Diagnosis of Occupational Asthma: An Update
Work-related asthma (WRA) includes patients with sensitizer- and/or irritant-induced asthma in the workplace, as well as patients with preexisting asthma that is worsened by work factors. WRA is underdiagnosed; thus, the diagnosis is critical to prevent disease progression and its potential for morbidity and mortality. The interview is the first diagnostic tool to be used by physicians, and the question, “Does asthma improve away from work?” is of the highest sensitivity. However, history can show numerous false positives, and the relationships between asthma worsening and work should be confirmed by objective methods such as peak expiratory flow (PEF) at and away from work. PEF sensitivity and specificity can be enhanced in combination with nonspecific bronchial hyperresponsiveness to histamine/methacholine (NSBP) before and after 2 weeks at work and a similar period off work. Immunologic testing, especially skin prick test (SPT) or specific IgE, is useful for high molecular weight allergens and some low molecular weight agents. Other immunologic tests, as well as induced sputum, measurement of exhaled nitric oxide, exhaled breath condensate, and specific inhalation challenge (SIC) are methods that contribute to the diagnosis and are typically performed at specialized facilities. A diagnosis of occupational asthma (OA) should no longer be based on a compatible history only but should be confirmed by means of objective testing. SIC is the diagnostic gold standard. When SIC is not available, the combination of PEF measurement, NSBP test , a specific SPT, or specific IgE may be an appropriate alternative in diagnosing OA.
KeywordsOccupational asthma Diagnosis Work related Peak expiratory flow Serial PEF measurement
In sensitizer-induced OA, avoiding allergen inhalation increases the possibility of improvement or cure [14, 15, 16], particularly during the first year after onset of symptoms [17, 18, 19]. Early diagnosis and removal from exposure is the most effective way to prevent progression to moderate and severe asthma with the corresponding burden of morbidity and disability. Workers exposed to the occupational agent, even after adoption of preventive measures to reduce exposure, usually present a steeper lung function decline than those who cease exposure. This difference becomes significant after 4 years from the cessation of exposure . Upon detection of a worker with OA in the workplace, primary prevention involves taking measures to avoid exposure to agents that can cause asthma, therefore inhibiting new occurrences in coworkers .
The diagnosis requires first that bronchial asthma be diagnosed (spirometry with reversibility test, peak expiratory flow [PEF] variability, and/or airway hyperreactivity [AHR] test), then that the relationship with work be established, and that the offending sensitizers or irritants in the workplace be identified.
Patients with asthma should be asked about their work. The interview is essential for the diagnosis of OA and should be as detailed and thorough as possible. Symptoms appear or worsen in the work environment and improve away from work , but they can also occur after the working day as late asthmatic responses, which are relatively frequent with occupational allergens, particularly those of low molecular weight (LMW) [1, 15, 23]. Temporal relationships between symptoms and work are essential, as are the agents to which patients are and have been previously exposed. Occupational asthma due to sensitizers occurs with a latency period—the period between the beginning of exposure and the onset of symptoms—ranging from weeks to years. The latency period is typically within 2 years for LMW sensitizers, such as isocyanates and plicatic acid, and for some high molecular weight (HMW) sensitizers, such as laboratory animals and enzymes [8••, 24], while it is slightly longer for most HMW sensitizers, such as flour or latex [3, 25, 26, 27]. Once sensitization is present, the response to work exposures can be immediate (within minutes of such exposure), late, or dual .
Do asthma symptoms improve during weekends or holidays?
Positive responses are given by 88 % of the patients with confirmed sensitizer-induced OA, but also in 76 % of patients with non-OA . Of those patients with asthma that was not work related, 41 % and 54 %, respectively, reported improvement during weekends and holidays, emphasizing the need for additional objective tests for accurate diagnosis [1, 22].
Were there changes in work processes in the period preceding the onset of symptoms?
Such changes could expose the worker to new agents or to increased levels of an agent that was previously present. Sensitizing agents carry the greatest risk for sensitization and OA, especially in the first few years of exposure, although this can occur after many years of ongoing contact . WEA could occur from a change in the work environment, with increased exposure to conditions triggering asthma.
Was there an unusual work exposure within 24 h before the onset of initial asthma symptoms?
