08 separ 5186 (457-474)ing

Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.
Ramon Orriols Martínez (coordinator),a Khalil Abu Shams,b Enrique Alday Figueroa,cMaría Jesús Cruz Carmona,a Juan Bautista Galdiz Iturri,d Isabel Isidro Montes,e Xavier Muñoz Gall,aSantiago Quirce Gancedo,f and Joaquín Sastre Domínguez.f Working Group of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR).
aServei de Pneumologia, Hospital Universitari Vall d’Hebron, Barcelona, Spain.
bSección de Neumología, Hospital Virgen del Camino, Pamplona, Navarra, Spain.
cServicio de Neumología, Instituto Nacional de Seguridad e Higiene en el Trabajo, Madrid, Spain.
dServicio de Neumología, Hospital de Cruces, Baracaldo, Vizcaya, Spain.
eServicio de Neumología Ocupacional, Instituto Nacional de Silicosis, Hospital Central de Asturias, Oviedo, Asturias, Spain.
fServicio de Alergia, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
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 patient’s workplace or other sites. Thus, the benefits areimportant 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 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 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 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 doses of an irritant. Its onset, however, is linked to asingle exposure. It is also known as OA without a latentperiod, since the symptoms appear within 24 hours of Definition
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 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.
– Potroom asthma. This occurs in workers involved Pg. Vall d’Hebron, 119-129. 08035 Barcelona. España.
E-mail: rorriols@vhebron.net Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 High Molecular Weight Agents That Cause Immunologic Occupational Asthma
Product, Occupation, Industry
Wheat, barley, rye, oats, maize, sunflower, Baker’s shop, bakery, cake shop, mill, transport, agriculture Coffee, castor-oil plant, pea, carob, soya, Oil industry, food processing industry, bakery, meat product Printing, rubber industry, dental hygienist, etc Bacillus subtilis, trypsin, papain, pepsin, Bakery, pharmaceutical, plastics, and detergents industries, etc Aspergillus, Cladosporium, Trichoderma Baking, agriculture, domestic tasks, technicians, saw mill Farmers, dairy workers, butchers, cake shops, tanneries, etc casein, etcBeetle, locust, cockroach, cricket, fly, Museum, laboratory, fishing, agriculture, cosmetics, entomology, Fisherman, fish farms, and feed, coral, and mother of pearl industries Health care workers, production of gloves and condoms, etc, manipulation of grains, hairdressing Low Molecular Weight Agents That Cause Immunologic Occupational Asthma
Product, Occupation, Industry
Polyurethane, plastic varnishes, insulation material, spray Phthalic acid, trimellitic acid anhydride, Plastics and resins, adhesives, chemical industry, flame hexahydrophthalic acid, tetrachlorophthalic acid, Platinum salts, cobalt sulfate, chromium sulphate Platinum refinery, polishers, silver and chrome-containing and chromium salts, potassium dichromate, Chemical industry, spray paints, ski manufacture, polishes, aliphatic amines, aminoethanolamine, hexamethylene tetramycin Glutaraldehyde, persulfate salts, cyanoacrylate, Nursing/endoscopy, hairdressing, orthopedics, glues, paper methylmethacrylate, polyethylene, chloramine, packaging, plastic bags, sterilizer in food and pharmaceutical Agents That Cause Nonimmunologic Occupational Asthma
More than 300 agents have been implicated in the Product, Occupation, Industry
development of OA (Tables 1-3). A complete list ofthose agents can be found in certain research articles Cleaning, paper, sewage treatment, bleach Prevalence and Incidence
Notable discrepancies are found in the data on prevalence and incidence currently available in the Other products Resins, hydrochloric Chemical, cleaning, and medical literature. Differences in the design of epidemiologic studies, the definition of OA, the study population, and the country in which the study was Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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% ofhealth 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 hospitalfor 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 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, 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 In addition to the causative agent itself, the intensity ofthe exposure also appears to be an important determinantin the appearance of RADS.8 Pathogenesis
Genetic predisposition. Atopy is a risk factor for asthma induced by high molecular weight substances.31 Forinstance, 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 Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 Types of Occupational Asthma According to the Mechanism Involved and the Principal Characteristics*
Immunologic OA
Nonimmunologic OA
Interval between onset of exposure and symptoms *OA indicates occupational asthma; Ig, immunoglobulin; RADS, reactive airways dysfunction syndrome.
inflammatory cells that ultimately provoke an changes in vascular permeability but would also inflammatory reaction in the airways characteristic of provoke an increase in mucosal secretion that would contribute to the chronic inflammation seen in biopsymaterial. During the process of recovery the IgE-independent mechanisms. Most low molecular inflammation would be resolved, leading to recovery of weight substances that cause OA act via a mechanism the epithelium, inhibition of neuronal activity, and that, while probably immunologic, does not involve improvement of vascular integrity. However, complete IgE.36 Specific IgG and IgG antibodies appear to be recovery would not always be achieved and sequelae of associated more with the level of exposure than with the the inflammatory response would persist in the form of disease 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 Immunologic
Occupational Asthma
inflammation by secreting interleukin (IL) 5. IL-5 is apotent stimulator and activator of eosinophils and is the Diagnosis of immunologic OA requires a series of main cytokine involved in the recruitment and activation of eosinophils during delayed asthmatic responses.45Increased numbers of activated T lymphocytes (which express the receptor for IL-2), activated eosinophils, andmast cells have been observed in bronchial biopsies A clinical history is essential for the diagnosis of from patients with OA caused by low molecular weight OA. The patient should be questioned not only about the existence of bronchial symptoms but also about nasal symptoms and symptoms of the eyes, skin, and nonimmunologic proinflammatory effects. If they bind upper airways. Those symptoms often precede the deficiency, which can reduce defense against oxidizing molecular weight antigens are involved. Prior to agents.48 In fact, it has been reported that exposure to entering the symptomatic period of the disease there is isocyanates is associated with elevated intracellular normally a highly variable period of time that can last concentrations 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 having amplify or initiate a response to low molecular weight performed the same job for years without presenting symptoms. Sudden-onset asthma in an adult with nohistory of respiratory or allergic disease may be cause Irritation or toxicity. The mechanisms underlying for suspicion of OA. It is important to be able to link RADS deserve special mention.8 The massive initial asymptomatic periods with absence of exposure and epithelial lesion would probably be followed by direct symptomatic periods with exposure. Sometimes the activation of sensory nerves that would give rise to patient will spontaneously report the presence of neurogenic inflammation. This would not only induce symptoms minutes after exposure to the causative Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 notedin the evening or only during the night. In those cases, it is less likely that patients will associate thesymptoms with their daytime activities. In general,improvements are observed at the weekend or during holidays, but this is not always the case. In fact, this association is more common at the onset of clinical symptoms, since as the symptoms progress they oftenbecome more persistent and recurrent and this can prevent the patient from associating their asthma with work. Nevertheless, questions about the improvementof asthma symptoms during the weekend andespecially during holidays display a greater diagnostic yield than those relating to the worsening of symptomsat work.51 Sometimes, as occurs with red cedar andisocyanates, the symptoms continue for months or years after exposure is discontinued.52 Furthermore, in some industries the chemical and operational processesare complex and cause the release of substances thatremain completely unnoticed. For this reason, one of the keys to the diagnosis of OA is a year by year workhistory and awareness of the products found in the workplace that can cause asthma. It is useful to reviewthe safety information provided with the products usedby the worker and determine whether the causative agent thought to be involved has been previously linked to asthma of occupational origin. A clinicalhistory indicative of OA is not sufficient to establishthe diagnosis, since the opinion of the physician only coincides with a true diagnosis of OA in slightly morethan half of suspected cases.53 Physical Examination, Chest Radiography, StandardWorkup, and Lung Function Testing 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, theyallow a diagnosis of asthma to be made, and secondly, 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 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 immunologic mechanism, this antibody cannot be Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 detected, 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 at molecular weight substances, such as isocyanates, least 3 days away from work; and d) maximal appear to display a good specificity.59 When a positive deterioration on Monday with recovery over the course result is obtained, the possibility of an accurate of the week. Sometimes different patterns can also be diagnosis of OA should once again be considered in observed, such as periodic reductions when the worker case of uncertainty or when a diagnosis of OA has