Hypersensitivity pneumonitis

• Hypersensitivity pneumonitis is an immune-mediated interstitial lung disease produced by repeated inhalation of an environmental or occupational antigen in a susceptible person.
• The disease spans a spectrum from acute, inflammatory, often reversible lung injury after heavy exposure to slowly progressive fibrosis that can mimic idiopathic pulmonary fibrosis.
• The older labels acute, subacute and chronic have been replaced in current guidance by two phenotypes: non-fibrotic (purely inflammatory) and fibrotic (inflammatory plus fibrotic) disease; fibrosis is the main determinant of outcome.
• Identifying and removing the antigen is the only intervention that reliably changes the natural history; drugs control inflammation and, when disease progresses despite this, aim to slow fibrotic decline.
• The diagnosis rests on exposure history, the high-resolution CT pattern, bronchoalveolar lavage lymphocytosis and, when needed, lung biopsy, all discussed in a multidisciplinary setting.

By the end of this page you should be able to:

1. Explain hypersensitivity pneumonitis as a combined type III and type IV immune reaction to an inhaled antigen, and distinguish it from asthma and other occupational airway diseases.
2. List the common exposure categories (farmer's lung, bird fancier's lung, humidifier lung, hot tub lung, mould and other bioaerosols) and explain why finding the source matters.
3. Classify a patient as non-fibrotic or fibrotic (and relate this to the older acute, subacute and chronic descriptions), and predict reversibility.
4. Interpret the characteristic high-resolution CT findings: ground-glass opacities, centrilobular nodules, mosaic attenuation, air trapping and the three-density pattern.
5. Use bronchoalveolar lavage lymphocyte counts, serum precipitins and biopsy findings as probability modifiers rather than stand-alone diagnostic tests.
6. Separate hypersensitivity pneumonitis from asthma, sarcoidosis and idiopathic pulmonary fibrosis on exposure, distribution and histology.
7. Outline a phenotype-based management plan: antigen avoidance, corticosteroids, immunosuppression and antifibrotics, with supportive care and transplant referral.
8. Give a guarded prognosis and recognise the red flags of progressive fibrotic disease.

The reaction is not a simple allergy. Type III (immune-complex, largely IgG) and type IV (T-helper cell) responses both participate: an inhaled antigen is processed by the innate immune system, antibody is generated, and T cells accumulate around small airways and alveoli, forming poorly formed non-necrotizing granulomas. Chronic or repeated injury can switch the process towards epithelial damage and fibroblast activation. ^[1]

The inciting agents are extraordinarily diverse. Recent reviews have catalogued more than 200 inciting agents and over 1,000 potential triggers, spanning microbes (fungal spores, thermophilic actinomycetes, non-tuberculous mycobacteria), animal proteins (bird droppings, feathers), plant proteins and low molecular weight chemicals that act as haptens. ^[2][3] Exposure occurs at home, at work and during hobbies. Crucially, no antigen is identified in 30 to 50% of cases evaluated in interstitial lung disease referral centres, despite a thorough history; difficulty in identifying an antigen should never be used to exclude the diagnosis. ^[1][2]

Hypersensitivity pneumonitis begins as a bronchiolocentric interstitial disease, not a pure airway disease, and that distinction organises the whole topic.

Two schemes are in circulation, and students confuse them.

Older clinical labels. Hypersensitivity pneumonitis was historically divided by symptom duration into acute (hours to days after heavy exposure, with fever, chills, cough and breathlessness), subacute (weeks to months of repeated lower-level exposure) and chronic (insidious cough and breathlessness with fibrosis). Current guidelines regard these labels as of little clinical value, because they overlap and do not predict outcome well. ^[1][6]

Current phenotype-based classification. The 2020 ATS/JRS/ALAT guideline (American Thoracic Society / Japanese Respiratory Society / Asociacion Latinoamericana del Torax) categorises patients as non-fibrotic (purely inflammatory) or fibrotic (mixed inflammatory plus fibrotic, or purely fibrotic) hypersensitivity pneumonitis, on imaging and, where available, histology. ^[1] The American College of Chest Physicians expert panel report adopts a similar non-fibrotic / fibrotic split. ^[6] Fibrosis is the single most important determinant of prognosis and of treatment choice. ^[1] A patient whose high-resolution CT shows only ground-glass change, centrilobular nodules, mosaic attenuation and air trapping has non-fibrotic disease; a patient with reticulation, traction bronchiectasis or honeycombing has fibrotic disease, even if inflammation is also present. ^[1][2]