A positive response raises the suspicion of RADS (reactive airways dysfunction syndrome) [1, 28, 29, 30, 31, 32, 33]. Typically, the symptoms of the initial event are severe enough to require first aid or emergency treatment . Irritant-induced OA comprises those cases that do not meet these criteria (eg, those in which there is a lag of several days after the episode, or after repeated fewer severe exposures over days or weeks) [31, 32, 33, 34].
Are there symptoms of allergic rhinitis and/or conjunctivitis symptoms that are worse with work?
The presence of rhinoconjunctivitis worsening at work in addition to wheezing increases the probability of OA from HMW sensitizers and is less consistent from LMW sensitizers [35, 36, 37]. Rhinoconjunctivitis may precede or concur with the onset of OA. The risk of the development of OA is higher in patients with rhinoconjunctivitis, especially during the first year after the onset of the upper airway disease [9•].
Wheezing at work was the most specific symptom in the study carried out by Vandenplas et al. . In this study, no factors were significantly associated with the presence or absence of OA due to LMWagents, while in subjects exposed to HMWagents, improvement in symptoms during weekends and on vacations was the most sensitive symptom, although it was less specific . Dysphonia worsening at work is negatively associated with OA , as vocal cord dysfunction is frequently confused with asthma. More than 70 % of the patients with sensitizer-induced OA have a typical history, but given their low specificity, the relationship between asthma and work should be confirmed by objective tests. In the study by Vandenplas et al. , positive responses correctly predicted only 42 % of OA cases. In patients with irritant-induced OA, the key to a correct diagnosis is based on careful history taking as well as the objective measurement of airflow reversible obstruction or bronchial hyperreactivity . Diagnosis of WEA in patients with preexisting asthma is usually based on history, increased medication use, and/or emergency department visits or hospitalizations during work periods.
Exposure to Agents Leading to Onset or Exacerbation of Bronchial Asthma
Exposure history should focus on exposures occurring at the time that asthma started or worsened. There are more than 250 sensitizers described for various industries and work environments, many of which are listed on http://www.asmanet.com. Multiple exposures can occur in the same work area, termed mixed environments, with both sensitizers and irritants, which can increase the risk of asthma [1, 2••, 7, 38]. The risk of sensitization and onset of OA increases as the level and frequency of exposures are higher [39, 40]. The use of masks and other methods to reduce exposure might not completely protect against sensitization. Skin contact with the sensitizer may be an important factor, as it has been proven in isocyanate asthma [41, 42, 43]. Seven of the 10 most common occupational contact allergens are possible causes of OA (epoxy resin, nickel sulfate, cobalt chloride, potassium dichromate, p-phenylenediamine, formaldehyde, and glutaraldehyde) . Material safety data sheets are valuable tools for physicians and can be requested of the employee or checked on the Web (eg, http://www.msds.com or http://www.ilpi.com/msds), but they may not identify sensitizing substances as such, particularly if present in low concentrations (ie, <1 %) . Other important sources of information are workplace site visits, industrial hygiene reports, and symptom reports of other workers [2••].
Objective Tests for Work-Related Asthma
Despite the low specificity of history taking for the diagnosis of OA, 60 % of occupational physicians and pulmonologists in the United Kingdom diagnose OA and adopt work-related measures based on the history alone . In the presence of a patient with confirmed bronchial asthma, and with a history suggestive of WRA, such a relationship should be confirmed by objective tests [1, 2••, 22, 23, 39].
Serial PEF Recording
Serial PEF recording at work and away from work explores the relationship between lung function and actual work exposure. This is the method most frequently used for lung function testing, as it is inexpensive, noninvasive, and both specific and sensitive [1, 23, 39]. In a study carried out by Beach et al. , the sensitivity of PEF in comparison with specific inhalation challenge (SIC) was 64 % .
PEF data can be recorded in a diary that can also be used to record symptoms and specific tasks at work. Data loggers are useful because they prevent the possibility of errors or fabrication of PEF recordings.
The frequency and duration of PEF recordings are still controversial, although the more frequent and prolonged the measurements, the higher the sensitivity and specificity of the methods, but at the same time, adherence and correct data recording are reduced. The duration of testing should allow for workplace exposures to affect PEF or for recovery to occur away from exposure, and this may take several days. Therefore, a recording period of 4 weeks is recommended, and at least 1 week away from work. The diagnostic performance of serial peak flow measurements falls when fewer than four readings per day are made and records are shorter than 3 weeks [8••, 9•]. The patient should be as stable as possible, and medication should be minimal and remain unchanged throughout the testing period. Changes in work shifts should also be recorded, as they will affect interpretation. Exposure to irritants or intercurrent infections should be similarly documented .
