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OCCUPATIONAL ALLERGIESALLSA Congress, Sept 2017, P/Elizabeth
Prof Mohamed F Jeebhay – Head of Division
Dr Shahieda Adams – Director, Occupational Medicine Clinic, Groote Schuur Hospital
Dr Amy Burdzik – Occupational Medicine Consultant, Occupational Dermatology clinic
Occupational Medicine DivisionSchool of Public Health and Family MedicineUniversity of Cape Town
• Diseases resulting from a hypersensitivity (exaggerated response)
of the immune system to substances encountered in the work
environment
• Constitute 15% of all occupational diseases (Finland data)
• Features:
- initial contact with antigen
- latent sensitisation period of weeks to years between first
exposure and development of symptoms
- temporal symptoms on exposure to very low doses of allergen
- (exposure to non-specific irritants may trigger a reaction)
• ALLERGENS/SENSITISERS:
- High Molecular weight agents - Proteins (animal, plant,
microbial), enzymes (synthetic)
- Low molecular weight agents - Chemicals
OCCUPATIONAL ALLERGIES
Urticaria Rhinitis/Asthma
Allergic alveolitis
COMMON OCCUPATIONAL ALLERGIES
Contact dermatitis
OCCUPATIONAL RHINITIS AND ASTHMA
Prof Mohamed F Jeebhay
MBChB DOH MPhil (Epi) MPH (Occ Med) PhD
OCCUPATIONAL MEDICINE DIVISIONSchool of Public Health and Family MedicineUniversity of Cape Town, South Africa
ALLSA Congress, Sept 2017, Port Elizabeth
DEFINITION AND CLASSIFICATION
Work-related asthma includes occupational asthma and work-
exacerbated asthma:
Occupational asthma (OA): asthma due to causes and conditions
attributable to a particular occupational environment and not to stimuli
encountered outside the workplace
Work-exacerbated asthma (WEA): pre-existing asthma worsened by
moderate-to-low level workplace exposures (e.g. dusts, smoke, fumes,
sprays) and physical factors (e.g. cold air, humidity, strenuous work)
but initially not caused by work
At least 15% of adult asthma is work-related (Blanc and Toren, BMC Pulm Med, 2009)
More than 25% of working adults with asthma have exacerbations of
asthma at work (Fishwick, BMB, 2014)
DEFINITIONS
CLASSIFICATION OF WORK-RELATED ASTHMA
Work-related asthma (WRA) (PAF: 25%)
Asthma caused by work: Occupational asthma
(OA) – (PAF: 15%)
Sensitiser-induced (allergic) OA(80-85%)
IgE-mediated asthma(HMW substances / protein allergens)
Non-IgE mediated asthma
(?LMW chemicals)
Irritant-induced OA(5-15%)
Acute onset IIASingle high exposure to LMW chemicals
(RADS) no latency, close
temporalassociation
Subacute IIAMultiple high level
symptomatic exposures to LMW chemicals (latency)
Low-dose IIAChronic moderate
exposures
Pre-existing asthma exacerbated by work:
Work-exacerbated asthma (WEA) – (PAF: 25%)
(Jeebhay, CACI, 2012)
WORK-RELATED ASTHMA AND RHINITIS
EAACI Consensus statement, Allergy, 2008
- Isocyanates
- Cereal flour and grain
- Natural rubber latex
- Cleaning agents (instruments, surface)
- Platinum salts
- Laboratory animals (e.g. rat urinary proteins)
Common causes of occupational asthma in
South Africa
PATHOPHYSIOLOGICAL MECHANISMS
Allergens, particle size and lung deposition
(EAACI Position Paper, Allergy, 2015)
Allergic reactions are the result of:
• de novo inhalation or skin contact/puncture with products
containing single or multiple allergens (e.g. flour dust containing
cereal flours, seafood, insect stings, isocyanates)
• re-exposure through an alternative route in a known food allergic
individual (e.g. seafood)
• cross-reactivity to homologous protein allergens:
- taxonomical homology (e.g. wheat vs. rye, shell-fish species,
mites, latex-fruit)
- structural similarities (e.g. profilins, cross-reactive carbohydrate
determinants in pollen-food syndromes)
ALLERGEN SOURCES AND ROUTES OF
EXPOSURE
Mechanisms Involved in Sensitizer-Induced Asthma and Irritant-Induced Asthma.
