to achieve aindispensable to first focus suspicion on a specific certain stability.466 Arch Bronconeumol. 2006;42(9):457-74
  11. 11. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. ORRIOLS MARTÍNEZ R ET AL. GUIDELINES FOR OCCUPATIONAL ASTHMA Environmental Monitoring of Protein Aeroallergens method for a new allergen, it is necessary to determine the stability of the allergen on the filter and the Quantification of environmental allergens has various efficiency of extraction. In addition, sample storage is applications that can also be useful in the diagnosis also important. The filters can generally be stored for a of OA. Specifically, their quantification allows a) number of months at -20oC. Although it is also possible monitoring of specific concentrations of allergens in the to store the eluted allergen, in some cases the allergen is workplace or the environment; b) confirmation of less stable in aqueous solution due to protease activity; exposure to a given allergen as the cause of disease; in those cases it is possible to lyophilize the extract to and/or c) occasionally, establishment of the improve storage. concentrations of a given allergen that represent a risk.114 Analytic Techniques Sampling Techniques Various techniques are used to measure the When analyzing environmental allergens it should be environmental conservation of aeroallergens. taken into consideration from the outset that the process Quantification of some airborne pollens, which display involves various stages that can generate variability in a characteristic morphology, can be performed by the results obtained and that it is therefore important to optical microscopy based on morphologic criteria. undertake the necessary standardization. Firstly, Those techniques, along with culture methods, are also samples must be taken of particles present in the air, a employed for environmental quantification of process that requires environmental sampling microorganisms; they are highly sensitive and offer the equipment. Such equipment contains an aspirator that advantage of also allowing taxonomic classification.114 pulls a known volume of air through filters on which However, in most cases the air samples are made up of the allergen particles are deposited. Accurate complex mixtures that contain, among other substances, standardization of the characteristics of the sampling amorphous allergenic substances that cannot be visually (time and airflow) are important in order to collect identified. Such cases require the use of specific sufficient allergen on the filter to allow subsequent immunoassay techniques such as radioimmunoassay quantification. The volume of filtered air usually varies and enzyme-linked immunosorbent assay (ELISA), between 0.5 and 1000 m3, although in many cases the which can be classified as capture (also known as airflow is fixed and it is the sampling time that is sandwich methods) or competitive (inhibition ELISA or varied. Extended sampling times present the problem inhibition radioallergosorbent test [RAST]). that it is impossible to detect temporal changes in the Those methods are currently used for the analysis of concentration and what is measured is the mean many different aeroallergens, including those derived concentration over the sampling period. from dust mites (Dermatophagoides pteronyssinus),115 Various types of sampler exist for the different domestic cats (Felis domesticus),116 laboratory environments in which an allergen might be measured animals,117 enzymes such as α-amylase,118 and latex.119 and it is important to choose the most appropriate one. The most recently described include an immunoassay Area samplers operate with an airflow of 1 to 3 L/s, can developed to analyze the environmental concentration measure and confirm the presence of a given allergen, of phytase, an enzyme used as an additive in animal and can work for extended periods. Built-in particle- feed.120 size analyzers (cascade impactors) allow the quantity of Capture immunoassays display an acceptable biologically active allergen to be determined. Personal reproducibility and sensitivity, since they can detect samplers allow measurements to be made that are protein concentrations of between 100 pg/mL and related to an individual’s specific workplace. However, 1 ng/mL; consequently, they can be used to assess the cascade impactors and personal samplers can have the relative environmental concentrations of most protein disadvantage of not collecting a sufficient quantity of aeroallergens, which in many cases are low, particularly allergen for subsequent detection since they work at when allergens are measured in the atmosphere. This flow rates that are lower than area samplers. type of analysis requires 2 specific monoclonal antibodies that recognize 2 different epitopes of the allergen, or alternatively purified polyclonal antibodies. Extraction of Allergens Analysis using monoclonal antibodies offers substantial The second step involves extraction of soluble advantages: higher specificity and reproducibility, as allergens from the filter with buffered aqueous well as the possibility of unlimited production of the solutions. The choice of filter is also essential. It must antibodies if the producing cell line is maintained.121 offer low resistance to airflow along with efficient However, there are disadvantages to their use when retention of breathable particles. In addition, it should analyzing complex material such as environmental prevent denaturation of proteins, should not absorb the samples because they are designed to detect only a allergen, and should allow extraction in small volumes single component of the mixture and not all of the in order for the sensitivity of the assay to allow allergens present.122 Capture immunoassays that employ detection of the proteins. The best filters are made from polyclonal antibodies have the advantage that the polytetrafluoroethylene, Teflon, or glass fiber. During antibodies can be prepared using various animal species the development and validation of a measurement and are easier to obtain. Furthermore, they are Arch Bronconeumol. 2006;42(9):457-74 467
