Introduction
Methods
Study population
Clinical diagnosis criteria of patients with presumed asthma and MDI exposure history |
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Individual diagnosis criteria follow the ERS guidelines (see text for details) |
Differential diagnosis and exclusion (COPD, pulmonary embolism, congestive heart failure, pulmonary infiltration with eosinophils, vocal cord dysfunction, aspiration pneumonia, anti-inflammatory medication, mechanical obstruction, tumor) |
Conditions, see isocyanate asthma diagnostic flow chart |
Key indicators: obstructive ventilation pattern, recurrent wheeze, difficulty in breathing, chest tightness, poor respiratory effort |
Typical exposure-related asthmatic symptoms, asthmatic symptoms occur or worsen at work; occupational MDI-related exposure history, isocyanate exposure assessment, presence of workplace-related bronchial hyperresponsiveness after exposure to MDI, positive MDI-SIC result, positive MDI-SPT result |
Additional criteria considered were |
Lung function: FEV1 below lower limit of normal, presence of non-specific bronchial hyperresponsiveness (NSBHR) |
Presence of MDI-specific IgE antibodies |
Routine diagnostic procedure for isocyanate alveolitis (with evaluation points) |
Case history: typical exposure-related symptoms, see above (3 points) |
Auscultation, crackles on lower lung fields (2 points) |
Serological test: IgG antibodies to MDI-HSA conjugates (1 point) |
Lung function tests: restrictive ventilation pattern, impaired diffusion capacity (2 points) |
Chest X-ray: lung infiltrates ground or glass pattern (2 points) |
Facultative diagnostic parameters |
BAL: lymphocytosis, CD4/CD8 < 1 (3 points) |
Serial lung functions testing demonstrating work-related FVC decline of at least 20 % points) |
Specific inhalative challenge test: systemic inflammatory response plus restrictive ventilation response and/or impairment of diffusion capacity of at least 15 % (4 points) |
Systemic inflammatory response (fever, leukocytosis) (3 points) |
Positive diagnosis: when at least 10 points |
Pulmonary function test
NSBHR (non-specific bronchial hyper-responsiveness)
SPT (skin-prick testing)
SIC (specific inhalation challenge)
Clinical diagnosis of patients with MDI exposure history
Facultative diagnostic testing
Diagnosis of MDI hypersensitivity pneumonitis (MDI alveolitis)
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Occupational/environmental history: MDI exposure.
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Respiratory as well as systemic symptoms after a lag period of 3–12 h: fever, shivering, malaise, cough and shortness of breath.
Exposure assessment
Preparation of various MDI-HSA conjugates and immunological analysis
Detection of MDI-bound to HSA
LC-MS/MS measurements
Data analysis
Results
The antibody binding was higher in MDI-albumin conjugates prepared with volatile MDI as compared to the insoluble form, showing concomitant higher rates of the MDI incorporation on the other hand