Tarlo and Lemiere, N Engl J Med 2014
NATURAL HISTORY OF OCCUPATIONAL ALLERGY AND ASTHMA
EPIDEMIOLOGY OF OCCUPATIONAL ASTHMA
The incidence of OA in developing countries appears to be lower
than industrialised countries (Jeebhay&Quirce, IJTlD, 2007)
Under-detection or under-reporting or low risk populations?
Occupational asthma in
Great Britain, 2005-2015
(HSE)
Patterns of atopy and allergic sensitisation in working adults
in epidemiological studies of the Western Cape –
urban and rural differences
0
4
8
12
16
20
24
28
32
36
40West coast – seafood
workers (n=575)
0
5
10
15
20
25
30
Overberg – grape farm
workers (n=207)
0
5
10
15
20
25
30House dust mite
Cockroach
Rye grass
Bermuda grass
Mouldmix
Dog
Cat
Common inhalants (SPT)35
40Cape Town – bakery
workers (n=517)
(Jeebhay et al, Am J Ind Med, 2008
Jeebhay et al, Int Arch Allergy Immunol, 2007
Baatjies et al, Eur Resp J, 2009)
(Jeebhay & Quirce, IJTLD, 2007)Jeebhay CACI, 2012
RISK FACTORS FOR OCCUPATIONAL ALLERGY AND ASTHMA
Non work-related Asthma Work-related Asthma (sensitizer-induced)
Host Risk Factors
Younger age Younger age
Female Female (gendered distribution of work)
Family history of allergy/asthma Family history of allergy/asthma
Atopy Atopy (for HMW protein agents)
Obesity Obesity
Current/previous history of rhinitis or allergy Current/previous history of work-related
rhinitis
Previous bronchial hyperresponsiveness Previous bronchial hyperresponsiveness
Some serious childhood respiratory diseases
(e.g. viral infections)
Behavioural and Social Factors
Active and passive smoking Active smoking
Low household income Low household income (association with
greater risk of work exposure to sensitizers)
Environmental Risk Factors
Home environmental factors
(e.g. fuel combustion, dampness, mould,
environmental tobacco smoke)
HMW (protein) or LMW (chemical)
sensitizing agents at work
Exposure to cleaning sprays at home Cleaning/disinfectant agents at work
Air pollution .
Risk factors for WRA and non-WRA(Jeebhay et al, COACI, 2014)
Environmental factors:
• Exposure to the causative agent/substance (allergen)
• Elevated dose (duration and level of exposure)
Host-related factors:
• Atopy and genetic predisposition
• Cigarette smoking as a contributory factor
• Upper airway symptoms
• Pre-existing food/pollen allergy
• Dietary intake (?)
RISK FACTORS FOR SENSITISATION AND
INHALANT OCCUPATIONAL ALLERGIC
REACTIONS
(Source: Cullinan, Panminerva Med, 2006)
Exposure-response relationships for wheat allergen
exposure and asthma (Baatjies et al, OEM, 2015)
Work-related allergic rhinitis
Work-related allergic chest
symptoms
Baker’s asthma
Average current wheat exposure g/m3
0 10 20 30 40 50
Pre
vale
nce (
%)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
Sensitisation to wheat
Allergic chest symptoms
Probable occupational asthma
Allergic ocular-nasal symptoms
Allergic ocular-nasal symptoms
Probable occupational asthma
Sensitisation to wheat
Cross-reactivity between taxonomically-related inhalant
allergens of food origin
Spearman r = 0.74 (p<0.001)
0500
1000
1500
Pilc
hard
antigen c
oncentr
ation
0 2000 4000 6000 8000Anchovy antigen concentration
Fitted values ng/m3
Pilchard and anchovy environmental
antigen concentrations highly
correlated
Wheat and rye flour environmental
antigen concentrations highly
correlated
Spearman r = 0.97 (p<0.001)
(Baatjies et al, Ann Occ Hyg, 2010)(Jeebhay et al, Ann Occ Hyg, 2005)
Host-related predictors of flour dust-related allergy and
asthma phenotypes in bakers
(Baatjies et al, Eur Resp J, 2009)
Atopy is an effect modifier for wheat sensitisation
among bakers (Baatjies et al, OEM, 2015)
ATOPIC
NON-ATOPIC
Average current wheat exposure g/m3
0 10 20 30 40 50
Pre
vale
nce (
%)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Sensitisation in atopics
Sensitisation in non-atopics
Sensitisation in all workers
Relationship between wheat sensitisation and wheat allergen concentration among
supermarket bakery workers, stratified by atopic status
Atopic
Non-atopic
Platinum refinery salts:
14%/100 PYR sensitised
(20% symptoms)
Smoking modifies the risk of sensitisation with exposure to
platinum salts - hexachloroplatinic acid (Calverly et al, Occ Env Med, 1995)
DIAGNOSTIC APPROACH:EVALUATION OF THE PATIENT
CASE STUDY
A 42 year old man complains of a chronic cough and tight chest for the past six months. He is an ex-smoker.