is exposed to a specific substance only occasionally 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 can Bronchial 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 the in the workplace or produced by work activities. The use of a computer program allows the information to be measurement relates the occupation to the disease but stored and prevents it being manipulated.64 does not indicate which specific substance or agent isinvolved.60 However, if it is known that in that particular Specific Bronchial Provocation Test occupation a product is used that is commonly linked toOA, or if evidence of sensitization of the patient to a Although specific bronchial provocation tests are particular agent can be obtained through immunologic considered the gold standard for diagnosis of OA, in tests, diagnosis of OA caused by that agent is highly most cases they cannot be considered for routine likely. The test must be performed during or after a diagnosis.4 They may be indicated in the following period of time in which the patient is working and situations: a) when there is a new agent that may be a during or after another period in which the individual is possible cause of asthma; b) to identify the causative not. Those periods must generally be at least 2 weeks agent from among various substances to which a worker long and interference in the test due to factors such as is exposed; c) when severe asthmatic reactions may use of bronchodilators, presence of exacerbations, etc, occur when the individual returns to work; and d) when should be prevented. In some cases, such as when it is diagnosis is still doubtful after other tests have been suspected that irritant concentrations of particular 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 under suspicion. Measurement of the changes between2 periods can be performed in various ways. The 1. Via nebulization when the agents are soluble and method 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 at peak expiratory flow (PEF) during periods of exposure increasing concentrations. The concentration at which and lack of exposure, although serial monitoring of the technique is initiated is calculated using a formula forced expiratory volume in 1 second (FEV ) during both periods or periodic monitoring of FEV lowest concentration that generates a positive response nonspecific bronchial hyperreactivity at the end of each in skin prick tests. Forced spirometry is performed period can also be useful.61 In any case, they are not 10 minutes after each nebulization. The test result is incompatible with each other and sometimes a method positive if there is a reduction in FEV of at least 20%.
such as testing of nonspecific bronchial hyperreactivity The results are expressed as the PC of the allergen, or can reinforce the diagnosis obtained using another as the PD of the allergen if a dosimeter is used. If the method 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 important represents a significant change, a difference of more than 20% in PEF or FEV , or a reduction of at least 3 fold in the concentration of agent that causes a 2. In a challenge chamber, when the agents are reduction of at least 20% in FEV (PC ) between the 2 insoluble. The test involves exposure of the patient to a periods would be considered definitively positive.4,60,62 nonirritant concentration of the suspected causative It is noteworthy that qualitative visual analysis of serial agent. For this reason, means of measuring the PEF recordings by an expert has a very high sensitivity concentration of those agents should be available if and specificity, the highest among the different systems possible. The length of exposure varies according to the mentioned.61 Serial PEF recordings must nevertheless agent and the characteristics of the patient. The test be 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 FEV , or a positive response or significant Using that method, 4 types of response have been identified: a) deterioration during the working day, such prior to exposure.56,57 If the test is negative, exposure is that on returning the following day the patient has repeated for a longer period of time or with a higher completely recovered; b) progressive deterioration over concentration of the product on successive days.
Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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-inhalationdevices that employ capsules containing a specific Even though cases had already been described, the 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 systems, a known quantity of gas is mixed with anotherof 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, 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 greatercontrol over exposure and makes it safer for health care RADS occurs through direct toxic mechanisms.
Destruction of the respiratory epithelium andinflammation have been demonstrated to take placeduring the acute phase and with collagen regeneration 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 been observed with the use of inhaled bronchodilatorsand 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 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 Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 As admitted by Tarlo,5 there is currently a genuine of byssinosis cannot be ruled out in patients who do not debate 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 to be necessary to clearly establish and characterize the Asthma caused by exposure to grain dust. Asthma caused by exposure to dust from cereal grain occurs Other Variants of Occupational Asthma
mainly in workers involved with grain silos, mills, orbakeries but is also seen in agricultural workers.88 The 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 present, 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 result of exposure are less pronounced, airway The reported prevalence varies markedly in different hyperresponsiveness is not so notable or persistent, and studies. The asthma is often mild and the individual’s neutrophilic inflammation is present in the airways.1,4 work is not affected. In close to 50% of cases thesymptoms improve or disappear spontaneously, Byssinosis. Byssinosis develops in textile-industry suggesting a process of desensitization in some workers exposed to dust from cotton, flax, hemp, jute, and pita thread.82 The main agent responsible forbyssinosis seems to be a high concentration of Asthma in livestock workers. A higher rate of endotoxin from gram-negative bacilli present in the air, nonatopic asthma has been demonstrated in farm although 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 with individuals working in areas of production that generate exposure to endotoxins, fungal spores, and ammonia.89-91 the most dust has decreased from 50% to around 3%. Indeveloping countries the prevalence remains high at Asthma in aluminium potroom workers. Asthma is produced in aluminium foundry workers during Byssinosis in its classical form is characterized by production of the metal from an aluminium oxide such the appearance of a set of systemic and respiratory as corundum, in electrolytic cells. In this variant of symptoms, generally following more than 10 years of OA, increased airway hyperresponsiveness is not exposure. Fever, asthenia, loss of appetite, tightness in normally observed upon exposure and various the chest, dyspnea, and cough are characteristic immunologic and nonimmunologic mechanisms may be symptoms 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 be The symptoms diminish during the following working days despite continued exposure. As the diseaseprogresses, the symptoms also begin to present later in Differential Diagnosis
the week, although with less intensity, and eventuallythey appear every day of the week, including the weekend. The onset of symptoms during a shift canoccur either at the beginning of the shift (60%) or The term work-aggravated asthma refers to the during the second half (40%). Those symptoms are situation in which there is evidence of worsening of accompanied by lung function abnormalities, such as preexisting asthma as a consequence of environmental exposure in the workplace. Although it manifests as anincrease in the frequency and/or severity of asthma 1. Reduced FEV 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, diagnosis work); the reduction is more marked on the first day of should be performed on the basis of changes in 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.75 respiratory symptoms not associated with byssinosis, However, demonstrating such changes in a patient with asthma prior to workplace exposure is not always 3. Long-term reduction in spirometry values85,86 easy. As a consequence, some authors have suggestedthat work-aggravated asthma be distinguished from The main determining factor in the diagnosis is the symptoms of asthma aggravated by work. The second entity appears to be much more common than the first, symptoms typically appear or display the greatest although few publications have looked at its severity on the first working day of the week. Diagnosis Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 causes chronic cough, lavage, granulomatous pathologic reactions, and/or positive alveolar response to specific challenge test.103 wheezing. Its main characteristic is the presence of alarge number of eosinophils in sputum and the absenceof variable airflow obstruction and/or bronchial 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 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 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 onobservation of anomalous adduction of the vocal cords 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, dyspnea, tightness of the chest, and occasionally, 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 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) thedisease is chronic; c) a low level of exposure causes thesyndrome; d) the symptoms improve or disappear when 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 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 appreciable percentage of patients with hypersensitivity tightness of the chest, and presternal pain during inhalation. Clinical examination is usually normal, as are the various complementary tests, including tests of lung function and bronchial hyperresponsiveness.