  12. 12. Document dowloaded from http://www.archbronconeumol.org, day 26/12/2007. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. ORRIOLS MARTÍNEZ R ET AL. GUIDELINES FOR OCCUPATIONAL ASTHMAparticularly useful for the analysis of denatured proteins however, and it cannot be used systematically in OAsince they recognize multiple epitopes.121 patients despite its high diagnostic yield. Currently, When monoclonal antibodies and/or purified noninvasive methods that are relatively easy andpolyclonal antibodies are unavailable, competition or economical are available for the assessment ofinhibition assays are recommended for the bronchial inflammation; the tests display goodquantification of environmental allergens. The most reproducibility and they do not present complicationscommon inhibition methods are inhibition RAST and for the patient. Such methods include analysis ofinhibition ELISA.123,124 induced sputum and exhaled breath condensate, and A disadvantage of inhibition methods is that in most quantification of nitric oxide (NO). Although thosecases there is no international standardization and they methods were initially used for research, they are ofare considered semiquantitative methods with potential increasing importance in clinical practice.problems of long-term reproducibility caused by the useof antibody mixtures (eg, human antibodies).123 This Induced Sputummakes it difficult to compare absolute values betweendifferent laboratories and makes it necessary to Sputum induction is a safe technique that can beestablish the efficacy of the technique for each allergen. applied without complications in day-to-day clinicalThe antisera used in those methods made up of IgG practice. Sputum samples containing cells and cellularantibodies from animals offer advantages over the use and extracellular products can be obtained with thisof those made up of human IgE antibodies, since they technique. The most widely used method was describedare used at 10-fold to 1000-fold dilutions. However, the by Pizzichini et al.127 It involves pretreatment of theuse of human IgE antibodies ensures measurement of patient with inhaled salbutamol 10 minutes prior tothe disease-causing substance (ie, those allergens that nebulization of increasing concentrations of hypertonicare of clinical importance), particularly when the saline solution (3%, 4%, and 5%) over a period thatidentity of the allergenic molecules is unknown or generally ranges from 5 to 7 minutes. Prior to and afterpowders are used that contain complex mixtures of the first nebulization and following each subsequentallergens.114 nebulization, patients are asked to blow their nose and rinse their mouth with water to minimize contamination with nasal secretions or saliva. The patient is then askedIs It Possible to Establish an Environmental Limit to cough (effective cough) and sputum is obtained fromfor Allergens? the lower airways in a sterile container. The test is The goal of monitoring environmental concentrations considered complete after 3 nebulizations. Theof aeroallergens is not only to aid diagnosis but also to procedure is stopped if at any point a reduction of moreestablish the safe limit below which sensitized than 20% is observed for FEV1.individuals will not display symptoms. However, to Subsequently, sputum is processed in the laboratoryestablish a safety limit in the case of allergens is more to separate the cell pellet from the liquid supernatant.complex than with toxic materials, since the The pellet can be used to obtain a complete cell countconcentration that provokes symptoms in sensitized and a differential cell count (eosinophils, neutrophils,individuals can vary and depends upon the titers lymphocytes, and macrophages). The supernatant canof specific IgE the patient has against the allergen and be used to analyze inflammatory mediators produced bythe degree of bronchial hyperresponsiveness those cells.to methacholine or histamine.114 In addition, 2 Various authors have described the usefulness ofenvironmental allergen concentrations should be taken induced sputum in the diagnosis and monitoring of OA.into consideration: the sensitizing level and the level Some studies have demonstrated that an increase in thethat provokes symptoms in sensitized individuals. number of eosinophils in sputum when the patient isVarious authors report that the quantity of allergen working compared with rest days can aid the diagnosisnecessary for sensitization is around 100 to 1000 ng/m3, of the disease.128 In addition, a recent study reportedwhile that necessary to provoke symptoms once an that additional analysis of cells in induced sputumindividual is sensitized is around 10 ng/m3 or less.114 increases the specificity of PEF monitoring.129 Finally, itFurthermore, various studies analyzing sensitization to has also been demonstrated to be useful during specificallergens such as D pteronyssinus report that challenge tests. In this context, Lemière et al130concentrations above 80 µg per gram of domestic dust observed a significant increase in the number ofcould even sensitize healthy individuals.125 A safe limit eosinophils and neutrophils following specific bronchialto prevent sensitization and allergy has only been challenge in patients with OA caused by both high andestablished for a few allergens, such as wheat flour, low molecular weight substances.latex, and α-amylase.126 Exhaled Nitric OxideAnalysis of Inflammatory Markers Various studies have reported abnormalities in the Inflammation can be assessed in patients with OA by concentrations of NO in respiratory diseasesanalyzing bronchial biopsy material obtained by characterized by inflammatory processes. This markerfiberoptic bronchoscopy. That technique is invasive, has been extensively studied in asthma and it has been468 Arch Bronconeumol. 2006;42(9):457-74

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