Occupational Asthma (OA)

Background

It is estimated that occupational asthma (OA) accounts for 9-15% of adult-onset asthma and is recognised as the most common cause of occupational lung disease worldwide. There are numerous recognised OA allergens. The two most common causes of OA in the UK are flour dust and isocyanates. High-risk occupations include cleaning, chemical processing, spray painting, metalworking, woodworking, plastic and rubber manufacturing and baking.

OA is defined as asthma secondary to immunological or non-immunological stimuli found in the work environment. Causative allergens are categorised as low molecular weight (LMW) and high molecular weight (HMW) proteins. The two recognised forms of OA include allergic OA and irritant-induced asthma (non-allergic). In allergic OA, repeated exposure to HMW proteins produces an IgE-mediated immune response. Level of exposure serves as the greatest risk factor for developing OA. Individual factors such as atopy, smoking history, and genetic factors predispose individuals to developing OA. Non-allergic OA is a result of bronchial hyperresponsiveness following exposure to an irritant substance and does not involve immunological sensitisation. 

Presentation 

Allergic OA features:

• There is normally a history of atopy
• There is a recognised interval period between first exposure and onset of symptoms, which can range from several weeks to several years
• The presence of asthma-related symptoms such as rhinitis and conjunctivitis over a period whilst at work
• Improvement of symptoms when away from the workplace (e.g., on weekends and holidays)

Irritant-induced (non-allergic) OA features:

• Rapid onset of asthma symptoms following exposure to a substance at work
• Time of symptom onset is typically minutes to hours and can persist for longer periods of time (no interval period)
• Symptoms may last up to three months
• There is no association with smoking or atopy

Diagnosis

The diagnosis of OA relies on careful history-taking in order to help identify key risk factors such as atopy, smoking and exposure to sensitising agents and irritants. The following investigations help to support a diagnosis of OA.

Serial peak expiratory flow rate (PEFR) measurements

• This is the first-line investigation for OA
• Standard guidelines recommend PEFR measurements at least four times daily (equally spaced) over a period of at least three weeks
• PEFR measurements should be recorded alongside work tasks and any exposures 
• In work-related diseases, there will be an increase in diurnal variability of PEFR. 

Spirometry (pre- and post-bronchodilator)

• Values may be normal; however, this is useful as it provides a baseline for any future investigations.
• An increase in FEV1 and/or FVC of over 12% following bronchodilation confirms reversible airflow obstruction. This confirms the diagnosis of asthma.

Blood tests

• Specific serum IgE assays- These detect specific IgE antibodies to workplace allergens and can thus confirm sensitisation. 

Management 

The management of OA requires a holistic approach that considers medical and workplace factors. This includes:

• Removing the precipitating agent from the work environment 
• Redeployment within the same occupation
• OA may persist despite the above measures, developing into chronic asthma
  • Pharmacological management is the same as non-occupational asthma

References

• Karr, R. M. et al. (1978) “Occupational asthma,” The Journal of Allergy and Clinical Immunology, 61(1), pp. 54–65. doi: 10.1016/0091-6749(78)90474-8.
• Reid, P. A. and Reid, P. T. (2013) “Occupational lung disease,” The Journal of the Royal College of Physicians of Edinburgh, 43(1), pp. 44–48. doi: 10.4997/JRCPE.2013.111.
• Feary, J., Pinnock, H. and Cullinan, P. (2016) “Occupational asthma,” BMJ (Clinical research ed.), 353, p. i2658. doi: 10.1136/bmj.i2658.
• Kalra, P. A. (ed.) (2014) Essential Revision Notes for MRCP. 4th ed. Knutsford, England: Pastest.
• Tan J, Bernstein JA. Occupational asthma: an overview. Curr Allergy Asthma Rep. 2014 May;14(5):431. doi: 10.1007/s11882-014-0431-y. PMID: 24633615.
• Barber, C. M. et al. (2022) “British Thoracic Society Clinical Statement on occupational asthma,” Thorax, 77(5), pp. 433–442. doi: 10.1136/thoraxjnl-2021-218597.
• Nicholson, P. J. et al. (2005) “Evidence based guidelines for the prevention, identification, and management of occupational asthma,” Occupational and environmental medicine, 62(5), pp. 290–299. doi: 10.1136/oem.2004.016287.