Worsening during a workday that remains unchanged during the work week and improves on the weekend or other days off work.
Worsening during the work day with progressive aggravation over the work week and worsening over successive weeks of work.
Intermittent fall in PEF during the work week, with improvement after several days away from work .
Determine the difference between maximum and minimum PEF during the day. Establish the number of days with a difference greater than 20 % during work period and compare it with days off work .
To improve the variability in the interoperation of recordings among different professionals, a computer-assisted diagnostic aid has been developed that is based on a visual analysis OASYS 2 (Occupational Asthma SYStem) . However, differences between expert interpretation of PEF records and the computer-based system still persist . By calculating the area under the curve of these computerized recordings, diagnostic sensitivity and specificity can be improved and measurements can be performed over shorter periods, although more measurements per day will be required. When PEF was recorded 8 times per day during 8 workdays and 3 rest days, sensitivity was 68 % and specificity 91 % . Anees et al.  studied the minimum requirements for records of adequate quality and obtained good sensitivity and specificity with four readings per day during more than 2.5 weeks and more than 3 consecutive days in each period.
The use of PEF values over different hourly periods is based on a similar method introduced by Stenton et al.  (using forced expiratory volume in 1 s [FEV1]) to detect late asthmatic responses in inhalation challenge tests. The advantage is the minimization of the effect of the circadian rhythm on bronchial variability. A minimum of four time point comparisons were needed. Records with more than 2 time points significantly lower on workdays had a sensitivity of 67 % and a specificity of 99 % for the diagnosis of OA against independent diagnoses. Time point analysis complements other validated methods of PEF analysis .
Anees et al. [53•] studied different PEF variability indices and found the mean PEF between workdays and rest days is the best simple index for differentiating subjects with OA from those with non-OA or irritant-exposed healthy subjects, with a sensitivity of 70 %. Differences of 16 L/min or greater were significant for such differentiation [53•].
The methacholine and/or histamine challenge tests are used for the diagnosis of OA. The tests are performed toward the end of the work week and are repeated over a period of 10 to 14 days off work. The threefold or greater change (the regular positivity threshold of this method) in methacholine /histamine concentration required to cause a 20 % fall in FEV1 (PC20)  would indicate workers are sensitive to an agent in the workplace . A smaller shift in PC20 would be less definitive in the diagnosis . Patient-related factors such as a high or low respiratory infection within the 6 weeks prior to testing , exposure to allergens, the use of inhaled corticosteroids , or the presence of gastroesophageal reflux , among others, can impact the results of this test. Such factors must be considered when evaluating results. Results are more reliable when baseline FEV1 is similar among tests . In some patients with longstanding OA from a sensitizer and with airway remodeling, AHR improvements may be very slow and may take months or even years once exposure is finished. This test is of lower sensitivity and specificity in comparison with the specific inhalation challenge .
This test can be positive in WEA with no sensitization. In a study of OA and rhinitis in bakers, AHR determined by histamine (PC20 <8 mg/ml) had a diagnostic sensitivity of 67.6 % and a specificity of 73.6 %. When combined with a positive skin prick test to occupational allergens, such as flour or α-amylase, sensitivity was close to 90 % .
In a recent study, Malo et al.  found that the level of sputum eosinophils provides slightly higher positive predictive values than PC20 for the likelihood of presenting OA in comparison with non-OA. AHR was more often normal (PC20 >16 mg) on the control day before specific exposure in workers with OA (27 % instances) in comparison with non-OA patients (8 %). This finding can be accounted for by a mean time away from work of 76 days in this group, thereby stopping exposure to the relevant occupational agent .
In conclusion, although the sensitivity and specificity of serial AHR testing have not been defined, careful measurements appear as an additional and useful tool for the diagnosis of OA. The ACCP Consensus recommends the following: “In individuals with suspected sensitizer-induced OA, working at the job in question, perform a methacholine challenge test or obtain comparable measurements of non-specific airway responsiveness during a working period and repeat it during a period (optimally, at least 2 weeks) away from the work to identify work-related changes” . A single measurement of nonspecific reactivity has only moderate specificity and sensitivity for the validation of OA [8••, 9•].