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, Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 paints, and detergents. It is important to note that the symptoms can occur in response to a wide variety of sometimes impossible, to identify the agent. It must agents, commonly leading to a substantial reduction in be remembered that a specific agent normally patient quality of life. Since there is no specific requires a particular type of sampling in order to treatment for this syndrome, many authors favor then use the appropriate analytic technique. The web encouraging patients to carry on with their lives as pages of various organizations publish sampling normally as possible, including the work activities that methods and analytic techniques for a variety of have caused the disease, and to learn to live with the symptoms, since to date it has not been demonstratedthat this leads to deterioration of any organ in Sampling involves collecting a sample of air to be taken to the laboratory, where the agent it contains is Environmental 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 the in the environment may be important for a number of reasons109: a) it is sometimes necessary to confirm a Sampling of gases is performed in plastic, Teflon, or diagnosis of OA in the laboratory or workplace; b) aluminium bags into which air is pumped. The flow and monitoring should be used to ensure that exposure to time of use of the pump allow the concentration of the high concentrations of certain agents is prevented to agent studied to be calculated. Sampling in bags is guard against the development of OA in the workforce; limited to stable gases that do not react with the and 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 usually may sometimes be necessary to monitor the agent undertaken through adsorption on a solid such as following introduction of safety measures or workplace activated charcoal or silica gel. This can be performed 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 to measurements of possible causative agents should not be considered in isolation and should form part of the If the substance is in the form of an aerosol, dust, or general principles of industrial safety. Within this smoke, it can be captured using filters or membranes process, the following elements are often necessary: made of materials such as Teflon, cellulose, polyvinylchloride, 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 air materials until the final product is obtained. This involves exhaustive monitoring of the primary materialfrom the moment it enters the company and as it passes through the processes that alter it and may involve otherchemicals that could lead to the appearance of Various analytic techniques exist, such as gas intermediate substances or other byproducts before the final product or products are obtained.
chromatography, atomic absorption, ultraviolet, and/or 2. Inventory and identification of substances that may be 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 equipment working environment, we should look at manufacturer’s safety data sheets, which nearly always provide the simultaneously carries out analysis of air for various necessary 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 should the substances normally present in the production be used with caution in the workplace due to the process but rather a substance produced by an possibility of interference from the environmental anomalous industrial process or a substance that does not form part of the process but for one reason or Various organizations, such as the Spanish national occupational safety commission (Instituto Nacional de company; such substances may include cleaning Seguridad e Higiene en el Trabajo) have established products, 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 limits a dust, aerosol, gas, or vapor, since this can affect its appear to be inadequate either for prevention of interaction with the body and the way in which it must immunologic OA or for protection of workers who have already developed the disease. However, they maybe sufficient to protect a worker who has suffered Prior to sampling and analysis it is usually RADS and waited a sufficient period to achieve a indispensable to first focus suspicion on a specific Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 determinethe 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 concentrations of a given allergen that represent arisk.114 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 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- 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 monoclonalantibodies that recognize 2 different epitopes of theallergen, or alternatively purified polyclonal antibodies.
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 Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 particularly useful for the analysis of denatured proteins however, and it cannot be used systematically in OA since they recognize multiple epitopes.121 patients despite its high diagnostic yield. Currently, When monoclonal antibodies and/or purified noninvasive methods that are relatively easy and polyclonal antibodies are unavailable, competition or economical are available for the assessment of inhibition assays are recommended for the bronchial inflammation; the tests display good quantification of environmental allergens. The most reproducibility and they do not present complications common inhibition methods are inhibition RAST and for the patient. Such methods include analysis of induced sputum and exhaled breath condensate, and A disadvantage of inhibition methods is that in most quantification of nitric oxide (NO). Although those cases there is no international standardization and they methods were initially used for research, they are of are 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 makes it difficult to compare absolute values betweendifferent laboratories and makes it necessary to Sputum induction is a safe technique that can be establish the efficacy of the technique for each allergen.
applied without complications in day-to-day clinical The antisera used in those methods made up of IgG practice. Sputum samples containing cells and cellular antibodies from animals offer advantages over the use and extracellular products can be obtained with this of those made up of human IgE antibodies, since they technique. The most widely used method was described are used at 10-fold to 1000-fold dilutions. However, the by Pizzichini et al.127 It involves pretreatment of the use of human IgE antibodies ensures measurement of patient with inhaled salbutamol 10 minutes prior to the disease-causing substance (ie, those allergens that nebulization of increasing concentrations of hypertonic are of clinical importance), particularly when the saline solution (3%, 4%, and 5%) over a period that identity of the allergenic molecules is unknown or generally ranges from 5 to 7 minutes. Prior to and after powders are used that contain complex mixtures of the first nebulization and following each subsequent nebulization, patients are asked to blow their nose andrinse their mouth with water to minimize contaminationwith nasal secretions or saliva. The patient is then asked Is It Possible to Establish an Environmental Limit to cough (effective cough) and sputum is obtained from the lower airways in a sterile container. The test is The goal of monitoring environmental concentrations considered complete after 3 nebulizations. The of aeroallergens is not only to aid diagnosis but also to procedure is stopped if at any point a reduction of more establish the safe limit below which sensitized individuals will not display symptoms. However, to Subsequently, sputum is processed in the laboratory establish a safety limit in the case of allergens is more to separate the cell pellet from the liquid supernatant.