He has been a baker for the past five years and prior to this he worked as a clerk in a joinery, which assembled furniture.
He feels that his chest problem was caused by his work, but he is reluctant to report this to his employer for fear of losing his job
Diagnostic approach based on pathophysiologicalmechanisms involved
Occupational history
Environmental monitoring
ImmunoCAP, Immunoblot
SPT, CAST / Basophil
Activation test
(Jeebhay, CACI, 2011)
Molecular markers
(cytokines)
• Serial PEF
• Spirometry
• NSBH
• FeNO
• Specific
Challenge
Assess the probability of work-related asthma based on clinical
history:
Absence of symptoms prior to working in the current job
Changes in work processes in the period prior to the onset of
symptoms
Unusual work exposure within 24 hours before the onset of initial
asthma symptoms
Asthma symptoms differ during times away from work such as
weekends, holidays or other extended times away from work
Symptoms of allergic rhinitis and/or conjunctivitis that worsen with
work
Increased probability of work-related symptoms in the first
2 years of employment – high risk
STEP I. Clinical and occupational exposure history
Work-related asthma should be considered in all adult patients with
new-onset or worsening asthma through taking an appropriate history
Ascertain the nature and degree of exposure to a respiratory sensitiser or irritant to assess level of risk:
• A history of the job duties and duration
• Assess the level of airborne exposures of the job (degree of perceived dustiness) and exposure duration
• Use and adequacy of control measures and use of protective devices/equipment (respirators, goggles, gloves)
• A list of the hazardous exposures (obtain chemical safety data sheets of agents used from workplace) and cross-check against a list of known agents causing OA from reliable electronic databases, e.g. http://www.occupationalasthma.com/occupational_asthma_causative_agents.aspx or http://www.csst.qc.ca/en/prevention/reptox/occupational-sthma/Pages/bernsteinang.aspx
• Assess sensitising potential of the agent (QSAR Hazard Index for LMW agents) - http://www.population-health.manchester.ac.uk/epidemiology/COEH/research/workrelatedillhealth/asthma
An occupational exposure history is crucial in assessing the probability of exposure to potential asthmagenic
agents
Work activities that generate excessive aerosolisation of particulates dusts, vapours and fumes pose a higher risk
Fish gutting
Fish cooking
Bread dough mixing
Dusting dough table
Spice blending
Spice mix packing
Quantitative Structural Activity Relationship (QSAR) Hazard Indexfor occupational asthma causation (Jarvis et al, OEM, 2005)
Confirm the diagnosis of asthma using any one of the ff:
• Spirometry: a post-bronchodilator increase of ≥ 12% accompanied by a ≥ 200 ml increase in FEV1
• Serial peak expiratory flow (PEF) monitoring over a 2-week period: diurnal variation of ≥ 20% (especially useful for low molecular weight exposures)
• Steroid trial: > 20% improvement in FEV1 after 2 weeks
• Non-specific challenge test with methacholine/histamine: PC20 < 8mg/ml(A negative methacholine challenge (PC20 >16mg/ml) in a subject still exposed to the causative agent at work makes the diagnosis of occupational asthma very unlikely)
Differential diagnosis:
• Irritable larynx syndrome
• Eosinophilic bronchitis
• Asthma-like syndromes (e.g. byssinosis, aluminium potroom asthma, grain dust COPD)
It is best to complete the evaluation of the patient and/or refer to an occupational medicine specialist before removing the patient from work
STEP II. Confirmation of asthma
Establish the work-relatedness of asthma using objective tests:
Serial PEF testing using a portable peak flow meter (at work and away from work ≥4 per day for 4 weeks) in patients who are still working in the job
OASYS Graph of a worker handling cellulose fibre:
• >20% variability in PEF measurements