Hypersensitivity pneumonitis

Background

Hypersensitivity Pneumonitis (HP), also known as Extrinsic Allergic Alveolitis (EAA), is an interstitial lung disease (ILD) characterised by alveolar and bronchiolar inflammation triggered by a non-IgE immunological response secondary to repeated inhalation of an antigen.

Pathophysiology

HP is a result of complex genetic predisposition and environmental factors. Differences in susceptibility to HP are related to polymorphisms of the major histocompatibility complex (MHC) class II molecules (mainly HLA-DR and DQ). These are responsible for presentation of processed exogenous antigens to T-lymphocytes, which initiate the antigen-specific immune response.

A combination of type III (immune complex-mediated) and type IV (delayed) hypersensitivity reactions are implicated in HP. Exposure to the causative agent triggers a type III reaction after initial sensitisation. Repetitive exposure leads to a delayed hypersensitivity (Type IV) reaction, triggering activation of CD8 cytotoxic T cells. This leads to macrophage activation and granuloma formation. Disease progression, such as in fibrotic HP, is linked to an exaggerated T-cell immune response, specifically the TH2 response, which is believed to promote collagen deposition and fibrosis of the lung.

Aetiology

There are a vast range of implicated antigens in HP. The most common include the following:

Bacteria/Fungi

• Thermophilic actinomycetes-this includes Micropolyspora faeni and Thermoactinomyces vulgaris
  • Farmer’s lung
    • Occurs following exposure to mouldy crop
    • Micropolyspora faeni is the most common antigen
• Mycobacterium avium complex (MAC)- Found in poorly maintained hot tubs
• Aspergillus clavatus– malt worker’s lung (found in mouldy malt)
• Penicillium casei– cheese-worker’s lung (found in mouldy cheese)

Animal proteins

• Avian proteins– Bird fancier’s lung
  • Found in bird droppings or feathers of birds
  • Includes pigeons, chickens, turkeys, parakeets, and ducks 

Reactive chemicals

• Acid anhydrides 
• Isocyanates- these include varnishes and chemical foams
• Metalworking fluids

In addition, colonisation of various atypical mycobacteria and moulds in wind instruments can be implicated in the development of HP amongst wind instrument players.

Presentation

Traditionally, the clinical presentation of HP has been classified as acute, subacute, and chronic. Recent classification systems now consider separate phenotypes dependent on the presence or absence of fibrosis, thus categorising HP as fibrotic and non-fibrotic.

HP presents heterogeneously; common symptoms of both fibrotic and non-fibrotic disease include dyspnoea and chronic cough. Less common symptoms include constitutional symptoms such as fever, weight loss and malaise. 

Acute presentations are more in keeping with non-fibrotic HP, whereas progressive symptoms are more consistent with fibrotic disease. Smoking is found to be a protective factor in developing HP.

Non-fibrotic HP features:

• Acute presentations typically occur 6 to 18 hours following high-level exposure to a causative agent
  • Symptoms may include fever, malaise, cough, and dyspnoea
• Patients may also present sub-acutely with similar progressive symptoms. This occurs over a period of weeks to months
• Physical examination may be normal- but inspiratory crackles and squeaks can be heard due to small airways inflammation

Fibrotic HP features:

• Insidious onset of dyspnoea, cough, anorexia, and weight loss
• Occurs secondary to chronic exposure to the sensitised antigen
• On examination, digital clubbing, focal or diffuse inspiratory crackles, and inspiratory squeaks may also be present. Wheezing is rare.

Diagnosis 

There is no single gold standard diagnostic test for HP. Diagnosis is based on detailed exposure history, clinical presentation, and a combination of investigations. 

Laboratory tests

• Serum IgG (precipitins) against causative antigens
  • Only indicates exposure to specific antigens rather than diagnosis of HP
  • High false negative rate
  • The specific causative antigen may not be represented in the testing panel due to the vast range of causative agents.