The pellet can be used to obtain a complete cell count concentration 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 can of specific IgE the patient has against the allergen and be used to analyze inflammatory mediators produced by the degree of bronchial hyperresponsiveness those cells.
to methacholine or histamine.114 Various authors have described the usefulness of environmental 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 the that provokes symptoms in sensitized individuals.
number of eosinophils in sputum when the patient is Various authors report that the quantity of allergen working compared with rest days can aid the diagnosis necessary for sensitization is around 100 to 1000 ng/m3, of the disease.128 In addition, a recent study reported while that necessary to provoke symptoms once an that additional analysis of cells in induced sputum individual is sensitized is around 10 ng/m3 or less.114 increases the specificity of PEF monitoring.129 Finally, it Furthermore, various studies analyzing sensitization to has also been demonstrated to be useful during specific challenge tests. In this context, Lemière et al130 concentrations above 80 µg per gram of domestic dust observed a significant increase in the number of could even sensitize healthy individuals.125 A safe limit eosinophils and neutrophils following specific bronchial to prevent sensitization and allergy has only been challenge in patients with OA caused by both high and established for a few allergens, such as wheat flour, Analysis of Inflammatory Markers
Various studies have reported abnormalities in the Inflammation can be assessed in patients with OA by concentrations of NO in respiratory diseases analyzing bronchial biopsy material obtained by characterized by inflammatory processes. This marker fiberoptic bronchoscopy. That technique is invasive, has been extensively studied in asthma and it has been Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 observed to be correlated with the number of monitor inflammation and that allows longitudinal eosinophils and the concentration of eosinophil cationic studies to be undertaken. However, analysis of this type protein in sputum. It is produced by both constitutive NO synthase (to mediate physiologic processes) and standardization to allow future comparison of data inducible NO synthase (in pathologic processes).131 The obtained in different laboratories and assessment of its systems currently used for analysis vary in complexity possible usefulness in patients with OA.
but are based on chemiluminescence techniques. Theconcentration of NO is measured in air samples as parts Impairment and Disability: Medicolegal
per billion (ppb) and the equipment calculates the Considerations
concentration of the gas over a preselected period oftime based on the guidelines of the European The concept of workplace prevention is relatively Respiratory Society and the American Thoracic recent compared with that of compensation for injury Switzerland, Germany, and Austria, began to provide demonstrated to be useful for the diagnosis and follow- compensation for industrial injury at the end of the 19th up of patients with asthma,134 its usefulness in the case century and later other countries followed suit.
of OA is less clear. Some authors have suggested that According to this system, employees agree not to take elevation of this marker is involved in the legal action for workplace injuries against the company pathophysiologic mechanism through which different that contracts them in return for financial compensation, agents cause OA. Thus, elevated concentrations of NO medical treatment, and rehabilitation paid for by private or state insurance schemes. Diseases caused by immunologic mechanisms involving IgE; this inorganic material, particularly silicosis, were the first association is less clear in patients whose asthma is and have been the most frequent motives for nonimmunologic, mediated by irritants.131 In addition, compensation. However, OA is currently surpassing it the possibility has recently been reported that as a motive for compensation in many industrialized measurement of NO during specific bronchial challenge tests may be useful to establish a positive test result The regulations affecting compensation policies vary independently of the reduction in FEV .135 according to the country or region. The difficulties associated with definition and diagnosis of the disease, concentrations than nonsmokers, administration of the involvement of factors such as atopy or smoking in inhaled corticosteroids interferes with NO synthesis, causing asthma or the difficulty in detecting the cause, and higher NO concentrations may be observed in the the possibility of prior asthma, the variability of the context of other pulmonary diseases or viral infections, disease, and its persistence following discontinuation of the use of this marker for diagnosis of OA cannot yet be work represent some factors that complicate the development of regulations. Consequently, countries prepared lists or tables of types of asthma,occupations, and causes in order to establish when compensation should be provided for OA. These were Exhaled breath contains aerosols and water vapor soon found to be too restrictive and they were not that can be condensed by freezing. The method used to updated often enough in response to new scientific tests collect the condensate by passing exhaled breath that would have obliged changes to be made. Even through a condenser, which freezes it, is noninvasive, today, although many countries accept claims for simple, and safe. The equipment that is currently available can collect 1 to 2 mL of condensate in In Spain, although the diagnosis of OA is not subject collected depends mainly on the total volume of breath to rigid criteria, when associated disability is proposed, exhaled and the temperature of the condenser.136,137 certain premises and recommendations are usually This water vapor can carry nonvolatile substances arising from the respiratory system and it is possible toanalyze volatile oxidants such as hydrogen peroxide, 1. Confirmation of occupational disease, defined as neutrophil chemoattractants such as leukotriene B4, disease contracted as a result of work activities changes in pH, concentration of nitrites and nitrates, performed as an employee and that fall within etc.134,137 There is currently increasing interest in the use established regulations, whenever the disease involves of exhaled breath condensate for proteomics studies.
substances or elements that are indicated for each Thus, some studies have reported the detection of occupational disease within the aforementioned various cytokines in this type of sample; however, due regulations (article 116 of the Spanish social to the high dilution, to perform such studies it must be security law [Ley General de la Seguridad Social] of remembered that methods with a very high sensitivity June 20, 1994). Currently, self-employed or freelance workers are also covered by the same regulations In summary, analysis of exhaled breath condensate is (Spanish Royal Decree 1273/2003, of October 20, a noninvasive technique that can be repeated in order to Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 2. Consideration of a series of diagnostic criteria.139 receipt of benefits. Periods of temporary occupational Notably, a positive bronchial challenge test is not disability for the same disease are added together until the maximum period is reached, even when periods of 3. Consideration of a series of causative agents. OA work are interspersed, so long as those periods are less appears in the section covering occupational diseases caused by chemical agents (up to 43 agents are 2. Permanent total disability for the individual’s included) and in those diseases caused by inhalation of usual occupation, when the individual can undertake a agents not included in other categories.140 Thus, it is an different one. This occurs when the individual cannot be open list that will soon be adapted to the transferred to another position in the company without recommendations of the European Commission and that continuing to be exposed to the causative agent. The can already be consulted at the web site of the Spanish level of compensation would correspond to 55% of the Health Ministry (Ministerio de Sanidad y Consumo).141 3. Qualified total permanent disability, when the Once diagnosis of OA has been made, the best option circumstances of the beneficiary suggest that they will is to relocate the patient in the workplace to a role in have difficulty in obtaining a different type of work.
which they are no longer exposed to the causative agent This can be accessed from the age of 55 years and the if the OA is caused by hypersensitivity, or return the amount can reach 75% of the calculation basis.
worker to their original role once stabilized, so long as 4. Absolute permanent disability, when the worker is the patient is not unable to perform the job and the unable to undertake any occupation. The amount of the safety conditions are appropriate, if the asthma was compensation would be 100% of the calculation basis.
caused by irritants. In this last case it would also be In the case of OA, this would occur if the disease acceptable to relocate the worker to a post in which caused symptoms that prevented the individual from they were exposed to lower levels of irritants.
undertaking any task. In such cases, the worker would If those options are not possible, disability should be have to be evaluated once he or she were stable, assessed. At this point, it is important to realize that receiving appropriate treatment, and at least 2 years there is one set of terminology that is medical and after diagnosis and without exposure to the causative another that is legal. The latter is specific to each agent, after which time it is assumed that functional country and is essentially the concept on which improvement would have plateaued. Various guidelines are available for assessment of asthma-related In relation to medical terminology, the World Health disability. Tables 5A and 5B show the guidelines of the Organization has established 3 terms142,143: 1. Impairment refers to functional deficit or loss, which in asthma would be assessed quantitatively byspirometry and the measurement of nonspecificbronchial hyperreactivity.