In clinical cohorts, non-fibrotic disease tends to show acute or subacute onset, often reverses with antigen removal and carries a favourable prognosis. Fibrotic disease tends to show insidious onset, a weaker temporal relationship with exposure, a potentially progressive and irreversible course and poorer prognosis. Cryptogenic hypersensitivity pneumonitis (hypersensitivity pneumonitis of undetermined cause) is the label when the typical picture is present but no inciting antigen can be found. ^[2][6]

Hypersensitivity pneumonitis is uncommon, and its true burden is uncertain because diagnostic criteria and exposure patterns vary. Estimates suggest it accounts for about 2 to 15% of all interstitial lung diseases, though the proportion in individual registries ranges from 2 to 47%. ^[2][1] A large United States registry reported about 5% of patients referred to specialised ILD centres had hypersensitivity pneumonitis, with an annual incidence of 1.28 to 1.94 cases per 100,000 people and a prevalence of 1.67 to 2.71 per 100,000. ^[2] Available general-population studies estimate an incidence of 0.3 to 0.9 per 100,000. ^[1] In the United Kingdom, incidence during 1991 to 2003 was 0.9 per 100,000, nearly twice that reported in Spain. ^[2][1] An Indian ILD registry found hypersensitivity pneumonitis the most common ILD at 47.3%, ahead of connective tissue disease-associated ILD at 13.9% and idiopathic pulmonary fibrosis at 13.7%. ^[2] In Brazil, hypersensitivity pneumonitis made up 23% of ILD diagnoses in one series. ^[2] A meta-analysis of occupational hypersensitivity pneumonitis found prevalence of 16.71% in South America, 15.19% in Asia and 8.52% in North America. ^[2] Bird breeder's disease has been reported at 4.9 per 100,000 people over ten years, or 54.6 per 100,000 bird breeders. ^[1]

Average age at diagnosis is the fifth or sixth decade, although the disease occurs in younger adults and in children; childhood hypersensitivity pneumonitis may represent up to half of all childhood interstitial lung diseases. ^[1] Antigen is identified in only 30 to 50% of cases, so the inability to find one is common in referral practice. ^[1][2]

Hypersensitivity pneumonitis is not caused by a single organism or chemical. It is the result of host immune reactivity meeting a sufficient antigen load in a susceptible lung: the same mouldy house or pigeon loft causes disease in only some people. Over 200 inciting agents have been catalogued in six categories: fungal, animal protein, bacterial, mycobacterial, plant protein, and chemical or metal exposure. ^[3]

Major exposure categories:

• Farmer's lung: thermophilic actinomycetes and fungi in mouldy hay, grain and silage, classically in cool, humid climates. ^[3][2]
• Bird fancier's lung: avian proteins in pigeon, budgerigar and other bird droppings and dust, including a loft, a dovecote, or a feather-filled duvet. This is among the most common causes worldwide. ^[2][6]
• Humidifier lung: bacteria, fungi and amoebae in contaminated humidifiers, air conditioners, ventilation systems and water reservoirs. ^[2][3]
• Hot tub lung: non-tuberculous mycobacteria in aerosols from hot tubs and spas. This can be hard to separate from mycobacterial infection, so multidisciplinary discussion matters. ^[2][3]
• Mould and other bioaerosols: Aspergillus, Penicillium, Cladosporium and similar fungi on water-damaged building materials, compost, decaying vegetation, mushroom cultivation and food processing. ^[3][5]
• Other occupational or domestic antigens: grain flour, malt, wood dust, isocyanates, acid anhydrides, acrylates, cobalt and other metals, and pharmaceuticals. ^[3][5]

Susceptibility is governed by the type, intensity, frequency and duration of exposure, by genetic susceptibility including HLA-DR and HLA-DQ alleles, MUC5B promoter variants and telomere-related genes, and by host factors such as age and smoking. ^[2] Smoking dampens IgG precipitin responses while promoting a fibrotic repair pattern, so it shifts the disease toward fibrosis and insidious, chronic presentation. ^[2][6] When no antigen is identified, disease tends to present more aggressively, with greater likelihood of chronicity and worse survival. ^[2]