Specific Immunologic Testing
HMW AgentsIn OA induced by HMW agents, specific IgE is usually present.
SPTs. They are more sensitive than in vitro tests [55, 63]. Reagents for some of these agents are commercially available (ie, for latex, bee venom, food [flour], and animal epithelia). However, commercial skin test reagents are not available for many of this kind of occupational agents. Negative skin test cannot entirely exclude the diagnosis but can make it very unlikely. A positive skin test confirms sensitization but does not confirm OA .
Serological tests for specific IgE. Several occupational allergens and components are available in order to assess for some HMW, but also to some LMW allergens (Phadia ImmunoCAP) (Table 1).
Phadia ImmunoCAP occupational allergens for in vitro specific IgE measurement
Abachi wood dust
Green coffee bean
Hexahydrophtalic anhydrid (HHPA)
Trimellitic anhydride (TMA)
When there is a suggestive history, objective test to confirm asthma and specific IgE sensitivity for an allergen present at work is highly indicative of OA, even more so if a decline in lung function is evidenced after workplace exposure. This test has a high sensitivity and negative predictive value; thus. a negative SPT could potentially rule out the OA induced by this allergen [1, 64]. In a study that included health care workers and food processors exposed to latex carried out by Vandenplas et al. , the SPT showed a sensitivity of 100 % and a specificity of 21 % when compared with the results of the specific inhalation challenge (SIC). All the subjects with positive SIC results had positive SPTs, while the SPT was positive in 79 % with negative SICs. The latter group experienced contact dermatitis while wearing latex gloves as well as rhinitis during SIC . In workers exposed to amylase and other industrial enzymes, Merget et al.  found the SPT had a sensitivity of 100 % and a specificity of 86 % when compared with bronchial provocation tests, while sensitivity was 62 % and specificity 96 % against a specific serum IgE. These tests can become negative when the worker is no longer exposed to the agent, as the estimated half-life of serum-specific IgE for detergent enzymes is about 20 to 21 months . Conversely, Wiszniewska et al.  found low sensitivity for SPT in OA of bakers (72.8 % to occupational allergens, 41.7 % to wheat flour).
In conclusion, both SPTs and serological tests are sensitive for detecting specific IgE and OA caused by most HMW agents but are not specific for diagnosing asthma [9•].
The immunologic mechanisms involved in LMW-induced OA tend to be complex. Some agents have been associated with specific IgE antibodies (eg, acid anhydride compounds, chloramine, persulfates, reactive dyes, and platinum salts) ; however, the sensitivity of specific IgE detection explored by SPT and/or specific IgE by ImmunoCAP (Table 1) is typically lower than with HMW proteins.
No standardized allergens are commercially available for prick test, and the agent acts as a hapten and must bind to proteins to be able to attach to immunocompetent cells. Reagents are thus prepared by combining the agent with human serum albumin (HSA), but this process may not be applicable to all chemical sensitizers. In a study with (phthalic, maleic, trimellitic, and pyromellitic) acid anhydrides conjugated with HSA that included nine exposed patients with symptoms, Baur and Czuppon  found positive SPT and positive serum specific IgE in four and six patients, respectively. Park et al.  evaluated 42 patients with OA from reactive dyes confirmed by bronchial challenge test. SPT was positive in 76 % of the patients, and serum IgE detection by ELISA in 54 %, with a specificity of 91 % and 86 %, respectively. Positive predictive values were 80 % versus 63 %, and negative predictive values were 89 % versus 80 %, which shows better results for SPTs than for the in vitro tests.
In workers with isocyanate-induced OA confirmed by provocation tests or workplace challenge, IgE specific to isocyanate HSA has been detected in 18 % to 27 % of the cases, with a specificity of 96 % to 98 % . The half-life of specific IgE is around 6 months. Specific IgG antibodies, on the other hand, appear to be a marker for exposure. In a study with apprentice car painters exposed to hexamethylene diisocyanates, Dragos et al.  found increased levels of specific IgE and IgG in subgroups of these workers associated with duration of exposure. Specific IgG was inversely related to the development of work-related lower respiratory symptoms, and specific IgG4 was negatively associated with nasal symptoms, suggesting a protective effect on the work-related respiratory symptoms.