2. Disability refers to the difficulty or inability to 1. Bernstein IL, Bernstein DI, Chan-Yeung M, Malo JL. Definition perform a job (occupational disability) or day to day and classification of asthma. In: Bernstein IL, Chan-Yeung M, activities (general disability). This is a difficult concept Malo JL, Bernstein DI, editors. Asthma in the workplace. NewYork: Marcel Dekker; 1999. p. 1-3.
to quantify since it involves assessment both by the 2. American Thoracic Society. Guidelines for assessing and managing asthma risk at work, school, and recreation. Am J 3. Handicap refers to the negative repercussions of Respir Crit Care Med. 2004;169:873-81.
impairment and disability in the life of the individual.
3. Vandenplas O, Malo JL. Definitions and types of work-related asthma: a nosological approach. Eur Respir J. 2003;21:706-12.
Assessment of handicap does not generally form part of 4. Mapp CE, Boschetto P, Maestrelli P, Fabri LM. Occupational the evaluation for possible industrial compensation.
asthma. Am J Respir Crit Care Med. 2005;172:280-305.
5. Tarlo SM. Workplace irritant exposures: do they produce true Regarding legal terminology in Spain, the current occupational asthma? Ann Allergy Asthma Immunol. 2003;90Suppl:19-23.
legal provisions relating to these areas can be obtained 6. Chang-Yeung M, Lam S. Occupational asthma. Am Rev Respir at the web site of the Ministerio de Trabajo y Asuntos Sociales,144 where Decree 3158/66 and Spanish Royal 7. Bernstein DI. Occupational asthma caused by exposure to low- Decree 1/1994 of June 20, 1994 can be consulted along molecular-weight chemicals. Immunol Allergy Clin North Am.
with their subsequent modifications.
8. Gautrin D, Bernstein IL, Brooks S. Reactive airways dysfunction From a legal standpoint, while suffering from OA the syndrome or irritant induced asthma. In: Bernstein IL, worker may be in the following situations: ChanYeung M, Malo JL, Bernstein DI, editors. Asthma in theworkplace. New York: Marcel Dekker; 1999. p. 565-93.
Chan-Yeung M, Malo JL. Tables of major inducers of 1. Temporary occupational disability, when the occupational asthma. In: Bernstein IL, Chan-Yeung M, Malo JL, worker is temporarily disabled for the purposes of Bernstein DI, editors. Asthma in the workplace. New York: work. This is normally an observation period whilst further studies are performed or whilst the individual 10. Bernstein DI. Allergic reactions to workplace allergens. JAMA.
awaits a new work position. The maximum length of 11. Cullinan P, Newman Taylor AJ. Aetiology of occupational this period is 12 months, extendable for up to 6 more in asthma. Clin Exp Allergy. 1997;27:41-6.
Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 22. Orriols R, Costa R, Albanell M, Alberti C, Castejón J, Monsó E, Assessment of Occupational Disability in Asthma*
et al. Reported occupational respiratory disease in Catalonia.
Occup Environ Med. In press 2006.
Percentage Degree
23. Brooks SM, Weiss MR, Bernstein IL. Reactive airways Requirement
Change in Hyperresponsiveness
dysfunction syndrome (RADS): persistent asthma syndrome for Medication
PC (mg/mL)
after high level irritant exposures. Chest. 1985;88:376-84.
24. Tarlo SM, Broder I. Irritant-induced occupational asthma. Chest.
25. Bardana EJ. Reactive airway dysfunction syndrome (RADS): fact or fantasy. Allergy. 1999;54:33-5.
26. Costa R, Muñoz X, Avilés B, Drobnic ME, Orriols R. Síndrome de disfunción reactiva de las vías respiratorias. Estudio de 18 casos. Med Clin (Barc). 2005;11:419-26.
27. Matte TD, Hoffman RE, Rosenman KD, Stanbury M.
Surveillance of occupational asthma under the SENSOR model.
28. McDonald JC, Keynes HL, Meredith SK. Reported incidence of occupational asthma in the United Kingdom 1989-1997. Occup 29. Tarlo SM. Workplace respiratory irritants and asthma. Occup 30. Meredith SK, Taylor VM, McDonald JC. Occupational respiratory disease in the United Kingdom 1989: a report of the British Thoracic Society and the Society of Occupational Medicine by the SWORD project group. Br J Ind Med.
31. Venables KM, Hawkins ER, Tee RD, Longbottom JL, NewmanTaylor AJ. Smoking, atopy and laboratory animal allergy. Br J Ind Med. 1988;45:667-71.
32. Fish JE. Occupational asthma and rhinoconjunctivitis induced by natural rubber latex exposure. J Allergy Clin Immunol.
*FEV indicates forced expiratory volume in 1 second; PC , concentration in the challenge test that leads to a reduction in FEV of at least 20%.
33. Mapp CE, Beghe B, Balboni A, Zamorani G, Padoan M, Jovine †800 µg beclomethasone or equivalent.
‡1 µg beclomethasone or equivalent (>800 µg budesonide; >500 µg fluticasone; L, et al. Association between HLA genes and susceptibility to >2 mg flunisolide or triamcinolone; or >400 µg ciclesonide) toluene diisocyanate-induced asthma. Clin Exp Allergy. 2000;30:651-6.
34. Home C, Quintana PJ, Keuwn PA, Dimich-Ward H, Chang- Yeung M. Distribution of DRB1 and DQB1 HLA class alleles in Assessment of Occupational Disability in Asthma
occupational asthma due to western re cedar. Eur Respir J. 2000;15:911-4.
Overall Score
35. Newman-Taylor AJ. HLA phenotype and exposure in development of occupation asthma. Ann Allergy Asthma 36. Sastre J, Vandesplas O, Park H-S. Pathogenesis of occupational asthma. Eur Respir J. 2003;22:364-7.
37. Wan H, Winton HL, Soeller C, Tovey ER, Gruenert DC, Thompson PJ, et al. Der p1 facilitates transepithelial allergendelivery by disruption of tight functions. J Clin Invest.
12. van Kampen V, Merget R, Baur X. Occupational airway 38. Agius RM, Nee J, Mc Govern B, Robertson A. Structure activity sensitizers: an overview on the respective literature. Am J Ind hypotheses in occupational asthma caused by low molecular weight substances. Ann Occup Hyg. 1991;35:129-37.
13. Mapp CE. Agents, old and new, causing occupational asthma.
39. Newman-Taylor A. Asthma and work: the Colt Lecture, delivered at the Ninth International Symposium on Inhaled 14. Available from: www.worldallergy.org/professional/ Particles, Cambridge, September 2001. Ann Occup Hyg.
allergicdiseasecenter/occupationalallergens/index.shtml 40. Chan-Yeung M, Malo JL. Occupational asthma. N Engl J Med.
