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RECOMMENDATIONS OF THE SPANISH SOCIETY OF PULMONOLOGY AND THORACIC SURGERY (SEPAR)
Guidelines for Occupational Asthma
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. Introduction Classification
Occupational asthma (OA) is the most common
The following types of OA are distinguished
occupational disease in industrialized countries and it is
according to the pathogenesis of the disease1-4:
estimated that approximately 15% of all adult asthma is
1. Immunologic OA or OA caused by hypersensitivity.
occupational in origin. Correct diagnosis and early
This requires a period of time for sensitization to the
management are key factors affecting disease prognosis
causative agent to develop, and therefore, there is a
and socioeconomic consequences. The individual
latent period between exposure and the appearance of
patient is not the only one affected when measures are
symptoms. The following subtypes are distinguished
taken; the consequent changes in working conditions
according to the substances responsible for causing the
can also prevent the appearance of other cases at the
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
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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
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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
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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 Characteristics IgE-Mediated Non-IgE-Mediated
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
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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
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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.
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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
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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
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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,
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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
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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
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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
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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
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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:
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