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Keywords:

  • asthma;
  • immunotherapy;
  • occupational medicine

Abstract

  1. Top of page
  2. Abstract
  3. Conflict of interest
  4. References

Background

The management of severe occupational asthma (OA) remains problematic and new alternative treatments providing better disease control are required, ideally enabling affected individuals to remain in their job.

Methods

Ten patients with severe uncontrolled OA were treated with the monoclonal anti-IgE antibody omalizumab. In six cases the causative agent was a high molecular weight (HMW) compound and in four cases it was a low molecular weight (LMW) chemical. All of the patients had well documented OA despite workplace adjustments.

Results

During treatment, nine patients exhibited a lower rate of asthma exacerbations and used less oral or inhaled corticosteroids. Seven patients were able to continue working at the same workplace as before treatment.

Conclusion

We have demonstrated that omalizumab is a potential treatment for severe uncontrolled OA and enabled seven of the ten patients in the study to remain in their job.

Patients with uncontrolled severe allergic asthma are a challenging and difficult-to-treat population in whom omalizumab might represent a new treatment option [1]. Given the health consequences and socioeconomic impact of severe occupational asthma (OA) [2], it is important to establish whether omalizumab can enable patients with severe OA to keep their job.

We report the results of the first field study in a cohort of ten patients with OA treated with omalizumab and followed for a period of 6 months to 4 years. Questionnaires on the management of OA were sent to French pulmonologists specialized in severe asthma. Between 2009 and 2011, we received 13 reports of patients with OA receiving anti-IgE therapy, and of them, ten were selected for the study (Fig. 1). Three were excluded (insufficient follow-up period or unclear-cut history of OA).

image

Figure 1. Study flow diagram. OA, occupational asthma; HMW, high molecular weight; LMW, low molecular weight. *Well-documented severe occupational asthma with persistent symptoms despite therapy with both high-dose inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs).

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Table 1 shows the patients' characteristics. In all cases, the diagnosis of OA was based on a well-documented clinical history. Asthma severity was clearly related to work conditions, the patients did not have work-aggravated asthma [3], and omalizumab had not been prescribed for preexisting severe atopic asthma.

Table 1. Demographic, occupational, and follow-up data
PatientSexAgeSmokerOccupationAgentDuration OAAtopyTotal IgE levelFollow-up
  1. OA, occupational asthma. The duration of OA is given in years since diagnosis, and the follow-up during anti-IgE treatment is given in months. Total IgE level is given in units/ml.

1M31BakerWheat flour6+1066
2F34VeterinaryCat7+3918
3M45+FarmerStorage mites3+137648
4M40VeterinaryRabbit2+7642
5M20FarmerAltemaria0.5+538
6F57BakerWheat Flour8+83328
7M56+Car painterIsocyanate5+102919
8M47Dry-cleanerTelrachlo methylene2+25712
9M24Car painterIsocyanate1+130730
10M20Rubber workerAcrylate4576
Mean 37.4   3.85 51321.7

In the six cases in which the causative agent was a high molecular weight (HMW) compound, skin prick tests were positive and two patients also had a positive challenge test (wheat flour). The causative agents were wheat flour, cat, rabbit, storage mite and Alternaria (severe exacerbations strictly related to work facilities in a high concentration of spores).

In four cases, the causative agent was a low molecular weight (LMW) compound. The role of isocyanate was demonstrated by a challenge test in one patient (Genasic chamber), while another had significant levels of isocyanate-specific IgE (antitoluene diisocyanate: 0.13 units/ml, threshold >0.10 units/ml). In the acrylate case, the eviction/rechallenge tests were positive and skin prick tests remained negative to other occupational allergens. The role of tetrachloroethylene was supported by well-documented symptoms only in the workplace, while sensitization to mites and pollens was not relevant.

In all cases, workplace adjustments were made at the time of diagnosis of OA to maximize avoidance of the causative agent, although complete avoidance was not possible. During the follow-up, no change in occupational exposure and in habits or conditions of working were notified.

All patients had severe uncontrolled asthma and were receiving optimized asthma therapy: high-dose inhaled corticosteroids (mean daily beclometasone-equivalent dose: 3200 μg) combined always with long-acting beta-agonists; inhaled rescue medication was used at least 1 day per week. They all had experienced severe exacerbations requiring an emergency consultation and prescription of oral corticosteroids (2–8 exacerbations during the past year; mean 5.2), sleep disturbances, impaired quality of life or missed work days due to asthma. Five patients received daily oral corticosteroids (mean daily prednisone-equivalent dose: 19 mg; range: 10–30 mg). Before omalizumab treatment, six patients had a FEV1 ≤ 80% of the predicted value (Table 2).