Patient no. # | Demographic data | MDI exposure. (lag time) year | Art of exposure to MDI (job description) | Immunological status | Duration of resp. sympt (year) | Lung function | SPT MDI-HSA | MDI-SIC | MDI-HSA-specific antibodies | Final clinical diagnosis | |||||||
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Sex | Age | Smoking status | SPT comm. allerg. | Total IgE kU/L | FVC % pred | FEV1 % pred | NS-BHR | MDI-sIgE kU/L | MDI-sIgG mg/L | ||||||||
Group A: MDI-exposed patients referred to our clinic with presumed isocyanate asthma diagnosis | |||||||||||||||||
1 | M | 29 | Yes | 5.5 (1) | MDI-PUR glue heated; harder, binder | Pos. | 279 | 4 | 86 | 76 | Pos. | Pos. | Pos. | 13.3 | <3 | OAI
| |
2 | M | 63 | Yes | 14 (0.8) | MDI-PUR synthesis | Pos. | 1669 | 12 | 97 | 69 | Pos. | Pos. | Pos. | 50.4 | 7.3 | OAI
| |
3 | M | 36 | Ex | 3 (1) | MDI-PUR manufacture; MDI-lack bystander | Neg. | 427 | 1 | 90 | 60 | Pos. | Pos. | Pos. | 4.8 | 9.6 | OAI
| |
4 | M | 34 | Ex | 14 (0.7) | MDI-PUR glue heated, MDI cont. coatings | Pos. | 226 | 8 | 97 | 94 | Pos. | Pos. | Pos. | 3.3 | <3 | OAI
| |
5 | M | 57 | Ex | 4 (0) | MDI-PUR foam manufacture | Pos. | 61 | 3.4 | 74 | 78 | Pos. | Pos. | Pos. | <0.02 | <3 | OAI
| CI
|
6 | M | 54 | Ex | 5 (0) | MDI cont. production of elastomers | Neg. | 102 | 4 | 85 | 58 | Neg. | Neg. | Pos. | <0.02 | 74.0 | PI
| |
7 | M | 35 | Ex | 0.4 (0) | MDI-PUR cont. plastic manufacture | Pos. | 51 | 0.4 | 81 | 69 | Pos. | Neg. | Pos. | <0.02 | 4.9 | OAI
| |
8 | M | 47 | No | 11.5 (0) | MDI-PUR electrical potting, | Neg. | 15 | 10.5 | 79 | 68 | Pos. | Neg. | Pos. | <0.02 | 20.2 | PI
| |
9 | M | 49 | Yes | 11 (0) | MDI-PUR manufacture of. hard plastic parts | Neg. | 8 | 2.5 | 85 | 62 | Neg. | Neg. | Pos. | <0.02 | 3.3 | OAI
| |
10 | F | 43 | Yes | 0.3 (0) | MDI-PUR-durable elastomeric wheels,-foam | Neg. | 108 | 0.1 | 100 | 57 | Pos. | Neg. | Pos. | <0.02 | 14.8 | A1
| PI
|
11 | M | 49 | Ex | 13 (0.8) | MDI glue, heated, plastic, wood panels | Neg. | 12 | 6 | 79 | 72 | Neg. | Neg. | Neg. | <0.02 | 3.6 | P1
| |
12 | M | 43 | Ex | 2 (0.2) | MDI-PUR powder, acryl lack parts | Neg. | 2 | 1.5 | 81 | 73 | Pos. | Neg. | Neg. | <0.02 | 3.7 | A1
|
Patient no. # | Demographic data | MDI exposure. year (*PPE) | Biomonitoring MDA values (at the time of sampling) Air monitoring. median value 5 ppb | Immunological status | Reported duration of resp. sympt (year). | Lung function | SPT MDI-HSA | MDI-SIC | MDI-HSA-specific antibodies | Final clinical diagnosis | ||||||
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Sex | Age | Smo-king status | SPT comm. allerg. | Total IgE kU/L | FVC % pred | FEV1 % pred. | NS-BHR | MDI-sIgE kU/L | MDI-sIgG mg/L | |||||||
Group B: Workplace field controls; workers currently exposed to MDI | ||||||||||||||||
1 | M | 38 | Yes | 11.3 | 0.16 μg MDA/g Creatinine | Neg. | 39.3 | – | 98 | 84 | n.d. | n.d. | n.d. | <0.02 | <3 | RCI
|