16. Available from: www.asthme.csst.qc.ca 17. Balmes J, Becklake M, Blanc P, Henneberger P, Kreiss K, Mapp 41. Venables KM, Topping MD, Howe W, Luczynska CM, CE, et al. American Thoracic Society statement: occupational Hawking R, Newman-Taylor AJ. Interactions of smoking and contribution to the burden of airway disease. Am J Respir Crit atopy in producing specific IgE antibody against a hapten protein 18. Tilles SA, Jerath-Tatum A. Differential diagnosis of 42. Biagini RE, Moorman WJ, Lewis TR, Bernstein IL. Ozone occupational asthma. Immunol Allergy Clin N Am. 2003; enhancement of platinum asthma in a primate model. Am Rev 19. Contreras GR, Rousseau R, Chang-Yeung M. Occupational 43. Park HS, Hong CS. The significance of specific IgG and IgG4 respiratory diseases in British Columbia, Canada in 1991. Occup antibodies to a reactive dye in exposed workers. Clin Exp 20. Kopferschmitt-Kubler MC, Ameille J, Popin E, Calastreng- 44. Maestrelli P, Saetta M, Mapp C, Fabri LM. Mechanisms Crinquand A, Vervloet D, Bayeux-Dunglas MC, et al.
of occupational asthma. Clin Exp Allergy. 1997;27 Suppl 1:47- Occupational asthma in France: a 1-yr report of the Obsservatoire National de Asthmes Professionels projet. Eur 45. Maestrelli P, del Prete GF, de Carli M, D’Elios MM, Saetta M, di Stefano A, et al. CD8 T-cell clones producing interleukin-5 21. Muñoz X, Cruz MJ, Orriols R, Bravo C, Espuga M, Morell F.
and interferon-gamma in bronchial mucosa of patients with Occupational asthma due to persulfate salts. Diagnosis and asthma induced by toluene diisocyanate. Scan J Work Environ Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 46. Saetta M, Di Stefano A, Maestrelli P, De Marzo N, Milani GF, 68. Vandesplas O, Malo JL, Cartier A, Perreault G, Cloutier Y.
Pivirotto F, et al. Airway mucosal inflammation in occupational Closed-circuit methodology for inhalation challenge test with asthma induced by toluene diisocyanate. Am Rev Respir Dis.
isocianates. Am Rev Respir Dis. 1992;145:582-7.
69. Orriols R, Drobnic S, Muñoz X, Rodrigo MJ, Morell F. Asma 47. Frew AJ, Chan H, Lam S, Chan-Yeung M. Bronchial ocupacional por isocianatos: estudio de 21 pacientes. Med Clin inflammation in asthma due to western red cedar. Am J Respir 70. Taivainen AI, Tukiainen HO, Terho EO, Husman KR. Powered 48. Day BW, Jin R, Basalyga DM, Kramarik JA, Karol MH, et al.
dust respirator helmets in the prevention of occupational Formation, solvolysis and transcarbamoylation reactions of asthma among farmers. Scand J Work Environ Health.
bis(s-glutathionyl) adducts of 2,4- and 2,6-diisocyanotoluene.
71. Obase Y, Shimoda T, Mitsuta K, Matsuse H, Cono S. Two 49. Elms J, Beckett PN, Griffin P, Curran AD. Mechanisms of patients with occupational asthma who returned to work with isocyanate sensitization. An in vitro approach. Toxicol in Vitro.
dust respirators. Occup Environ Med. 2000;57:62-4.
72. Marabini A, Siracusa A, Stopponni R, Tacconi C, Abbritti G.
50. Quirce S, Sastre J. Occupational asthma. Allergy. 1998;53:633- Outcome of occupational asthma in patients with continuous exposure: a 3 year longitudinal study during pharmacologic 51. Nicholson PJ, Cullinan P, Taylor AJ, Burge PS, Boyle C.
Evidence based guidelines for the prevention, identification and 73. Dewitte JD, Chan-Yeung M, Malo JL. Medicolegal and management of occupational asthma. Occup Environ Med.
compensation aspects of occupational asthma. Eur Respir J.
52. Chang-Yeung M, Malo JL. Natural history of occupational 74. Vandesplas O, Toren K, Blanc PD. Health and socioeconomic asthma. In: Chang-Yeung M, Bernstein IL, Malo JL, Bernstein impact of work-related asthma. Eur Respir J. 2003;22:689-97.
DI, editors. Asthma in the workplace and related disorders. 2nd 75. Chan-Yeung M. Assessment of asthma in the workplace. ACCP ed. New York: Marcel Dekker; 1999. p. 129-44.
consensus statement. American College of Chest Physicians.
53. Malo JL, Ghezzo M, L’Archevêgue J, Lagier F, Perrin B, Cartier A. Is the clinical history a satisfactory mean of diagnosis 76. Lemière C, Malo J-L, Boulet L. Reactive airways dysfunction occupational asthma? Am Rev Respir Dis. 1991;143:528-32.
syndrome due to chlorine: sequential bronchial biopsies and 54. Gilbert R, Auchncloss JH. Post-test probability of asthma functional assessment. Eur Respir J. 1997;10:241-4.
following methacholine challenge. Chest. 1990;97:562-5.
77. Chester E, Kaimal J, Payne CB Jr, Kohn PM. Pulmonary injury 55. Mapp CE, dal Vecchio L, Boschetto P, de Marzo N, Fabbri LM.
following exposure to chlorine gas. Possible beneficial effects of Toluene diisocyanate-induced asthma without airway steroid treatment. Chest. 1977;72:247-50.
hyperresponsiveness. Eur Respir J. 1996;68:89-95.
78. Chan-Yeung M, Lam S, Kennedy SM, Frew A. Persistent 56. Sastre J, Fernández-Nieto M, Novalbos A, de las Heras M, asthma after repeated exposure to high concentrations of gases in Cuesta J, Quirce S. Need for monitoring nonspecific bronchial pulmills. Am J Respir Crit Care Med. 1994;149:1676-80.
hyperresponsiveness before and after isocyanate inhalation 79. Bherer L, Cushman R, Courteau JP, Quevillon M, Cote G, Bourbeau J, et al. Survey of construction workers repeatedly 57. Vandenplas O, Delwiche JP, Jamart J, van de Weyer R. Increase exposed to chlorine over a three to six month period in a in nonspecific bronchial hyperresponsiveness as an early marker pulpmill: II. Follow up to affected workers by questionnaire, of bronchial response to occupational agents during inhalation spirometry, and assessment of bronchial responsiveness 18 to 24 months after exposure ended. Occup Environ Med. 1994;51:225- 58. Ruëf F, Thomas P, Reissig G, Przybilla B. Natural rubber-latex allergy in patients not intensely exposed. Allergy. 1998;53: 445- 80. Gautrin D, Leroyer C, Infante-Rivard C, Ghezzo H, Dufour JG, Girard D, et al. Longitudinal assessment of airway caliber and 59. Tee RD, Cullinan P, Welch J, Burge PS, Newman-Taylor AJ.
responsiveness in workers exposed to chlorine. Am J Respir Crit Specific IgE to isocyanates: a useful diagnostic role in occupational asthma. J Allergy Clin Immunol. 1998;101:709-15.