• Work effect Index (WEI) = 3.8 (Cut off = <2.5)
(http://www.occupationalasthma.com/oasys.aspx)
AWAY FROM WORK
STEP III. Confirmation of work-related bronchoconstriction
Serial PEF measurement is a feasible, sensitive
(82%), and specific (88%) test for the diagnosis
of occupational asthma, when potential sources
of error are understood (Moore et al, AoRM 2009)
Immunologic assessment aims to:
- Identify presence of atopy as a risk factor
Atopic workers exposed to high molecular weight agents (proteins) are at increased risk of becoming sensitised to occupational allergens
- Support the diagnosis of occupational allergic rhinitis/asthma in symptomatic patients exposed to respiratory sensitisers
Various techniques are used:
• Skin prick tests
• Allergen-specific IgE (ImmunoCAP)(http://www.phadia.com/en/Products/Allergy-testing-products/ImmunoCAP-Allergen-Information/Occupational-Allergens/)
• Immunoblots
• Basophil activation / CAST ELISA assay
STEP IV. Confirmation of sensitisation to occupational allergens
Skin Prick Testing
SPT results of a supermarket bakery worker:
• Atopic (HDM, rye grass, cockroach)
• Occupational allergens + (wheat, rye, corn flour)
• Positive test: wheal >3mm than negative control
Allergen-specific serum IgE testing
Asymptomatic IgE reactivity vs. true latex allergy in dental health care workers (n = 41) – relevance of cross-reactive carbohydrate determinants (CCDs)
(Ratshikhopha et al, Occ Health SA, 2016)
Prevalence of true latex allery = ~ 50% of initial 9.7% on K82 ImmunoCAP for latex
Increased probability of clinical reactivity with
elevated levels of IgE antibodies
Williams et al, Clin Exp Immunol, 2009
Immunoblot Testing
1 2 3 4 5 6 7 8 9150kDa
100kDa75kDa
50kDa
37kDa
25kDa
20kDa
1 = molec. weight marker
2 = maize meal
3 = garlic powder
4 = raw garlic
5 = onion flakes
6 = raw onion
garlic 2.37 <0.35
onion 2.05 <0.35
Serum specific IgE (kU/l)
Patient Ref
(Van der Walt et al, Int Arch Allerg Immunol, 2010)
ImmunoCAP and
Immunoblot results of a
spice mill worker:
- Garlic and onion IgE +
- 50kDa protein binding to
serum IgE
CAST ELISA Test
CONTROL
ImmunoCAP and
CAST ELISA test of
2 garment workers:
- sulphidoleukotriene release
(Lopata et al, Int Arch Allergy Immunol, 2007)
Patient A
Latex
(k82) 1.70 <0.35
Patient B
Latex
(k82) 11.6 <0.35
Serum specific IgE (kU/l)
PATIENT A PATIENT B
Patient Ref
STEP V. Specific bronchial challenge test – the gold standardConfirmation of the causal role of occupational agent
SBT results of a furniture joinery worker:
- >15% decline in FEV1
post challenge(Vandenplas, ERS Taskforce on OA, 2014)
(Jeebhay, et al, JACI, 1996)
Meranti wood dust (control)
Imbuia dust (causative agent)
Acute onset IIA / RADS:
diagnosis of asthma
onset of asthma after a single exposure or accident to an irritant
vapour, gas, fumes or smoke in very high concentrations
(within mins. to <24 hrs)
exclusion of pre-existent asthma
Asthma symptoms and NSBH persistence (> few weeks) after
exposure
Subacute IIA (multiple high level exposures):
Similar to above except that there is evidence of multiple
symptomatic exposures to irritant vapours, gas, fumes or smoke with
latency
Subacute IIA (multiple low level exposures):
Chronic low dose exposures to chemicals with latency
Assessment and diagnosis of
Irritant-induced Occupational Asthma(EAACI Position Paper, Allergy, 2014)
Suspect work exacerbated asthma (WEA) in individuals with:
pre-existing asthma
moderate-to-low level workplace exposures to dusts, smoke,
fumes, sprays or extreme physical factors (e.g. cold air, humidity,
strenuous work)
worsening of asthma symptoms (increase in doctor visits or
medication use) or deterioration of lung function
no documented workplace exposure to agents known to induce
occupational asthma (OA)
OA and WEA are managed differently - OA patients need to be
removed from the specific exposure as soon as possible,