Pulmonary function tests

• Non-fibrotic HP demonstrates a restrictive pattern
• Fibrotic HP- demonstrates both an obstructive and restrictive features

Imaging 

Chest radiography

• Chest x-rays may be normal 
• Where changes are present (more common in fibrotic HP), there are predominantly upper zone reticular interstitial changes with lung volume loss

High-resolution CT scan (HRCT)

• Typical findings in HP include:
  • Centrilobular ground-glass nodules due to bronchiolar inflammation
  • Air trapping occurs following inflammation of small airways, leading to retained air
  • Ground glass changes– interstitial inflammation leads to increased lung density

In HP, HRCT typically demonstrates a “three density pattern” which describes varying areas of attenuation- ground glass changes, decreased lung density (due to air trapping) and also areas of normal lung parenchyma. This is highly specific for HP. Such changes overlap with other forms of ILD. Sparing of bases and air trapping favours a diagnosis of HP.

Bronchoalveolar lavage (BAL)

• Flexible bronchoscopy with BAL typically displays lymphocytosis >30% in HP
• This helps to exclude other lung diseases which may present similarly to HP
• A low CD4+/CD8 + lymphocytosis is suggestive of HP
• Sarcoidosis presents with a high CD4+/CD8+ ratio of >3.5

Lung biopsy

• This should only be considered if a definitive diagnosis cannot be reached despite the above investigations.
• Lung biopsy histology shows a mixture of lung fibrosis, alveolitis and non-caseating granuloma formation.

Management 

Non- pharmacological management 

Antigen avoidance

• Identifying and eliminating the causative antigen is the most crucial step in management. 

Pharmacological management 

Glucocorticoids

• HP may respond to steroids initially and is used in both fibrotic and non-fibrotic disease. However, there is little evidence regarding long-term outcomes or progression of disease. 

Non-steroid therapies

• In fibrotic HP, anti-fibrotic agents have been suggested for treatment
• Nintedanib (a tyrosine kinase inhibitor) is licensed for use in chronic progressive fibrosing ILDs in several countries

References

• Chandra, D. and Cherian, S. V. (2021) Hypersensitivity Pneumonitis. StatPearls Publishing.
• “Erratum: Diagnosis of hypersensitivity pneumonitis in adults: An official ATS/JRS/ALAT clinical practice guideline” (2021) American Journal of Respiratory and Critical Care Medicine, 203(1), pp. 150–151. doi: 10.1164/rccm.v203erratum1.
• Hamblin, M., Prosch, H. and Vašáková, M. (2022) “Diagnosis, course and management of hypersensitivity pneumonitis,” European Respiratory Review: an official journal of the European Respiratory Society, 31(163), p. 210169. doi: 10.1183/16000617.0169-2021.
• Holling, T. M., Schooten, E. and van Den Elsen, P. J. (2004) “Function and regulation of MHC class II molecules in T-lymphocytes: of mice and men,” Human immunology, 65(4), pp. 282–290. doi: 10.1016/j.humimm.2004.01.005.
• Karr, R. M. et al. (1978) “Occupational asthma,” The Journal of allergy and Clinical Immunology, 61(1), pp. 54–65. doi: 10.1016/0091-6749(78)90474-8.
• Reid, P. A. and Reid, P. T. (2013) “Occupational lung disease,” The Journal of the Royal College of Physicians of Edinburgh, 43(1), pp. 44–48. doi: 10.4997/JRCPE.2013.111.

Pneumoconiosis

Background

Pneumoconiosis is a group of chronic interstitial lung diseases that develop following inhalation of mineral or metal dust, predominantly found in the work environment. These include asbestosis, silicosis, coal worker’s pneumoconiosis and berylliosis. The aetiology of pneumoconiosis is detailed below. The main clinical sequelae of pneumoconiosis include progressive pulmonary fibrosis, inflammation and progressive respiratory or heart failure.

Mineral/dust	Disease	Occupation/Industry
Silica	Silicosis	Mining, construction, foundry work, quarrying, sandblasting, ceramics, pottery, glass manufacturing, stone cutting
Beryllium	Berylliosis	Ore mining/processing, ceramics, nuclear bomb manufacturing, insulation industry
Coal dust	Coal worker’s pneumoconiosis	Coal mining
Asbestos	Asbestosis, pleural plaques, pleural thickening, benign pleural effusion, Mesothelioma	Shipyard, construction, mechanic, insulation, plumbers, textiles, cement, tile production NB- asbestos can be passed on clothes or footwear to co-inhabitants

Table 1- Aetiology of pneumoconiosis (Adapted from Table 1, Brown, L. (2013) “ClinicalKey,” Journal of the Medical Library Association: JMLA, 101(4), pp. 342–343. doi: 10.3163/1536-5050.101.4.023. )

Silicosis

Silicosis is caused by inhalation of crystalline silica (silicon dioxide), the most abundant mineral on earth. The main clinical subtypes of silicosis are acute, accelerated, and chronic silicosis. 

