Hypersensitivity Type And Responsible Allergen In Patients With Occupational Medicamentosa-like Dermatitis Induced By Trichloroethylene

BackgroundTrichloroethylene (TCE) is a chlorinated solvent used extensively in industrial operations involving metal cleaning and degreasing. Workers exposed to TCE present with acute occupational disease, which is characterized by fever, generalized skin disorder, liver dysfunction and superficial lymphadenopathy. The patients had history of industrial exposure to TCE. Since the manifestation and prognosis resemble to medicamentosa-like dermatitis, glucocorticoids therapy was effective in most cases, Some cases experienced recurrences after re-exposure to TCE, therefore, national occupational doctors called it Medicamentosa-like Dermatitis Induced by Trichloroethylene. In the Chinese National Legal Occupational Disease List, it was named Occupational Medicamentosa-like Dermatitis Induced by Trichloroethylene (OMDT). In other countries, since OMDT resembles drug-induced hypersensitivity syndrome, so OMDT also called Trichloroethylene Hypersensitivity Syndrome (THS).Cases with OMDT have so far been reported from China since 1988.Based on the associated clinical features, frequent relapse, low incidence but high mortality, OMDT has become an important occupational health issue in China. Numerous attentions have been drawn on OMDT. Over the last 20 years, worldwide studies on the etiology, pathogenesis, occupational epidemiology and countermeasures of OMDT have been published. Despite extensive research, critical questions remain unanswered. Firstly, the occupational epidemiological survey for part of OMDT has been reported, but for global epidemiological survey is still open for research. A relative big sample survey is needed to understand the epidemiological features, especially the relationship between TCE exposure and disease onset. Secondly, the prescribe of time, dose and taping methods for glucocorticoids is far from consensus, the irregular glucocorticoids therapy is harmful for prognosis, so that it call for evident and big-sample based glucocorticoids therapy guideline for OMDT. Thirdly, studies on patients with OMDT have indicated that it is an occupational immunological disease. However, the major type of hypersensitivity of OMDT remains the subject of debate. Although OMDT is probably a type VI hypersensitivity, our previous study found that complement 3 reduced in the acute stage suggest types II and III hypersensitivity also seem to be related to OMDT. Hence, the reason for reduction of complement 3 and the relationship with liver impairment should be explored. Fourthly, sequelaes for the cases and long-term effects, such as carcinogenicity, is seldomly reported. Fifthly, patch test performed in OMDT demonstrated a positive reaction for TCE and its metabolites. Positive results are more frequently seen with compound of TCE than parent chemical, therefore, it’ not known that the culprit causative compound for OMDT is TCE itself or its metabolites. This important question prevents the development of tools to be used for screening and protecting susceptible populations, as well as golden diagnostic criteria. The present study pertains to shed light on the relative questions, for the sake of the health of workers and the study for occupational immunological disease.Part 1Investigation on the characteristics of Occupational Medicamentosa-Like Dermatitis Induced by TrichloroethyleneObjective:To analyze occupational epidemiologic characteristics of occupational medicamentosa-like dermatitis induced by trichloroethylene (OMDT) based on the global reported cases. Methods:The data were obtained from National Information System for Disease Control and Prevention and collected from municipal level occupational disease report as well as documentation retrieval, were evaluated and analyzed. Detergents used in the factories of cases and control were collected and analyzed for organic volatile component and impurities by the gas chromatogram. And the data were analyzed by Wilcoxon test. Results:During 1988 to 2014 years, 472 patients with OMDT were collected, including 446 cases (94.49%) from China (including Taiwan province) and 26 cases (5.51%) from other countries. Among the 379 OMDT cases with relative complete data, the prevalence of OMDT shows a rising trend during 1999 and 2006, the highest in 2005 was up to 43 cases per year. Cases had clear trichloroethylene exposure history, and the duration of exposure until the occurrence of OMDT was 28(22,36) days. Totally 80.9% of the cases, the trichloroethylene exposure concentration were higher than national occupational health standards. Urine trichloroacetic acid (TCA) levels was 107.68 (53.58, 53.58)mg/L, and 75.00% of the cases, the urine TCA levels were higher than occupational exposure biological limited. The percentage of TCE [82.58 (51.34, 96.94)] from organic volatile components analyzed is higher than the control group factory [55.17 (27.58,58.31)] (P< 0.05). The total cure rate was 90.23%, the fatality rate was 