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