Other Tests (Only to Be Used in Research)
Another laboratory test used for isocyanate asthma is the production of monocyte chemoattractant protein-1 (MCP-1) by mononuclear cells after coincubation with isocyanate HSA. In a study with 54 exposed workers, sensitivity and specificity of the MCP-1 test were 79 % and 91 %, respectively, in comparison with specific provocation tests .
Measurement of cytokines in the sera of subjects exposed to isocyanates showed that matrix metalloproteinase (MMP)-9 combined with vascular endothelial growth factor (VEGF) and interleukin (IL)-8 was the best combination to detect OA, with a sensitivity of 82.6 % and a specificity of 75.8 %. MMP-9 was the cytokine of higher specificity and sensitivity (80 % and 79.7 %), and could be used as a single test for early diagnosis of isocyanate asthma .
Specific Inhalation Challenge
This test involves exposing patients to the suspected sensitizer. The SIC has often been considered the “gold standard” for the diagnosis of OA; however, the AHRQ (Agency for Healthcare Quality and Research) review  and the ACCP Consensus Statement  recommend the use of “reference standard,” as false-positive and false-negative tests can be found, there is yet no definitive diagnostic test for OA, and its availability is limited to specialized centers.
The form of inhalation may vary according to the agent characteristics (eg, water-soluble proteins or volatile chemical compounds) and the work activity, always trying to simulate exposure conditions at the workplace. Bronchial provocation test, nebulizing the substance in increasing doses to obtain a fall in FEV1, can be used, but in most LMW agents, exposure chambers are required. Regardless of the method, the purpose is to expose the patient to increasing doses of the suspected agent to reach a fall in expiratory flows, an increase in airway responsiveness, and/or an increase in inflammation markers [73, 74]. The patient must be stable, and the challenge is first performed with a control agent and then with the active substance on different days. Newly commercialized closed-circuit devices allow the performance of challenges with various HMW and LMW substances and a very good control of the level of exposure, which increases the safety of the procedure .
HMW agents typically produce immediate reactions, defined as a fall in FEV1 of 20 % or greater within the first hour after the exposure, as well as dual responses, in which the initial fall is reverted and a new fall of FEV1 15 % to 20 % or greater occurs 2 to 8 h after the exposure (late reaction). LMW agents tend to produce immediate, late, dual, and atypical responses [73, 76].
Dufour et al.  studied the responses of 247 patients and found similar falls in FEV1 for HMW and LMW agents, with LMW agents inducing more frequently late or dual responses and higher increases in airway responsiveness after the challenge. Patients exposed to HMW agents with late responses experienced a higher increase in AHR than those with immediate reactions alone. All the patients with atypical reactions were sensitized to LMW agents. The potential risk of these reactions and of isolated late responses has limited the use of this tool.
The SIC is performed in specialized centers and can confirm the diagnosis when the findings of other tests have been inconclusive. It can identify the specific agent if the worker is exposed to more than one OA-causative agent [1, 23, 76]. False-negative responses can occur, for instance, in cases of loss of specific airway responsiveness away from exposure, inadequate concentration or timing of the exposure, or the use of medications to treat asthma before the challenge. Measuring airway responsiveness before and after challenges may reduce the number of false-negative tests by detecting changes in AHR even without significant changes in FEV1 during the test .
When an offending agent cannot be identified or an SIC is not available, an inhalation challenge may be undertaken in the field or at the workplace by monitoring spirometry before and after the worker’s natural exposure [1, 78].
The ACCP Consensus Statement established that “in individuals with suspected sensitizer-induced OA, conducting a SIC (where available) is suggested when the diagnosis or causative agent remains equivocal; however, this testing should only be performed in specialized facilities, with medical supervision throughout the testing” .
Sputum eosinophils and neutrophils increase after exposure to both HMW and LMW agents such as isocyanates, cyanoacrylates, or red cedar . Lemière et al. . compared induced sputum in workers with respiratory symptoms after exposure to occupational agents, in workers with OA, and in asthmatic subjects without any history of OA. Eosinophils increased in 13 of 17 patients with OA and in 2 of 14 subjects with respiratory symptoms after exposure. No changes were found in asthmatic patients with no OA exposed to flour and cyanoacrylate.
The same group studied the kinetics of changes in sputum after exposure to increasing doses of different HMW and LMW sensitizers over 3 days and found an increase in sputum eosinophils, IL-5, and eotaxin before the significant fall (20 %) in FEV1 and the increase in PC20 to methacholine .