81. Blanc PD, Galbo M, Hiatt P, Olson KR. Morbidity following 60. Burge S, Moscato G. Physiological assessment: serial acute irritant inhalation in a population based study. JAMA.
measurements of lung function. In: Bernstein IL, Chang-Yeung M, Malo JL, et al, editors. Asthma in the workplace. New York: 82. Niven RMl, Pickering CAC. Byssinosis: a review. Thorax.
61. Leroyer C, Perfetti L, Trudeau C, L’Archevêque, Chang-Yeung 83. Pickering CAC. Byssinosis. In: Hendrick DJ, Sherwood Burge M, Malo JL. Comparison of serial monitoring of peak expiratory P, Beckett WS, Churg A, editors. Occupational disorders of the flow and FEV in the diagnosis of occupational asthma. Am J lung: recognition, management and prevention. Edinburgh: Respir Crit Care Med. 1998;158:827-32.
62. Perrin B, Lagier F, L’Archeveque J, Cartier A, Boulet LP, Cote 84. Fishwick D, Fletcher AM, Pickering CAC, Niven RML, J, et al. Occupational asthma: validity of monitoring of peak Faragher EB. Lung function, bronchial reactivity, atopic status expiratory flow rates and non-allergic bronchial responsiveness and dust exposure in Lancashire mill operatives. Am Rev Respir as compared to specific inhalation challenge. Eur Respir J.
85. Glindmeyer HW, Lefante JJ, Jones RN, Rando RJ, Weill H.
63. Anees W, Gannon PF, Huggins V, Pantin CF, Burge PS. Effect Cotton dust and across-shift change in FEV , as predictors of of peak expiratory flow data quantity on diagnostic sensitivity annual change in FEV . Am J Respir Crit Care Med.
and specificity in occupational asthma. Eur Respir J.
86. Christiani DC, Wang X-R, Pan L-D, Zhang H-X, Sun B-X, Dai 64. Gannon PFG, Newton DT, Belcher J, Pantin CF, Burge PS.
H, et al. Longitudinal changes in pulmonary function and Development of OASYS-2: a system for the analysis of serial respiratory symptoms in cotton textile workers. A 15-year measurement of peak expiratory flow in workers with suspected follow-up study. Am J Respir Crit Care Med. 2001;163:847-53.
occupational asthma. Thorax. 1996;51:484-9.
87. WHO. Recommended health-based occupational exposure limits 65. Cartier A, Malo JL. Occupational challenge tests. In: Bernstein for selected vegetables dust. Report of a WHO study group.
IL, Chang-Yeung M, Malo JL, et al, editors. Asthma in the Technical Report Series 684. Geneva: WHO; 1983.
workplace. New York: Marcel Dekker; 1993. p. 211-33.
88. Chan-Yeung M, Emerson DA, Kennedy SM. The impact of 66. Sastre J, Quirce S, Novalbos A, Lluch M, Bombin C, Umpierrez grain dust on respiratory health. Am Rev Respir Dis.
A. Occupational asthma induced by cephalosporins. Eur Respir 89. Magarolas R, Monsó E, Aguilar X, Radon K, Nowak D, 67. Hammad YY, Rando RJ, Abdel-Kader H. Considerations in the Martínez C, et al. Prevalencia y factores de riesgo de síntomas design and use of human inhalation challenge delivery systems.
respiratorios en la agricultura y la ganadería. Med Clin (Barc).
Folia Allergol Immunol Clin. 1985;32:37-44.
Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 90. Borghetti C, Magarolas R, Badorrey I, Radon K, Morera J, derived from domestic cat ( Felis domesticus) . Am Rev Resp Monsó E. Sensibilización y asma ocupacional en los avicultores.
117. Price JA, Longbottom JL. ELISA method for the measurement 91. Eduard W, Douwes J, Omenaas E, Heederick D. Do farming of airborne levels of major laboratory animal allergens. Clin exposures cause or prevent asthma? Results from a study of adult Norwegian farmers. Thorax. 2004;59:381-6.
118. Lillienberg L, Baur X, Doekes G, Belin L, Raulf-Heimsoth M, 92. Soyseth V, Kongerud J, Ekstrand J, Boe J. Relation between Sander I, et al. Comparison of four methods to assess fungal exposure to fluoride and bronchial responsiveness in aluminium amylase in flour dust. Ann Occup Hyg. 2000;44:427-33.
potroom workers with work-related asthma-like symptoms.
119. Raulf-Heimsoth M, Sander I, Chez Z, Borowitzki G, Diewald K, van Kampen V, et al. Development of a monoclonal antibody- 93. Tarlo SM, Leung K, Broder I, Silverman F, Holness DL.
based sandwich ELISA for detection of the latex allergen Hev b Asthmatic subjects symptomatically worse at work: prevalence 1. Int Arch Allergy Immunol. 2000;123:236-41.
and characterization among a general asthma clinic population.
120. Zahradnik E, Raulf-Heimsoth M, Brüning T, Doekes G, Sander I. Development of a sandwich enzyme immunoassay for 94. Gibson PG, Fujimura M, Niimi A. Eosinophilic bronchitis: quantification of phytase derived from Aspergillus niger clinical manifestations and implication for treatment. Thorax.
[abstract]. Actas del Exposure Assessment in a Changing Environment Congress; 2004; p. 49. 28-5. Utrecht, The 95. Quirce S. Eosinophilic bronchitis in the workplace. Curr Opin 121. Coligan JE, Kruisbeek AM, Margulies DH, Shevach EM, 96. Quirce S, Fernández-Nieto M, De Miguel J, Sastre J. Chronic Strober W. Antibody detection and preparation. In: Coligan JE, cough due to latex-induced eosinophilic bronchitis. J Allergy Kruisbeek AM, Margulies DH, Shevach EM, Strober W, editors.
Current protocols in immunology. New York: John Wiley & 97. Ryu JH, Myers JL, Swensen SJ. Bronchiolar disorders. Am J Respir Crit Care Med. 2003;168:1277-92.
122. Renström A, Gordon S, Hollander A, Spithoven J, Larsson PH, 98. Orriols R, Bravo C. Bronquiolitis obliterante: dificultades de la Venables KM, et al. Comparison of methods to assess airborne definición. Arch Bronconeumol. 1995;31:1-2.
rat and mouse allergen levels II. Factors influencing antigen 99. Kreiss K, Gomaa A, Kullman G, Fedan K, Simoes EJ, Enright PL. Clinical bronchiolitis obliterans in workers at a microwave- 123. Renström A, Gordon S, Larsson PH, Tee RD, Newman-Taylor popcorn plant. N Engl J Med. 2002;347:330-8.
AJ, Malmberg P. Comparison of a radioallergosorbent (RAST) 100. Boag AH, Colby TV, Fraire AE, Kuhn C, Roggli VL, Travis inhibition method and a monoclonal enzyme-linked WD. The pathology of interstitial lung disease in nylon flock immunosorbent assay (ELISA) for aeroallergen measurement.
workers. Am J Surg Pathol. 1999;23:1539-45.