The process begins with inhalation of an antigen small enough to reach the alveoli. In a susceptible host, antigen-presenting cells drive both humoral and T-cell responses: antigen-specific IgG antibodies are produced, and CD4 T cells polarise towards Th1 and Th17 phenotypes, releasing interferon gamma, interleukin-17 and tumour necrosis factor. The result is a predominantly lymphocytic, granulomatous inflammation centred on small airways and alveoli. ^[1][2]

Early (non-fibrotic) disease is dominated by this inflammatory, T-cell-driven process and can resolve if the antigen is removed. With repeated or long-standing exposure, epithelial injury, impaired repair, fibroblast activation and extracellular matrix deposition take over, producing airway-centred fibrosis that may resemble other fibrosing interstitial diseases, including usual interstitial pneumonia. ^[1][2] Neutrophilic inflammation and impaired regulatory T-cell function may contribute in some phases. ^[1] Telomere-related variants and MUC5B promoter variants are associated with more fibrosis, a progressive course and shorter transplant-free survival, echoing observations in idiopathic pulmonary fibrosis. ^[2][6]

The practical consequence is that the window for reversibility closes as fibrosis develops; this is why early recognition and antigen avoidance matter.

Symptoms are nonspecific and overlap with other interstitial lung diseases, which explains diagnostic delay. Common features are progressive exertional dyspnoea, nonproductive cough and fatigue, often with unintentional weight loss in chronic cases. Fever, chills, malaise and chest tightness are more frequent with ongoing high-level exposure, particularly in non-fibrotic disease. ^[2] Inspiratory crackles are usual; squawks may be heard with bronchiolitis; digital clubbing is rare but can appear in advanced fibrotic disease. ^[2][1] Patients with advanced disease, especially those with hypoxaemia and group 3 pulmonary hypertension, may show signs of right-sided heart failure. ^[2]

Non-fibrotic disease often presents acutely or subacutely with cough, dyspnoea, fever and flu-like symptoms, usually with a clear and recent exposure. Fibrotic disease presents insidiously, with chronic dyspnoea and cough, often with an unclear or distant exposure, and may resemble idiopathic pulmonary fibrosis. ^[2]

A typical same-day vignette: a 55-year-old pigeon breeder develops breathlessness and cough after cleaning a loft, with fever, chills and crackles; pulmonary function improves after the loft is cleared."> The same person, five years later and still exposed, presents with insidious breathlessness, a nonproductive cough and fibrosis on high-resolution CT. The first presentation is non-fibrotic disease; the second is fibrotic disease.

Hypersensitivity pneumonitis must be separated from three broad groups: airway diseases (especially asthma and occupational asthma), granulomatous diseases (especially sarcoidosis), and other fibrosing interstitial lung diseases (especially idiopathic pulmonary fibrosis).

The absence of an antigen does not exclude hypersensitivity pneumonitis: in one prospective series, 43% of patients meeting criteria for idiopathic pulmonary fibrosis were reclassified as chronic hypersensitivity pneumonitis after further evaluation with exposure questionnaires, serum IgG testing, bronchial challenge and surgical biopsy. ^[3] Figure 2 from the Bridi review and its references are not reproduced here; the key clinical lesson is to revisit the exposure history repeatedly.

Mosaic attenuation is common in fibrotic hypersensitivity pneumonitis but can also be seen in idiopathic pulmonary fibrosis; the three-density pattern, however, is highly specific for fibrotic hypersensitivity pneumonitis in the appropriate clinical context. ^[3][2]

High-resolution CT is the central investigation. Scanning should include volumetric acquisition in the supine position at deep inspiration and after prolonged expiration; a prone acquisition is usually unnecessary. ^[1] The technical protocol specifies non-contrast imaging, submillimetre collimation, thin-section reconstruction of 1.5 mm or less, and a reduced radiation dose. ^[1]

