Occupational airborne exposure, specific sensitization and the atopic status: evidence of a complex interrelationship

The afore mentioned findings indicate that a positive association between latex sensitization and atopy can be interpreted as being due to biological interactions between structurally related protein epitopes of the occupational latex and environmental allergens which develop during the exposure period.

We have to examine how the case-only design of our study may have affected the results, i.e. to which extent the obtained ORs are unbiased estimates for the joint effect of factors in a standard case–control study. The equivalence of case-only and case–control studies has been thoroughly investigated in the context of gene-environment interaction studies. Correspondingly, the necessary assumptions for the equivalence have been defined within the framework of these studies, namely, i) the disease/its symptoms is rare; ii) the considering factors occur independently in the source/control population[35, 36]. The first assumption deals with general constructive conditions for odds-ratios models (it provides that the distribution of participants with each combination of factors in the control study group is the same as in the source group) and can be generally accepted. This condition is fulfilled in both our study groups: even in health care workers highly exposed to latex, the prevalence of occupational asthma was not higher than 2-10%[30], or 1–4%[37, 38]; for isocyanates annual occupational asthma incidence rates have been evaluated as < 1%, with a prevalence between 5-10%[39‐41]. However, the second assumption cannot be unscrupulous transferred to occupational settings. Whereas the factors considered in gene-environment studies remain constant, in occupational settings may be present the factors which are changed due to exposure. Specific sensitization is one exact extreme case: without occupational exposure no corresponding specific sensitization exists, the occupational exposure is the initiative cause of specific sensitization. The relationship between factors also arises during exposure. Obviously, the positive association between specific IgE-sensitization and atopy in symptomatic subjects is an integrated result from the interaction in both stages of the process leading to asthmatic symptoms via an IgE-sensitizing mechanism: in the stage of developing sensitization and in the stage of development of symptoms.

Hence, under the assumption that exposure and atopy occur independently in the source population we may consider the obtained association as an estimation for the joint effect of interaction between factors, namely, as a positive (synergistic) biological interaction (OR > 1) resulting in the development asthmatic symptoms via IgE-specific sensitization. We find this assumption reasonable since the likelihood of exposure is the same in atopics and non-atopics at the beginning of the work history (exposure).

If the main pathomechanism is known, it is also easy to assess the influence of the second form of bias - the healthy-worker effect - on constellations between factors in symptomatic subjects. In the case of latex asthma there is the simple corollary, i.e. specifically sensitized subjects are easily diagnosed with the use of allergological tests followed by quitting their jobs and being missed in groups with prolonged exposures. The decrease in latex sensitization and lower specific IgE values with longer periods of exposure may be due to these selective effects in the compilation of the subgroups.

Furthermore, taken into account the above consequences (we assumed that all bias processes have been reliably estimated), we can use the trend across the subgroups with different exposure durations for assessment of effects of exposure on atopy. On the basis of the negative selection of specifically sensitized subjects in the course of exposure, a parallel negative selective process of atopics can be expected. But the observed trend by atopics is increased (Figure 4); and it is strongly pronounced in the non-sensitized latex group (Table 2). We can interpret this trend as evidence that latex exposure may promote the atopy status both in the specifically sensitized as well as in the non-sensitized subgroup (see Figure 1B).

Results of Gautrin et al.[42], Nguyen et al.[43] and Skjold et al.[8] confirmed the hypothesis of biological interactions between atopy and exposure to allergenic substances. These authors observed an increase in the atopy incidence over a period of about three years among apprentices exposed to different allergens, even in the absence of specific sensitization, with significant increases in sensitization in the molds and pets group.

Taken all together, these studies as well as our own findings suggest that exposure to sensitizing protein allergens may promote the development of atopy.

As opposed to high molecular weight compounds such as latex allergens, specific IgE sensitization is not a major pathomechanism in isocyanate asthma (it is only detected in 10-30% of affected isocyanate workers[32, 44]); the non-IgE mediated form accounts for the majority of isocyanate asthma (87% in our study). So as opposed to latex, isocyanate asthma does not imply a single pathomechanism. There are at least two forms: i) an IgE-depended and ii) an IgE-independent non-immunological irritant form (isocyanates are potent irritants evident especially at high isocyanate concentrations)[31, 45]. Accordingly, the schema of Figure 1A cannot be simplified in case of isocyanate asthma (Figure 1C).

Atopy as a risk factor can be involved in different ways (in various paths) in the genesis of non-immunological isocyanate asthma; and the constellations in this subgroup may essentially affect (by selection processes) the relations between the factors in the small IgE-mediated subgroup. It is exactly in this situation that a collider bias can be expected. According to causal models, a collider bias reflects a general phenomenon known as Berkson’s paradox, when conditioning on a common consequence of two independent causes renders these causes statistical dependent (for details see J. Pearl[46]).