Pathophysiology

Following inhalation, silica particles deposit in the airways. This produces macrophage activation, which exerts toxic effects on the lung parenchyma, provoking an inflammatory cytokine response. This process promotes fibrosis of the lung and formation of upper lobe silicotic nodules. 

Silicosis can be further categorised based on radiological findings- simple silicosis and progressive massive fibrosis (PMF). Simple silicosis is characterised by rounded nodules, less than 10mm in size, found predominantly in upper lung zones. In PMF, these nodules coalesce, causing upper lobe lung parenchyma, which causes fibrotic retraction of upper lobes, which contributes to air trapping and emphysema in the lower lobes. 

Presentation

Broad symptoms of chronic and accelerated silicosis include cough and dyspnoea, and examination may reveal a range of findings, including wheeze and crackles. In cases of PMF, respiratory impairment and symptoms are more severe. PMF is not associated with clubbing. 

Unfortunately, once silicosis occurs, the damage is irreversible, and despite removal of the causative agent, it may continue to progress. Inhalation of silica is linked to other diseases such as lung cancer, tuberculosis, connective tissue diseases and renal diseases.

Chronic silicosis features

• Patients are initially asymptomatic until an interval of 10-20 post-exposure.
• Normally associated with simple radiological pattern

Acute silicosis features (silicoproteinosis)

• This occurs following short duration of high-concentration exposure
• Presentation within one year of exposure
• Symptoms include non-productive cough, dyspnoea, weight loss, fatigue, fever, and pleuritic pain.

Accelerated silicosis features

• Onset of symptoms following 5-10 years of exposure
• Accelerated progression of disease
• At higher risk of PMF

Diagnosis

Imaging – CXR/ HRCT

• Simple silicosis features
  • Well-defined upper zone opacities less than 10mm in size
• Progressive Massive Fibrosis features
  • Larger, coalescent nodules
  • Upper lobe fibrosis
  • Hyperinflation of lower lobes 
  • Hilar lymphadenopathy with eggshell calcification

Bronchoalveolar lavage 

• This is used to exclude other differentials
• Opaque effluent consistency
• Foamy macrophages and periodic acid-Schiff (pAS) staining

Berylliosis

Background

Berylliosis (also known as chronic beryllium disease) is a granulomatous lung disease caused by exposure to the alkaline earth metal beryllium. 

Pathophysiology

Beryllium exposure precipitates a delayed hypersensitivity cell-mediated immune response (Type IV hypersensitivity), which involves sensitisation to beryllium. Future exposure triggers proliferation of macrophages and CD4+ T lymphocytes, which aggregate in the lung. Over time, as this response progresses, these cells form noncaseating granulomas, which progress to fibrosis of the lung.

Presentation

• Predominantly a chronic disease, however, acute alveolitis secondary to beryllium exposure has been reported.
• Latency period between exposure and symptom onset varies from three months to thirty years.
• Common symptoms include dry cough, dyspnoea and, less often, constitutional symptoms such as weight loss, fatigue, and night sweats. 
• Physical examination findings include bi-basal crackles, rashes, cutaneous nodules, hepatosplenomegaly and clubbing in advanced disease.

Diagnosis

A definitive diagnosis of berylliosis requires all the following:

1. History of beryllium exposure
2. Beryllium lymphocyte proliferation test (BeLPT)
   • A positive blood or BAL test confirms sensitisation to beryllium
3. Tissue biopsy from bronchoscopy
   • This reveals non-caseating granulomas

Management

Corticosteroids are used in both acute and chronic berylliosis. In Chronic berylliosis, long-term glucocorticoid therapy is utilised with regular assessment (PFTs and imaging) to gauge response to treatment and plan future therapy. Immunosuppressants such as methotrexate and azathioprine are utilised in those who fail to respond to steroid therapy.