Girard et al. . evaluated 49 subjects suspected of having OA. Monitoring of PEF was performed during 2 weeks at and away from work. At the end of each period, induced sputum was collected, and SIC was performed at the end of the second period. OA was confirmed in 23 patients by SIC. Increase of eosinophils by greater than 1 % increased the specificity of PEF by 18 % and sensitivity by 8.2 %. When the cutoff value in eosinophils was greater than 2 %, specificity increased by 26.8 % and sensitivity decreased by 12.3 %.
In conclusion, the addition of induced sputum to the monitoring of PEF increased the specificity of this test, and its analysis can contribute to early diagnosis of OA but is still a research tool [74, 81, 82, 83].
Exhaled Nitric Oxide
Studies evaluating exhaled nitric oxide (ENO) in relation to work exposures or provocation tests in patients with sensitizer-induced OA have yielded dissimilar results. Allmers et al.  studied 27 subjects with isocyanate- and latex-induced OA and found no clear relationship between bronchial response, substance-specific IgE, and an increase in ENO levels . Baur and Barbinova  described an increase in ENO levels within 24 hours of positive challenge tests, with good correlation with bronchial obstruction. The same authors also found an increase in ENO levels in two thirds of the workers exposed to isocyanates who exhibited BHR, but also in half of the patients with AHR not exposed to isocyanates. Only an increase of greater than 50 % in ENO levels in combination with AHR was predictive of clinical symptoms during the challenge .
In 42 patients with OA from Poland, increased ENO levels were observed 24 hours after the SIC, while eosinophils in sputum increased at both 4 and 24 h after the SIC . Piipari et al.  investigated 40 workers with suspected OA in Finland and found that in those with positive challenges, ENO levels were elevated 24 h after the challenge only if they had a normal or slightly increased basal nitric oxide concentration.
Lemière et al.  evaluated a group of workers with suspected OA and found that in subjects with a positive challenge, an increase of 2.2 % or greater in induced sputum eosinophils achieved a much higher sensitivity and positive predictive value than a 10-ppb change in ENO. The authors concluded that sputum eosinophil counts constitute a more reliable tool than ENO to distinguish positive and negative SIC.
In a study that included baker, pastry maker, and hairdresser apprentices, Tossa et al.  analyzed the ENO levels over the 2 years of occupational training and found that the increase in ENO was associated with the incidence of BHR in both atopic and nonatopic subjects.
Exhaled Breath Condensate
Ferrazzoni et al.  measured pH of EBC, eosinophils in sputum, and ENO after specific inhalation challenges with isocyanates in sensitized subjects and in a control group. They demonstrated an increase in eosinophils and in ENO 24 hours after the challenge, but no acidification of EBC .
Practical Approach to the Diagnosis
Summary of major recommendations of the British Occupational Health Research Foundation (BOHRF) with revised SIGN grading levels
Occupational rhinitis and occupational asthma frequently occur as co-morbid conditions in IgE associated occupational asthma (ES12** SIGN 2+)
The risk of developing occupational asthma is highest in the year after onset of occupational rhinitis (ES14* SIGN 22)
Pre to post shift changes in lung function cannot be recommended for the validation or exclusion of occupational asthma (ES27* SIGN 3)
The sensitivity and specificity of serial peak expiratory flow (PEF) measurements are high in the diagnosis of occupational asthma (ES31** SIGN 3)
Changes in non-specific bronchial responsiveness at and away from work have only moderate sensitivity and specificity for diagnosis (ES35** SIGN 22)
Both skin prick and serological tests are highly sensitive for detecting specific IgE and occupational asthma caused by most HMW agents, but are not specific for diagnosing occupational asthma (ES37** SIGN 2+)
WRA is a common form of respiratory disease and still poses important diagnostic challenges. Physicians must keep in mind this possibility when evaluating an adult asthma patient. The clinical questionnaire is a simple and inexpensive tool, but relationships between asthma worsening and work should be confirmed by objective methods. A combination of different methods, including serial PFE measurements at and away from work, NSBP, and SPT (when feasible), is the best strategy. The reference standard for diagnosis, the SIC, is used in doubtful cases referred to specialized facilities.
No potential conflicts of interest relevant to this article were reported.
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