• Non-fibrotic disease: diffuse ground-glass opacities, profuse centrilobular nodules and marked air trapping, often with a diffuse distribution. ^[2]
• Fibrotic disease: reticulation, traction bronchiectasis or bronchiectasis and honeycombing, often with mosaic attenuation, centrilobular nodules, air trapping and the three-density pattern, distributed randomly in both axial and craniocaudal directions. ^[2][1]
• Three-density pattern: sharply demarcated areas of normal-appearing lung, high attenuation (ground-glass opacity) and low attenuation (luccency) with decreased vascularity. It reflects coexisting obstructive small airway disease and infiltrative disease and is highly specific for fibrotic hypersensitivity pneumonitis. ^[3][1]
• Terms matter: mosaic attenuation is a generic patchwork of differing attenuation; air trapping is exclusively an expiratory finding of abnormal air retention distal to obstruction. The two are not synonymous. ^[1]

The 2020 ATS/JRS/ALAT guideline suggests serum IgG testing against HP-related antigens with very low confidence, because sIgG identifies exposure rather than disease or causality. ^[1][5] A practical study of 219 subjects proposed cut-offs (in mgA per litre) of 33 for Aspergillus fumigatus, 22 for Penicillium chrysogenum, 34 for Cladosporium herbarum and 8 for Micropolyspora faeni by the 95th percentile method. ^[5] The four-mould panel (any of the four elevated) showed 57.1% sensitivity and 78.1% specificity for distinguishing hypersensitivity pneumonitis from other interstitial lung diseases. ^[5] A pooled sIgG using a Youden-derived cut-off of 53 mgA per litre gave a positive test a likelihood ratio of 3.29 and a negative test 0.51; at a pre-test probability of 61%, a positive test raises post-test probability to about 84% and a negative test lowers it to about 44%. ^[5] Multivariable analysis found an adjusted odds ratio of 4.03 for a positive four-mould panel. ^[5] These tests therefore refine a multi-component diagnosis; they must not be used in isolation. ^[5]

When standard panels are negative but clinical suspicion remains high, testing serum specific IgG against environmental material collected directly from the patient's surroundings as a customised assay can improve yield. ^[3]

Bronchoalveolar lavage is a minimally invasive adjunct. Current guidelines define a normal profile as more than 80% alveolar macrophages, fewer than 15% lymphocytes, fewer than 3% neutrophils and about 0.5% eosinophils and mast cells. ^[4] Lymphocytosis supports hypersensitivity pneumonitis, particularly above 30%, but no universally accepted threshold exists and overlap with cellular nonspecific interstitial pneumonia (moderate lymphocytosis 30 to 50%) is substantial. ^[4][6]

• Lymphocytes over 30% are supportive of hypersensitivity pneumonitis when exposure history and imaging are compatible; in fibrotic interstitial lung disease, lymphocytes over 30% are highly specific but their absence does not exclude the disease. ^[6][4]
• Lymphocytes over 50%, especially with mixed mild granulocytosis and a compatible exposure, provide strong support. ^[4][6]
• In non-fibrotic disease, absence of lymphocytosis lowers probability enough to exclude hypersensitivity pneumonitis in the sampled area. ^[6][4]
• CD4/CD8 ratio is often decreased in hypersensitivity pneumonitis; an elevated ratio favours sarcoidosis. ^[4]
• A high premorbid probability changes interpretation: with a typical exposure and compatible imaging, lavage may add little; with discordant history and imaging, it can tip the diagnosis. ^[6]
• Normal findings effectively exclude active hypersensitivity pneumonitis in the lavaged segment only, not elsewhere. ^[4]

Typical patterns are restrictive with reduced forced vital capacity and diffusing capacity; small airway inflammation can also produce obstruction and air trapping. Pulmonary function tests measure severity, progression and response, and are central to follow-up.

Biopsy is reserved for cases where clinical, radiological and lavage data leave diagnostic uncertainty. Non-fibrotic hypersensitivity pneumonitis typically shows small airway involvement, uniform cellular interstitial inflammation that is predominantly lymphocytic, and at least one poorly formed granuloma or multinucleated giant cell; granulomas are supportive rather than mandatory. ^[6] Fibrotic hypersensitivity pneumonitis shows airway-centred fibrosis with or without widespread peribronchiolar metaplasia, fibrosing interstitial pneumonia and poorly formed granulomas; granulomas become less common as fibrosis advances. Peribronchiolar metaplasia affecting more than 50% of bronchioles makes hypersensitivity pneumonitis more likely. ^[6] Centrilobular fibrosis and bridging fibrosis are characteristic. ^[2]

Transbronchial cryobiopsy is increasingly used at expert centres; surgical lung biopsy is more definitive but carries higher morbidity. ^[2][6]