Coal worker’s pneumoconiosis (CWP)

Coal worker’s pneumoconiosis arises from chronic coal dust inhalation. Like silicosis, CWP may present as simple pneumoconiosis or may progress to progressive massive fibrosis (PMF). Incidence of disease is linked to total dust exposure.

Pathophysiology

Following inhalation, coal particles are retained in the alveoli. Macrophages then engulf these particles, triggering an immune response that precipitates fibrotic lung changes. CWP is also a known cause of chronic obstructive pulmonary disease (COPD).

Presentation

Simple CWP features:

• Asymptomatic
• Incidental small, rounded opacities found in the upper zones
• Associated with focal emphysema

Progressive massive fibrosis features:

• Coalescence of small nodules to form larger, widespread masses of fibrotic tissue
• Lesions may cavitate
• Symptoms include progressive dyspnoea, cough, and black productive sputum.

Caplan syndrome features:

• This syndrome describes a combination of pneumoconiosis and features of/diagnosis of Rheumatoid Arthritis

Diagnosis 

Imaging 

Chest x-ray findings are similar to those found in Silicosis- small, rounded opacities in upper zones.

Pulmonary function tests

Mixed obstructive (due to emphysematous changes) and restrictive changes (due to fibrotic changes) 

Asbestosis

Asbestosis is a fibrotic lung disease caused by asbestos inhalation. Other asbestos-related pleural abnormalities may also present concurrently.

Pathophysiology

The deposition of inhaled asbestos fibres leads to alveolar macrophage alveolitis. This triggers an inflammatory response by releasing cytokines, including tumour necrosis factor (TNF) and interleukin-1 beta. This initiates the fibrotic process, which predominantly occurs in the lower lobes.

The deposition of inhaled asbestos fibres leads to alveolar macrophage alveolitis. This triggers an inflammatory response by releasing cytokines, including tumour necrosis factor (TNF) and interleukin-1 beta. This initiates the fibrotic process, which predominantly occurs in the lower lobes. 

Presentation

• History of progressive dyspnoea
• Cough, wheezing, and sputum production are less common
• Examination findings include bibasal end-inspiratory crackles, and clubbing may also occur
• Interval period between symptoms and exposure is normally over 20 years
• Severity of fibrotic disease is dependent on cumulative dose of exposure

Diagnosis

Imaging- Chest X-Ray/ HRCT

• Reticulonodular changes primarily in the lower lobes
• Concomitant pleural thickening and pleural plaques
• In advanced disease, reticulonodular changes become diffuse

Pulmonary function testing

• Restrictive pattern due to fibrotic changes
• Reduced transfer factor
• An obstructive pattern is uncommon in asbestosis- this is normally secondary to concomitant cigarette smoking history.

Overall management of Pneumoconiosis

There is no curative treatment for the chronic forms of pneumoconiosis (excluding berylliosis), and once fibrosis ensues, prognosis is poor. Therefore, the mainstay of management is supportive and focuses on symptom control and slowing or halting disease progression. 

• Early identification and removal of occupational exposure
• Smoking cessation
  • There is an increased risk of malignancy with both inhalation of mineral dust and smoking.
  • Cigarette smoking may also accelerate progression of pneumoconiosis 
• Bronchodilator therapy
  • COPD can be a complication of pneumoconiosis; therefore, in the presence of obstructive airways disease, bronchodilator therapy should be utilised
• Pulmonary rehabilitation
  • This a structured programme that incorporates exercise, patient health education, and behavioural change activities to improve symptom control, exercise tolerance and overall quality of life for chronic lung disease patients
• Long-term oxygen therapy (LTOT)
  • In end-stage ILD secondary to pneumoconiosis, LTOT may improve life expectancy.
  • Slows down progression of pulmonary hypertension secondary to hypoxaemia 