whereas WEA patients may continue to work in current job
provided there is close environmental control and asthma
treatment is optimised
Assessment and diagnosis of Work Exacerbated Asthma
EVALUATION OF THE WORK ENVIRONMENT
Evaluation of allergen content of manufactured products
Glove evaluation prior to
purchase
Underwear manufacture
(Ratshikhopha et al, SAMJ, 2015)
(Lopata, et al, Int Arch Allergy Immunol, 2007)
MANAGEMENT
1. Exposure avoidance
• Patients with allergic OA should be relocated to a job without exposure, or if this is not possible they should be moved to an area of low exposure
• The use of respirators is usually ineffective in preventing exposure and exacerbations
• Irritant-induced OA or WEA: optimise asthma treatment and reduce exposure to relevant workplace triggers, and if not successful change job to a workplace with fewer triggers in order to control asthma.
• RADS: patients can continue to work in the same job provided measures are taken to prevent further exposures to high concentrations of irritant agents
Early diagnosis and early avoidance of further exposure are key to the management occupational asthma
MANAGEMENT
Recommendations of the Scandinavian workshop on the
management of baker’s allergy and asthma following
surveillance
SYMPTOMS
SENSITISATION
MANAGEMENT
Asthmatics sensitised to flour or
fungal -amylase
Change to non-bakery work
Asthmatics without sensitisation Relocate to less exposed
bakery tasks
Bakers with rhinitis and
sensitisation
Investigate closely and
consider relocation to less
exposed tasks
Bakers sensitised but without
respiratory symptoms
Re-examine annually
Bakers with rhinitis only but
without sensitisation
Do not warrant re-examination
unless symptoms worsen
2. Optimise asthma treatment
Pharmacological treatment of WRA does not differ from
therapy of other types of asthma, and should comply with
the asthma treatment guidelines
Treat co-morbid conditions, e.g. allergic rhinitis
Counsel on cessation of smoking and avoidance of
exposure to common environmental irritants or
aeroallergens to which patients may also be sensitised
Early use of inhaled corticosteroids after the diagnosis
may improve symptoms, but insufficient evidence
whether pharmacological treatment alters course of
asthma in subjects who remain exposed
3. Ongoing follow up and assessment of impairment and
disability
Evaluate degree of impairment (presence of symptoms and
exacerbations, post-bronchodilator FEV1, degree of reversibility
or NSBH, type and dose of medication needed for control) and
disability evaluation (in relation to job)
Assessment is done three weeks after removal from exposure
and after two years when the asthma is stabilised
Asthma symptoms and airway hyperresponsiveness persist in
~70% of patients with occupational asthma, even after several
years of removal from exposure
Good prognostic factors for outcome of occupational asthma:
- early diagnosis
- cessation of exposure to the offending agent
- asthma is not yet severe (lung function preserved at diagnosis)
Monitor patient and if asthma severe or worsens consider job
change if still exposed
SUMMARY:
Diagnosis and
management of
occupational
asthma in the
South African
setting
TAKE HOME MESSAGES
• Work-related asthma should be considered
in all adult patients with new-onset or
worsening asthma
• Early diagnosis and early avoidance of
further exposure are key to the management
occupational asthma
Referral/advice centres for assistance with occupational diseases
Cape Town• Occupational Medicine Clinic (E16), Groote Schuur Hospital, (021)
404 4369• Respiratory Clinic, Tygerberg Hospital,
(021) 938 5524
Johannesburg• National Institute of Occupational Health, Braamfontein, (011)
712 6400• Medical Bureau for Occupational Diseases, Braamfontein, (011)
403 6322
Durban• Occupational Medicine Clinic, King Edward Hospital,
(031) 360 3512/3 or (031) 260 4507