Diagnosis is probability-based and should be made in multidisciplinary discussion. The two major guidelines differ in emphasis: the ATS/JRS/ALAT framework integrates exposure assessment, high-resolution CT patterns and bronchoalveolar lavage lymphocytosis; the CHEST report places greater weight on a clear, identifiable exposure and maintains a higher threshold for diagnosis in its absence. ^[2][6] In one prospective comparison of 213 confirmed cases, ATS/JRS/ALAT classified 18% as definite, 42% high confidence, 34% moderate and 4% low confidence, while CHEST classified 65% definite, 27% high and 7% low. ^[2]

Elimination of the inciting antigen is the cornerstone of therapy and is the main measure that changes outcome. ^[2][6] Antigen avoidance is far more effective than personal protective equipment. ^[2] Complete avoidance is associated with elimination of recurrences and prevention of progression to fibrosis, whereas incomplete avoidance is linked to relapse and fibrotic progression. ^[2] Strict avoidance has been associated with roughly halving the risk of death or lung transplantation even in fibrotic disease, while suspected but unavoidable antigens and unidentified exposures are associated with a more than twofold higher risk of adverse outcomes. ^[2] Because exposures occur at home as well as work, remediation often requires bird and feather removal, deep cleaning of soft furnishings, workplace change or relocation; patients unable to do these need honest, practical counselling. ^[2]

Corticosteroids provide symptomatic and functional relief in inflammatory disease, particularly non-fibrotic disease, but evidence for long-term benefit or slowing of fibrosis is limited. ^[2][6] A randomised trial of 36 patients with acute farmer's lung found prednisolone improved diffusing capacity at one month but no benefit in forced vital capacity or diffusing capacity at five years. ^[2] In one retrospective fibrotic and non-fibrotic cohort, corticosteroids plus antigen avoidance improved lung function only in non-fibrotic patients, converting a monthly forced vital capacity decline of 0.35% into an increase of 0.84% (p under 0.001). ^[2] Response is more likely when there is BAL lymphocytosis above 30% or extensive ground-glass opacity. ^[2] Typical starting dose is 0.5 mg per kg per day, tapered over weeks; some authors use 0.5 to 1 mg per kg per day for 6 to 12 weeks. ^[2] Relapse is common if the antigen is not eliminated. ^[2]

Azathioprine or mycophenolate mofetil are used in corticosteroid-dependent or relapsing inflammatory disease; they may stabilise lung function and reduce steroid requirements, with fewer metabolic complications than prolonged corticosteroids. ^[2][3] Retrospective studies show stabilisation or modest improvements in forced vital capacity and diffusing capacity, especially in non-fibrotic phenotypes; one retrospective study of 20 patients found rituximab stabilised or improved lung function in disease not responding to antigen avoidance and corticosteroids. ^[6][3] In fibrotic disease, benefit is uncertain, and combination with corticosteroids has not consistently outperformed corticosteroids alone. ^[6][2] Cyclophosphamide has been used in severe or rapidly progressive cases. ^[2]

Caution is needed: retrospective data raised concerns about chronic immunosuppression after the PANTHER-IPF experience with prednisone plus azathioprine in idiopathic pulmonary fibrosis; patients with short telomere length or fibrotic disease may be harmed rather than helped. ^[3][6] Biologically enriched trials are awaited.

Fibrotic hypersensitivity pneumonitis, particularly when it shows a progressive fibrosing phenotype resembling idiopathic pulmonary fibrosis, may be treated with antifibrotics. Nintedanib slowed the rate of forced vital capacity decline over 52 weeks by 57% compared with placebo in the INBUILD trial of 663 patients with progressive fibrosing interstitial lung diseases (not idiopathic pulmonary fibrosis); 173 patients (26%) had fibrotic hypersensitivity pneumonitis, and subgroup analyses suggested consistent benefit. ^[6] Pirfenidone has less robust evidence: the RELIEF study of progressive pulmonary fibrosis, which included 57 patients with hypersensitivity pneumonitis out of 127 enrolled, found a smaller decline in percent predicted forced vital capacity over 48 weeks than placebo; the study was terminated early. ^[6] Emerging agents such as nerandomilast are under evaluation. ^[2] Antifibrotics complement rather than replace antigen avoidance and anti-inflammatory treatment.