Simply, when the factors belong to independent pathomechanistic ways then the negative statistical associations are due to composition of those different pathways and do not reflect true biological relations between risk factors. Also in a situation, when one factor is involved in some pathomechanisms (perhaps at different times), the multiple connections may cause a selection bias inducing spurious relationships with other factors. This can be the reason for distinct assessment of relations between factors in isocyanate asthma when comparing the results from various studies. Therefore, for isocyanate-exposed subjects we cannot directly interpret the constellations between specific sensitization and atopy as biological such as in the case of the latex group.

The time trend of atopy represents an example of the possibility of such a complex relationship. We found a clear negative trend over time for atopy in the whole MDI group as well in the non-sensitized MDI subgroup (r_Spearman = − 0.2; p < 0.05); thereby in the shorter exposure set (< 7 years) atopics are found twice as frequently (49%) than in the group of prolonged exposure (25%). Because of the heterogenous pathomechanistic process we cannot assess whether it is a suppressing effect of exposure or the constellation of different time-dependent forms (e.g. atopics may develop symptoms earlier, so being reduced in subgroups with longer exposure). Accordingly, the process of specific sensitization which occurs mostly after long exposure periods may be affected. Interestingly, the only study in which a positive association between atopy and isocyanate asthma was reported (Meredith et al.,[14]) had used a definition of atopy based on a pre-employment history of hay fever, eczema and/or asthma. However, the authors found no association between duration of exposure and atopy.

The decrease of symptomatic atopic isocyanate workers over time is remarkable and could be due to the following reasons: i) the negative selection of the atopics (e.g. on the basis of an earlier development of non-IgE-mediated isocyanate asthma in atopics), ii) a protective effect of longer isocyanate exposure upon the development of atopy.

The study of Hur et al.[47] showed a similar constellations than our: atopics were less frequently found (15% vs. 31%) among those with work-related respiratory symptoms and all subjects with diagnosed isocyanate asthma or isocyanate-induced eosinophilic bronchitis (n = 7; 4 of those with IgG) were non-atopic; however, the authors did not discuss these observations.

The presence of different pathomechanisms in isocyanate asthma makes it impossible to assess the selection trend over time in our study as well as in others with a case-only design.

Nevertheless, if we take into account the studies with exposed workers (where the negative selection occurs less likely than in asthmatic subjects), we find agreement with our findings, too. Namely, a drastic reduction in atopy frequency was recently reported in a cross-sectional study of spray painters with a relatively high exposure to isocyanates[48] as well as in other isocyanate workers[11]. Recently, an immunological mechanism mediated by IgG antibodies has been observed. However, there was no association between symptoms and specific IgG finding, obviously the latter simply serve as a marker of exposure and not as a marker of disease[49]. There is even speculation about a possible protective effect of IgG or IgG4 on the incidence of work-related symptoms[39].

Taken together, there is no available data for isocyanate asthma patients or those exposed to isocyanate that resolves this dilemma of decrease of atopics under isocyanate exposure.

There is evidence also for involvement of genetic factors in the pathomechanism of isocyanate asthma. Some variants of polymorphisms within genes of the gluthathione S-transferase (GST) superfamily (e.g. GSTP1Val/Val) have been associated with susceptibility to isocyanate-induced asthma[41].

Further, the study of Piirila et al.[50] investigating the role of N-acetyltransferase (NAT) genotypes found that the slow acetylator genotype (NAT1) conferred a 2.5-fold increase in risk for isocyanate asthma. Recently, Bernstein[51] described a significant association between IL4RA and isocyanate asthma but only for subjects exposed to HDI, and not to MDI and TDI. Nevertheless, these genetic determinations can be realised by various pathomechanistic pathways. This makes the associations ambiguous and dependent on the contributions of other factors (e.g. downstream/epistatic genes) in the pathways. Additionally, the variety of environmental and occupational factors can interact with the genetic determinants and affect the development of disease[52]. Notably, Mapp al. reported a decreased risk of isocyanate OA in the GSTP1Val/Val genotype[53].

Despite the differences and complexity, it is notable that loci showing strong association with allergen-induced asthma (IL13, FCER1A) were not found to be associated with isocyanate asthma[52], which may support our hypothesis of two quite different (partially genetically determined), atopic and non-atopic immunological responses (see above).

In summary, the genes responsible for the primary and/or secondary regulation of pathomechanistic pathways of isocyanate asthma might be common and it is their expression or their manifestation that could be affected by multiple environmental as well as occupational factors. It can be assumed that prolonged exposure to isocyanates might increase the expression of genes associated with disease susceptibility. Further, we speculate that these processes are negatively conjugated with the processes of development of atopy.