9.77%. Conclusion:OMDT were almost reported from China, which appears to be a serious occupational health issue. Our studies suggest that the diseases onset may be associated with trichloroethylene exposure concentration, this call for combinging with genotyping, trichloroethylene exposure concentration to investigate dose-response relationship, in order to better protect susceptibility individuals.Part 2Critical therapeutic methods for Occupational Medicamentosa-Like Dermatitis Induced by TrichloroethyleneObjective:Critical therapeutic methods of glucocorticoids and the influence factors were explored, in order to standard treatment and improve the cure rate. Methods: 196 cured patients with OMDT were investigated on the main clinical manifestation, biochemical examination, routine blood test, glucocorticoids prescribes method. Illness degrees were classified based on fever, rash phenotypes, liver function damage. Glucocorticoids prescribes method were analyzed among different rash phenotypes, liver function damage degrees and illness degrees by Kruskal-Wallis H test. Using multiple linear stepwise regression analysis to study the effect factors for glucocorticoids prescribes. Results:Initial dose, maximum dose, mean dose, taping dose and total dose were statistically significant among the different rash phenotypes, liver function damage degrees and illness degrees. Influence factors for total dose includes C-reactive protein, TCE exposure concentration, rash phenotypes, aspertate aminotransferase, age and indirect bilirubin, total dose of glucocorticoids, determination coefficient R2=0.775. With the increase of C-reactive protein, TCE exposure concentration, aspertate aminotransferase and age, total dose of glucocorticoids increase accordingly. The result suggest higher total dose of glucocorticoids for exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysisphenotypes thanerythema multiform.For initial dose, includes Alanine transaminase, C-reactive protein, indirect bilirubin, rash phenotypes, white blood cell count and fever, determination coefficient R2=0.717. With the increase of white blood cell count, alanine transaminase and C-reactive protein, initial doseincrease correspondingly. Fever can probably increase the initial dose. The initial dose of exfoliative dermatitis is larger than erythema multiform. For maximum dose, include aspertate aminotransferase, rash phenotypes, C-reactive protein and indirect bilirubin, determination coefficient R2=0.747. With the increase of alanine transaminase and C-reactive protein, maximum dose increase correspondingly. The result suggest higher maximum dose of glucocorticoids for exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis phenotypes than erythema multiform. Rash phenotypes, alanine transaminase and C-reactive protein are the common influence factors. Conclusion:Rash phenotypes and liver function damage indicators is the critical indicators influence glucocorticoids prescribes. Meanwhile, C-reactive protein level is one of the important indicators. Taken together, glucocorticoids prescribes should follow the critical factors in order to guide clinical practice.Part 3Analysis on the immunologic function and the reduction of complement 3 in patients with Occupational Medicamentosa-Like Dermatitis Induced by TrichloroethyleneObjective:To explore immunity function and the reduction of complement 3 (C3) levels in acute stage in patients with occupational medicamentosa-like dermatitis induced by trichloroethylene (OMDT). Methods:A retrospective analysis was conducted in 182 patients with OMDT from Guangdong Province Hospital for Occupational Disease Prevention and Treatment. The patients’humoral and cellular immunity indicators, liver function enzymes and and urine trichloroacetic acid (TCA) were observed, and they were descript. According the indicator in acute stage, patients were grouped into C3 decline group and C3 normal group based on the C3 level, and they were grouped into interval 1,2,3,4 day and ≥5 day groups based on the 2 times checking before. Liver function damage and its extent were determined by alanine amino transaminase (ALT) and total bilirubin (TBIL) level in acute stage. Run sum test and multivariate Logistic regression were used to analysis. Results:The higher percentage level of CD3+(78.47±11.30) and CD3+CD8+(46.73±13.18) and lower percentage level of CD3+CD4+(27.52±10.00) and CD4/CD8(0.65±0.36) were observed at acute stage. The level of C3 on the acute stage was decreased significantly in comparison to the healing stage [0.86(0.76,1.04)vs0.95(0.84,1.05) g/L, P<0.01], while the level of immunoglobulin G (IgG) and IgA in serum were increased significantly[10.17(8.09,12.27)vs8.90(7.54,10.68) g/L,1.37(1.09,1.83)vs 1.24(0.94,1.58) g/L, P<0.01, P<0.05]. The level of ALT and TBIL in C3 decline group increased significantly in comparison to C3 normal group at acute stage [628.0(155.3,1009.5)vs282.5(113.0,738.8)U/L,75.2(16.3,204.2)vs19.3(12.1, 67.4) μmol/L, P<0.01]. The C3 level of severe liver function damage’s patients at the acute stage was