Antigen-specific management also includes vaccination, and many patients are monitored every six months initially with spirometry and high-resolution CT annually as indicated. ^[2]

Oxygen supplementation should maintain arterial oxygen saturation above 88 to 90% in patients with hypoxaemia. ^[2] Pulmonary rehabilitation improves exercise tolerance and quality of life. ^[2] Group 3 pulmonary hypertension, with reported prevalence of 28.3 to 59% in fibrotic hypersensitivity pneumonitis, worsens exercise capacity and survival and should be detected early. ^[2]

Lung transplantation is an option in advanced or progressive fibrotic disease. Among 31 patients with hypersensitivity pneumonitis transplanted at a single centre between 2000 and 2013, one-, three- and five-year survival was 96%, 89% and 89%. ^[6] Referral criteria include severe functional impairment (forced vital capacity under 50 to 60% predicted and diffusing capacity under 40% predicted), rapid decline or long-term oxygen dependence; early referral maximises eligibility. ^[2][6] Palliative care should be added when disease-modifying therapy is no longer effective or feasible. ^[2]

• Progressive fibrotic phenotype: some patients with fibrotic hypersensitivity pneumonitis progress with increasing fibrous abnormalities, declining lung function and early mortality. ^[6]
• Acute exacerbations: acute deteriorations can occur and carry high mortality. ^[6]
• Group 3 pulmonary hypertension: common in fibrotic disease and worsens symptoms and survival. ^[2]
• Respiratory failure and need for long-term oxygen therapy. ^[2]
• Comorbidity burden: common in fibrotic interstitial lung disease and linked to higher mortality. ^[2]
• Misdiagnosis and inappropriate therapy: a fibrotic patient labelled as idiopathic pulmonary fibrosis may miss antigen avoidance and the antifibrotic pathway. ^[3][6]

Non-fibrotic disease that avoids ongoing exposure often has a favourable course and may fully recover. ^[1][2] Fibrotic disease is different. Patients with non-honeycomb fibrotic hypersensitivity pneumonitis survived a median of more than 7.95 years in one comparison versus 5.20 years for idiopathic pulmonary fibrosis, but the presence of honeycombing in either disease carries a median survival of about 2.8 years. ^[2] Fibrotic patients with a usual interstitial pneumonia-like pattern have reduced survival similar to other fibrosing diseases. ^[1][2]

Factors associated with worse survival:

• inability to remove or identify the inciting antigen; ^[6][2]
• older age, male sex and smoking history; ^[6][2]
• lower BAL lymphocytosis; ^[6][2]
• presence and extent of fibrosis, honeycombing and traction bronchiectasis on high-resolution CT, with mosaic attenuation and air trapping associated with better survival; ^[6][2]
• usual interstitial pneumonia pattern on histology; ^[6][2]
• lower forced vital capacity or diffusing capacity, or a declining forced vital capacity; ^[6][2]
• telomere-related or MUC5B variants. ^[2][6]

Antigen identification itself predicts better outcome because removal is possible: in one series, identifying an antigen was associated with improved survival. ^[6] Conversely, unidentified antigen combined with a usual interstitial pneumonia pattern predicts relentless decline. ^[6]

There is no way to prevent the genetic susceptibility, but the burden can be reduced:

• All patients and at-risk workers need a structured exposure review at every visit, because exposures change and new sensitising agents may be introduced. ^[2]
• Control the source: remediate water damage, remove mould, service humidifiers, and (where possible) separate people from birds and feathers. ^[2][3]
• Smoking cessation matters: smoking promotes fibrotic disease and dampens antibody responses. ^[6][2]
• Surveillance of bird breeders and farmers with high-level exposure, and education about respiratory symptoms, may shorten delay. ^[1][2]
• A family history should be taken; genetic variants (HLA-DR, HLA-DQ, MUC5B, telomere-related genes) are associated with susceptibility and progression. ^[2]

Children. Hypersensitivity pneumonitis occurs in children and may account for up to half of childhood interstitial lung disease. ^[1] Paediatric antigen exposures (bird feathers, moulds, indoor air) may be domestic, and the same non-fibrotic/fibrotic framework applies.