2 | M | 43 | Yes | 10.1 | 0.90 μg MDA/g Creatinine. | Neg. | 42.9 | – | 102 | 98 | n.d. | n.d. | n.d. | <0.02 | <3 | RCI
|
3 | M | 33 | Yes | 8.2 (*) | 0.30 μg MDA/g Creatinine | Neg. | 97.3 | – | 104 | 84 | n.d. | n.d. | n.d. | 0.25 | 3.5 | H |
4 | M | 33 | No | 7.7 | 0.32 μg MDA/g Creatinine | Neg. | 37.7 | – | 97 | 88 | n.d. | n.d. | n.d. | <0.02 | <3 | CI
|
5 | M | 32 | Yes | 5.5 | 0.20 μg MDA/g Creatinine | Neg. | 13.3 | – | 109 | 91 | n.d. | n.d. | n.d. | <0.02 | <3 | CI
|
6 | M | 25 | No | 2.1 | 0.22 μg MDA/g Creatinine | Pos. | 28.6 | – | 96 | 92 | n.d. | n.d. | n.d. | <0.02 | <3 | RCIDI
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Clinical diagnosis and antibody analysis
Correlation with other diagnostic parameters and the antibody data
Presumed MDI-asthma cases (group A)
Control groups (B, C, D)
Subject | Demographic data | Immunological status | Lung function | MDI-specific antibodies | Final clinical diagnosis | ||||||
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No. # | Sex | Age | Smo-king status | Comm. allerg. | Total IgE kU/L | FVC % pred | FEV1 % pred. | NS-BHR | MDI-sIgE kU/L | MDI-sIgG mg/L | |
Group C: Unexposed healthy control subjects | |||||||||||
19 | F | 28 | No | Neg. | n.d. | n.d. | n.d. | n.d. | <002 | <3 | H |
20 | M | 28 | No | Pos. | n.d. | n.d. | n.d. | n.d. | <0.02 | <3 | H |
21 | F | 50 | No | Pos. | n.d. | n.d. | n.d. | n.d. | <0.02 | 3.3 | H |
22 | F | 54 | No | Neg. | n.d. | n.d. | n.d. | n.d. | <0.02 | <3 | H |
23 | M | 56 | No | Neg. | n.d. | n.d. | n.d. | n.d. | <0.02 | <3 | H |
24 | M | 30 | No | Pos. | 67 | n.d. | n.d. | n.d. | <0.02 | <3 | H |
25 | F | 31 | No | Neg. | 128 | n.d. | n.d. | n.d. | <0.02 | <3 | H |
26 | M | 55 | Ex | Neg. | 27 | n.d. | n.d. | n.d. | <0.02 | <3 | H |
27 | F | 57 | No | Neg. | 272 | n.d. | n.d. | n.d. | <0.02 | <3 | H |
28 | F | 61 | No | Neg. | 7.3 | n.d. | n.d. | n.d. | <0.02 | <3 | H |
29 | F | 47 | No | Pos. | 870 | n.d. | n.d. | n.d. | <0.02 | <3 | H |
30 | F | 43 | Yes | Neg. | 33 | n.d. | n.d. | n.d. | <0.02 | <3 | H |
31 | M | 40 | No | Pos. | 42 | n.d. | n.d. | n.d. | <0.02 | <3 | H |
Group D. Asthma patients not exposed to isocyanates | |||||||||||
32 | M | 42 | No | Pos | 83 | 88 | 86 | neg. | <0.02 | <3 | OAB
|
33 | M | 40 | No | Pos | 135 | 94 | 92 | Pos. | <0.02 | <3 | OAB
|
34 | M | 44 | No | Pos | 893 | 106 | 90 | Pos. | <0.02 | <3 | OAB
|
35 | F | 62 | Ex | Neg | 65 | 115 | 105 | Neg. | <0.02 | <3 | OAB
|
36 | F | 41 | Yes | Pos | 197 | 112 | 111 | Pos. | <0.02 | <3 | OAB
|
37 | M | 57 | Yes | Pos | 246 | 95 | 80 | Pos. | <0.02 | <3 | OAB
|
38 | M | 56 | Ex | Neg | 332 | 85 | 81 | Neg. | <0.02 | <3 | OAB
|
39 | M | 50 | Ex | Pos | 33 | 83 | 66 | Pos. | <0.02 | <3 | OAB
|
40 | M | 41 | No | Pos | 22 | 108 | 82 | Neg. | <0.02 | <3 | OAB
|
41 | M | 45 | No | Pos | 101 | 102 | 98 | Pos. | <0.02 | <3 | OAB
|
42 | M | 39 | No | Pos | 323 | 111 | 97 | Neg. | <0.02 | <3 | OAB
|
43 | M | 50 | No | Neg | 153 | 107 | 75 | Pos. | <0.02 | 4.86 | OAB
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