Table 2. Asthma parameters before and after anti-IgE therapy
PatientFEV1 pre %FEV1 post %Asthma control postICS pre (μg/day)ICS post (μg/day)Nb exacerb preNb exacerb postOC pre (mg/day)OC post (mg/day)Continued exposure to OAgContinued occup
  1. Pre, prior to anti-IgE therapy; post: during anti-IgE therapy; FEV1: forced expiratory volume in 1 s, expressed as percentage of the predicted value; asthma control using GINA guidelines; ICS, inhaled corticosteroids, expressed in μg/day of beclometasone-equivalent; Nb exacerb: number of severe asthma exacerbations per year; OC, oral corticosteroids, expressed in mg/day of prednisone-equivalent; OAg, occupational agent; occup, occupation.

  2. a

    Follow-up of only 6 months.

18091Partly control4000200040a00YesYes
27675Optimal control400020006100YesYes
38080Partly control2000200042200YesYes
4107125Optimal control4000400061150YesYes
5118115Optimal control400040002000YesYes
69393Optimal control4000400060300YesNo
77087Partly control400020004100YesNo
887104Partly control10005004000YesYes
96998Partly control2000200080205YesYes
103636Uncontrol3000300084a1010YesNo
Mean81.690.4 320025505.20.5193  

Omalizumab therapy was introduced according to GINA guidelines [4] and was initiated 0.5–8 years after diagnosis (mean: 3.85 years) (Table 1). The dose of anti-IgE therapy was based on body weight and total serum IgE level, with a maximum dose of 600 mg every 2 weeks if IgE level was more than 700 units/ml. Mean total serum IgE was 513 units/ml (range: 39–1376).

The patients were followed for at least 6 months during omalizumab therapy (mean: 21.7 months; maximum: 48 months), and asthma control was assessed for the first time 4 months after the start of treatment. Omalizumab was well tolerated by all the patients studied.

Asthma control improved in 9 of 10 patients, determined by the number of severe exacerbations per year (mean before omalizumab: 5.2; mean after evaluation of omalizumab therapy: 0.5, range: 0–2), and five experienced no exacerbation (Table 2). Optimal control was achieved in four patients and five were partly controlled according to the GINA classification [4].

Omalizumab therapy enabled 3 of 5 patients to discontinue oral corticosteroids. The mean dose of oral corticosteroids decreased from 19 to 3 mg/day at the end of the study (a decrease by 84%). Four patients reduced inhaled corticosteroids from a mean beclometasone-equivalent dose from 3200 to 2550 μg/day, a decrease by 20% (Table 2). An improvement in FEV1 was reported for five patients.

Seven patients were able to continue working at the same workplace as before treatment. Three patients had to stop job. Patient 10 (acrylates), the most severe, kept frequent uncontrolled symptoms and a very low FEV1. The patient 7 (isocyanates) was responder but underwent an early retirement at the age of 58. The patient 6 had soon stopped working 4 months before treatment, but remained symptomatic to flour for an indirect exposure. Despite a control of asthma, she did not return to work.

Our study demonstrated the efficacy of omalizumab in the atopic patients, regardless of whether the causative agent was HMW or LMW.

Our results confirm previous publications that have demonstrated a clinical benefit from omalizumab therapy in OA caused by HMW agents in healthcare workers with latex allergy [5] and in baker's asthma [6, 7].

However, in our study, 3 of 9 atopic patients had OA induced by a LMW chemical.

Two types of OA are distinguished in the international classification: immunologic OA and nonimmunologic (irritant-induced) OA [8]. Consequently, the efficacy of anti-IgE therapy in our three patients with OA induced by a LMW agent suggests that an immunologic mechanism was involved.

It must be stressed that 7 of 10 patients were able to remain in their job, as has previously been reported with omalizumab [6, 7]. This is important, because the financial consequences and loss of income are significantly higher in subjects with OA who leave their job than in those who retain their position [9].

We have demonstrated that omalizumab is a potential treatment for OA induced by LMW and HMW agents in atopic patients. Omalizumab could help patients who are unable to avoid allergen exposure in their workplace and may have a role in preventing the socioeconomic and financial consequences related to the loss of employment.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Conflict of interest
  4. References

François Lavaud, Philippe Bonniaud, Jean Charles Dalphin, Christophe Leroyer, Dominique Muller, Rafik Tannous, Gilles Mangiapan and Frédéric De Blay are consultants for Novartis-France.

References

  1. Top of page
  2. Abstract
  3. Conflict of interest
  4. References