Older adults. Presentation is more often insidious and fibrotic; delay is common because exposure is remote or unrecognised. ^[1]

Occupational settings. Farmer's lung and other workplace exposures are preventable; hygienist assessment, dust and moisture control, and (when possible) job change are more effective than masks. ^[2][3]

Pregnancy and immunocompromise. Published evidence specific to these groups is limited. Management should follow the same phenotype-based principles, with multidisciplinary care; no reliable source-derived dose adjustments were identified, so local specialists and formularies must guide therapy.

• A detailed, structured exposure history is free and is the single most informative test; it should be repeated because patients often omit exposures they regard as ordinary. ^[2][1]
• Where high-resolution CT is unavailable, chest radiography plus clinical context may suggest the diagnosis but cannot stage fibrosis; referral for CT whenever possible is worthwhile.
• Antigen avoidance (cleaning, bird removal, workplace change) works everywhere and should be the first intervention. ^[2]
• Serum precipitins and bronchoalveolar lavage are often unavailable; interpret them as exposure tests, not proof. ^[5][4]
• Corticosteroids at 0.5 mg per kg per day are inexpensive and are the main anti-inflammatory option when inflammation is suspected, but they are ineffective once fibrosis dominates. ^[2]
• Nintedanib and transplantation are unlikely to be available; care then focuses on avoidance, low-dose steroids used judiciously, oxygen, rehabilitation and palliation. ^[2]
• Hot tub and humidifier exposures should be recognised as avoidable sources of non-tuberculous mycobacteria and fungi. ^[2][3]

• Hypersensitivity pneumonitis is a type III and type IV immune reaction to an inhaled antigen, producing bronchiolocentric inflammation that may heal or progress to fibrosis.
• It accounts for about 2 to 15% of interstitial lung diseases, with incidence of 0.3 to 0.9 per 100,000 and prevalence of 1.67 to 2.71 per 100,000 in the United States; the antigen remains unidentified in 30 to 50% of cases. ^[2][1]
• Older acute/subacute/chronic labels are now considered of little value; guidelines divide disease into non-fibrotic and fibrotic phenotypes based on imaging and histology. ^[1][6]
• Farmer's lung, bird fancier's lung, humidifier lung, hot tub lung and mould or bioaerosol exposures dominate; more than 200 agents across six categories have been described. ^[3]
• Non-fibrotic disease presents acutely or subacutely and often reverses with antigen removal; fibrotic disease presents insidiously and behaves like other fibrosing interstitial diseases. ^[2]
• High-resolution CT is the key test: ground-glass opacities, profuse centrilobular nodules and air trapping in non-fibrotic disease; fibrosis and the three-density pattern in fibrotic disease; the three-density pattern is 93% specific for fibrotic hypersensitivity pneumonitis. ^[2][3]
• Bronchoalveolar lavage lymphocytosis above 30% supports the diagnosis; non-fibrotic absence argues against it; no threshold is perfect. ^[6][4]
• Serum IgG precipitins identify exposure, not disease; 95th percentile cut-offs such as 33 mgA per litre for Aspergillus fumigatus refine multi-component diagnosis. ^[5]
• Histology shows cellular bronchiolitis and poorly formed granulomas in non-fibrotic disease, and airway-centred fibrosis with or without peribronchiolar metaplasia in fibrotic disease. ^[6]
• Antigen avoidance is the most effective intervention and remains important even once fibrosis is present. ^[2]
• Corticosteroids at 0.5 mg per kg per day (0.5 to 1 mg per kg per day for 6 to 12 weeks in some schedules) help inflammatory disease; evidence for long-term fibrotic benefit is weak. ^[2]
• Immunosuppressants (azathioprine, mycophenolate) are used in relapsing or steroid-dependent disease, but benefit in fibrosis is uncertain and harm is possible with short telomeres. ^[2][3]
• Nintedanib slowed forced vital capacity decline by 57% over 52 weeks in the INBUILD population (173 of 663 patients had fibrotic hypersensitivity pneumonitis); pirfenidone has smaller, less robust data. ^[6]
• Patients with honeycombing have a median survival of about 2.8 years; those with non-honeycomb fibrotic disease survived a median of more than 7.95 years in one comparison. ^[2]
• Transplantation offers 96%, 89% and 89% survival at one, three and five years in series. ^[6]

Asthma, sarcoidosis, idiopathic pulmonary fibrosis, interstitial lung diseases as a group, and other causes of chronic cough such as bronchiectasis.