decreased significantly in comparison to the patients of under mild and mild liver function damage respectively [0.86(0.76,1.04)vs0.95(0.84,1.05) g/L, P<0.01]. In acute stage, the C3 level among the five time interval groups, except the C3 level in 1 day group is higher than2 days group, were no statistically significant difference (P>0.05), the second time ALT level were decreased significantly than the first time among the five time interval groups (P<0.05). In addition to the interval 1 day and 2 days group, the second time TBIL level were decreased significantly than the first time among the rest 3time interval groups (P< 0.05). After adjustment by gender, age, trichloroethylene exposure time, TCA level and OMDT clinical phenotype, the Logistic analysis showed that increased liver impairment levels was associated with the reduction of C3 level (OR= 1.609,95%CI:1.223-2.116). Conclusion:The major type of hypersensitivity of OMDT is T cell-mediated Ⅳ hypersensitivity. The liver impairment is most likely involved in the reduction of C3 in acute stage in patients with OMDT. The patients with more severity liver function damage were particularly prone to C3 levels decline. And the C3 level decline might not relate to II and III hypersensitivity.Part 4Explore on sequelae and culprit causative compound of Occupational Medicamentosa-Like Dermatitis Induced by TrichloroethyleneObjectives:The present study pertains to explore the sequelae and identify the culprit causative compound as well as category of immune reactions of OMDT, and to establish a screening test for subjects at risk of OMDT. Methods:19 case subjects diagnosed with OMDT were follow-up assessed by questionnaire investigation, health examination and patch test.TCE and its main metabolites chloral hydrate (CH), trichloroethanol (TCOH) and trichloroacetic acid (TCA) were used as allergens at different concentrations in a skin patch test. The patch test study included 19 case subjects diagnosed with occupational OMDT,22 control healthy workers exposed to TCE (exposure>12 weeks), and 20 validation new workers exposed to TCE for <12 weeks free of OMDT. All subjects were followed-up for 12 weeks after the patch test. Results:19 cases including 15 males and 4 females were follow-up after discharge ranging from 2 to 128 months. Subjects show itching, pigmentation and xerosis in skin, and abnormal results in ophthalmology Schirmer I Testand Tear Breakup Time. Body temperature, liver function, superficial lymph nodes were not found abnormal, no new rash relaps, liver function, blood, urine routine and autoimmune antibody were not found abnormal. None of them had carcinoma after discharge. The highest patch test positive rate in subjects with OMDT was for CH, followed by TCOH, TCA and TCE. The CH patch test positive rate was 100% irrespective of CH concentrations (15%,10% and 5%). The TCOH patch test positive rates were concentration-dependent (89.5%,73.7% and 52.6% for 5%,0.5% and 0.05%, respectively). Lower patch test positive rates were noted for TCA and TCE. All patch tests (including four allergens) were all negative in each of the 22 control subjects. None of the subjects of the validation group had a positive 15% CH patch test. Conclusions:These results suggest the OMDT will not relapse after glucocorticoid therapy. The dry eye syndrome might continue as one of sequelaes for OMDT. Chloral hydrate seems to be the culprit causative compound of OMDT and type IV hypersensitivity is the major immune mechanism of OMDT. The CH patch test could be potentially useful for screening workers at risk of OMDT and apply to be the goldem diagnostic criteria.Summary1. The pathomechanism of OMDT is mainly type IV hypersensitivity reaction. The evidence include:Cases had clear trichloroethylene exposure history, and the duration of exposure until the occurrence of OMDT was 28 days. The patients can be cured by glucocorticoids therapy. The higher percentage level of CD3+CD8+ was observed at acute stage. The patch test using the four allergens showed positive results. Since liver impairment is most likely involved in the reduction of C3 in acute stage in patients with OMDT, C3 level decline might not relate to II and III hypersensitivity.2. Chloral hydrate seems to be the culprit causative compound of OMDT, but not TCE. The CH patch test could be applied as golden diagnostic criteria for OMDT, and is potentially useful for screening workers at risk of OMDT3. Hypersensitivity in rehabilitation workers can last for more than 10 years, so that the survivors should avoid exposing to TCE and its metabolites, avoid the usage of the hypnotic and anticonvulsive drugs which chloral hydrate act as ingredient.4. The onset of OMDT probably related to the concentration of TCE exposure, but the threshold needs further verification.5. Critical therapeutic methods of glucocorticoids were developed and the influence factors were explored.6. After recover from glucocorticoid treatment, the disease will not relapse unless exposing to TCE. Xerophthalmia may continue as one of the sequelas for OMDT.