References

• Brown, L. (2013) “ClinicalKey,” Journal of the Medical Library Association: JMLA, 101(4), pp. 342–343. doi: 10.3163/1536-5050.101.4.023.
• Silicosis (no date) Bcmj.org. Available at: https://bcmj.org/worksafebc/silicosis (Accessed: April 12, 2022).
• bestpractice.bmj.com. (n.d.). Pneumoconioses – Symptoms, diagnosis and treatment | BMJ Best Practice. [online] Available at: https://bestpractice.bmj.com/topics/en-gb/1112?q=Pneumoconioses&c=suggested [Accessed 12 Apr. 2022].
• Sizar, O. and Talati, R. (2022). Berylliosis. [online] PubMed. Available at: https://www.ncbi.nlm.nih.gov/books/NBK470364/ [Accessed 12 Apr. 2022].
• www.uptodate.com. (n.d.). UpToDate. [online] Available at: https://www.uptodate.com/contents/asbestos-related-pleuropulmonary-disease.
• Qi, X.-M. et al. (2021) “Pneumoconiosis: current status and future prospects: Current status and future prospects,” Chinese Medical Journal, 134(8), pp. 898–907. doi: 10.1097/cm9.0000000000001461.
• DeLight N, Sachs H. Pneumoconiosis. [Updated 2021 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK555902/
• Hardinge, M. et al. (2015) “British Thoracic Society guidelines for home oxygen use in adults,” Thorax, 70 Suppl 1(Suppl 1), pp. i1-43. doi: 10.1136/thoraxjnl-2015-206865.
• Konečný, P. et al. (2018) “Immunity to the Dual Threat of Silica Exposure and Mycobacterium tuberculosis,” Frontiers in Immunology, 9, p. 3069. doi: 10.3389/fimmu.2018.03069.
• bestpractice.bmj.com. (n.d.). Asbestosis – Symptoms, diagnosis and treatment | BMJ Best Practice. [online] Available at: https://bestpractice.bmj.com/topics/en-gb/650?q=Asbestosis&c=suggested [Accessed 12 Apr. 2022].
• Qi XM, Luo Y, Song MY, Liu Y, Shu T, Liu Y, Pang JL, Wang J, Wang C. Pneumoconiosis: current status and future prospects. Chin Med J (Engl). 2021 Apr 13;134(8):898-907. doi: 10.1097/CM9.0000000000001461. PMID: 33879753; PMCID: PMC8078400.

Asbestos-related lung disease

Background

Asbestos describes a group of naturally occurring carcinogenic fibres that consist of magnesium silicates found in a variety of construction materials. Blue (crocidolite) asbestos is recognised as the most carcinogenic form of asbestos. Asbestos exposure can precipitate many pulmonary complications, including asbestosis, benign pleural disease, and malignant disease (Mesothelioma and lung cancer).

Pleural disease

Sequelae of asbestos exposure include pleural effusions, pleural plaques, and pleural thickening. These may occur independently or concomitantly. 

Pleural effusions features:

• Duration of time between exposure to onset of effusion is reported as 15 to 46 years
• Usually small and unilateral 
• Pleural fluid is exudative and can be blood-stained
• Other sinister causes such as Mesothelioma and lung malignancy, are to be investigated first; therefore, may require thoracoscopy +/- pleural biopsy
• Prognosis– normally self-resolving, and approximately one-third recur

Pleural plaques (PP) features:

• Benign finding on the parietal pleura 
• Most common manifestation of asbestos exposure
• They appear approximately twenty years after asbestos exposure
• Usually, asymptomatic and incidental findings

Pleural thickening features:

• Visceral pleural thickening secondary to asbestos exposure
• Adhesion of visceral and parietal pleura leading to diffuse pleural thickening (DPT)
• Extensive DPT can lead to restrictive lung disease and symptoms of dyspnoea and chest pain

Mesothelioma:

• Malignant disease of the pleura
• Asbestos exposure accounts for 85% of cases of Mesothelioma in the UK
• Latency period of over 30 years from exposure to presentation
• Chest pain and dyspnoea are the most common presenting symptoms as a result of pleural effusion
• Most common x-ray findings include pleural effusion and pleural thickening

• Prognosis is poor, with an average life expectancy between one to two years from diagnosis

References

• Murphy, D. C. et al. (2020) “A review of malignant pleural mesothelioma in a large North East UK pleural centre,” Pleura and peritoneum, 6(1), p. 20200144. doi: 10.1515/pp-2020-0144.
• Hajj, G. N. M. et al. (2021) “Malignant pleural mesothelioma: an update,” Jornal brasileiro de pneumologia: publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia, 47(6), p. e20210129. doi: 10.36416/1806-3756/e20210129.