101. Orriols R, Manresa JM, Aliaga JLL, Codina R, Rodrigo MJ, 124. Cruz MJ, Rodrigo MJ, Antó JM, Morell F. An amplified Morell F. Mollusk shell hypersensitivity pneumonitis. Ann ELISAinhibition method for the measurement of airborne soybean allergens. Int Arch Allergy Clin Immunol. 2000;122:42-8.
102. Morell F, Roger A, Cruz MJ, Muñoz X, Rodrigo MJ. Suberosis.
125. Platts-Mills TA, Sporik RB, Wheatley LM, Heymann PW. Is Clinical study and new etiologic agents in a series of eight there a dose-response relationship between exposure to indoor allergens and symptoms of asthma? J Allergy Clin Immunol.
103. Patel AM, Ryu JH, Reed CE. Hypersensitivity pneumonitis: current concepts and future questions. J Allergy Clin Immunol.
126. Baur X. Are we closer to developing threshold limit values for allergens in the workplace? Ann Allergy Asthma Immunol.
104. Orriols R, Aliaga JLL, Antó JM, Ferrer A, Hernández A, Rodrigo MJ, et al. High prevalence of mollusc shell 127. Pizzichini E, Pizzichini MM, Efthimiadis A, Evans S, Morris hypersensitivity pneumonitis in nacre factory workers. Eur MM, Squillace D, et al. Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase 105. Lacasse Y, Selman M, Costabel U, Dalphin J, Ando M, Morell measurements. Am J Resp Crit Care Med. 1996;154:308-17.
F, et al. Clinical diagnosis of hypersensitivity pneumonitis. Am J 128. Lemière C, Pizzichini MM, Balkissoon R, Clelland L, Respir Crit Care Med. 2003;168:952-8.
Efthimiadis A, O’Sy D, et al. Diagnosing occupational asthma: 106. Newman KB, Mason UG, Schmaling KB. Clinical features of use of induced sputum. Eur Respir J. 1999;13:482-8.
vocal cord dysfunction. Am J Respir Crit Care Med. 1995;152: 129. Girard F, Chaboilliez S, Cartier A, Coté J, Hargreave F, Labrecque M, et al. An effective strategy for diagnosing occupational asthma.
107. Perkner JJ, Fennelly KP, Balkissoon R, Bartelson BB, Ruttenber Am J Respir Crit Care Med. 2004;170:845-50.
AJ, Wood RP, et al. Irritant-associated vocal cord dysfunction. J 130. Lemière C, Chaboilliez S, Malo JL, Cartier A. Changes in sputum cell counts after exposure to occupational agents: What 108. Cullen MR. The worker with multiple chemical sensitivities: an do they mean? J Allergy Clin Immunol. 2001;107:1063-8.
131. Lemière C. Non-invasive assessment of airway inflamation in 109. Lesage J, Perrault G. Environmental monitoring of chemical occupational lung diseases. Curr Opin Allergy Clin Immunol.
agents. In: Bernstein IL, Chan-Yeung M, Malo J-L, Bernstein DI, editors. Asthma in the workplace. New York: Marcel 132. Kharitonov S, Alving K, Barnes PJ. Exhaled and nasal nitric oxide measurements: recomendations. The European Respiratory 110. Available from: www.mtas.es/insht/mta Society Task Force. Eur Respir J. 1997;10:1683-93.
111. Available from: www.cdc.gov/niosh/nmam/nmammenu.html 133. American Thoracic Society. Recommendations for standardized 112. Available from: www.osha.gov/dts/sltc/methods/index.html procedures for the online and offline measurement of exhaled 113. Instituto Nacional de Seguridad e Higiene en el Trabajo. Límites lower respiratory nitric oxide and nasal nitric oxide in adults and de exposición profesional para agentes químicos en España.
children. Am J Respir Crit Care Med. 1999;160:2104-17.
Madrid: Ministerio de Trabajo y Asuntos Sociales. Instituto 134. Kharitonov S, Barnes PJ. Exhaled markers of pulmonary disease.
Nacional de Seguridad e Higiene en el Trabajo; 2003.
Am J Respir Crit Care Med. 2001;163:1693-722.
114. Reed CE, Swanson MC, Li JT. Environmental monitoring of 135. Campo P, Lummus ZL, Bernstein D. Advances in methods used protein aeroallergens. In: Bernstein IL, Chang-Yeung M, Malo in evaluation of occupational asthma. Curr Opin Pulm Med.
JL, Bernstein DJ, editors. Asthma in the workplace. 2nd ed. New York: Marcel Dekker Inc.; 1999. p. 235-55.
136. Montuschi P, Barnes P. Analysis of exhaled breath condensate 115. Price JA, Pollock I, Little SA, Longbottom JL, Warner JO.
for monitoring airway inflammation. Trends Pharmacol Sci.
Measurement of airborne mite antigen in homes of asthmatic 137. Hunt J. Exhaled breath condensate: an envolving tool for 116. Luczynska CM, Li Y, Chapman MD, Platts-Mills TAE.
noninvasive evaluation of lung disease. J Allergy Clin Immunol.
Airborne concentrations and particle size distribution of allergen Document downloaded from http://www.archbronconeumol.org, day 01/09/2009. 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 138. Bernstein IL, Keskiene H, Malo J-L. Medicolegal and 142. WHO. International classification of impairment, disabilities and compensation aspects. In: Bersntein IL, Chang-Yeung M, Malo JL,Bernstein DJ, editors. Ashtma in the workplace. New York: 143. WHO. CIDDM-2. Clasificación internacional del funcionamiento de la discapacidad y de la salud. 2001. Available from: 139. Available from: www.mtas.es/insh/ntp/ntp-327.htm 140. Cuadro de enfermedades profesionales. Real Decreto 1995/1978 144. Available from: www.mtas.es/guia2003/texto/30/30.6.html del 12 de mayo. BOE núm. 25, de agosto de 1978.
145. American Thoracic Society (ATS). Guidelines for the evaluation 141. Available from: www.mcs.es/Diseno/medioAmbient_salud_ of impairment/disability in patients with asthma. Am Rev Respir

Source: http://www.allergya.ru/statii/astma/2006GuidelinesforOccupationalAsthma.pdf


South Oxfordshire Riding Club Open Show Sunday 26/6/2011 Class 1 Mini Jumping: 1st Alice Beauchamp (Rayio Heartbreaker), 2nd Judith Millward (Chicnoir Roerie), 3rd Sarah Robertson - SORC (First Vintage), 4th J Smeeton (Harley), 5th Katie Kennett - SORC (As Sweet As Honey), 6th G Sinclair (Bethany), 7th Josh Simons (Nanna Moon), 8th Katy Jones (Jasper), 9th Linda Shortt - SORC (Samars's

Cyprus 3rd periodical report

EUROPEAN CHARTER FOR REGIONAL OR MINORITY LANGUAGES Third periodical report presented to the Secretary General of the Council of Europe in accordance with Article 15 of the Charter EUROPEAN CHARTER FOR REGIONAL OR MINORITY LANGUAGES THIRD PERIODICAL REPORT BY THE REPUBLIC OF CYPRUS OFFICE OF THE Nicosia, LAW COMMISSIONER 18 January 2011 Introd

Copyright ©2018 Drugstore Pdf Search