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Extrinsic allergic alveolitis 

Extrinsic allergic alveolitis
Extrinsic allergic alveolitis

D.J. Hendrick

and G.P. Spickett


July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

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Extrinsic allergic alveolitis is an uncommon inflammatory disorder of the lungs that results from hypersensitivity responses to inhaled environmental agents. Most varieties are occupational in origin, but sporadic cases arise in domestic settings or from recreational activities. Causal agents chiefly comprise allergenic microbial spores that contaminate stored vegetable produce (e.g. farmer’s lung caused by Saccharopolyspora rectivirgula, previously known as Micropolyspora faeni, and Thermoactinomyces vulgaris) or reservoirs of water, but a number of animal proteins (particularly those present in feather bloom, e.g. pigeon fancier’s lung) and a few reactive chemicals are also inducers.

Pathology—acute disease is characterized by a nonspecific diffuse pneumonitis with inflammatory cellular infiltration of the bronchioles, alveoli, and interstitium; subacute disease by the formation of epithelioid noncaseating granulomas; and chronic disease by fibrosis, particularly in the upper lobes.

Acute disease—following a sensitizing period of exposure, which may vary from weeks to years, the affected subject experiences repeated episodes of an influenza-like illness accompanied by cough and undue breathlessness some hours (usually 3–9) after commencing exposure to the relevant organic dust. Fever and basal crackles are the main physical signs. Most patients recover fully from each acute exacerbation within a day or so, and if the cause is recognized and further exposure avoided there is little risk of persisting pulmonary dysfunction.

Chronic disease—typically seen following long-standing low-level antigenic exposure, e.g. in the person who keeps a single budgerigar (parakeet) in the home. Presents less dramatically than acute disease with increasing shortness of breath, but without systemic upset except for weight loss in some cases. Clinical features are similar to those of other varieties of pulmonary fibrosis, but clubbing is uncommon. Permanent fibrotic lung damage can eventually lead to hypoxaemia, pulmonary hypertension, right heart failure, and death.

Investigation—is directed towards the lungs, the relevant exposure, and determination of hypersensitivity. (1) Lungs—in acute disease the chest radiograph may be normal or show a ground-glass appearance; in subacute disease small reticular opacities may be seen; in chronic disease there is fibrosis. CT provides better images, but no single feature or pattern is pathognomonic. Lung function studies show a restrictive pattern. (2) Determination of relevant exposure—in many cases the history alone is sufficient, but industrial hygiene measurements made from personal samplers may be required when the disease is suspected in an environment not previously incriminated. (3) Determination of hypersensitivity—demonstration of a serum IgG antibody response to the inducing organic dust is unsatisfactory for ‘confirming’ hypersensitivity because it correlates with exposure better than disease, but a negative test generally excludes the diagnosis. Some form of inhalation challenge test may be necessary when there is diagnostic doubt.

Management—requires that the diagnosis is secure, and then centres on reducing any further exposure to a minimum. There is debate as to whether the use of corticosteroids for acute episodes confers any long-term benefit. In acute disease cessation of exposure usually leads to complete resolution and in chronic cases usually prevents further progression. Persistent exposure can lead to progressive and permanent fibrotic damage in some cases, but not in all.

Historical perspective

Farmer’s lung is often regarded as the prototype of the alveolar, bronchiolar, and interstitial disorders that result from hypersensitivity to inhaled organic dusts. These occur worldwide and are known collectively by the term ‘extrinsic allergic alveolitis’ (or simply allergic alveolitis), although it is recognized that the underlying inflammatory response occurs diffusely throughout the gas-exchanging tissues and is not confined to the alveoli. For this reason many prefer the term ‘hypersensitivity pneumonitis’. These disorders were not clearly distinguished from asthma until 1932 when Campbell published his celebrated report describing three affected English farm workers, the appellation ‘farmer’s lung’ being suggested in 1944. However, the disease had been recognized in Iceland in the 19th century, and probably contributed to the occupational ailments of grain workers so graphically described by Ramazzini in the 18th century.

Part of the eminence of farmer’s lung itself stems from its industrial importance, and part from its historical role in the understanding of extrinsic allergic alveolitis. Its relation to the inhalation of dust from mouldy hay, straw, or grain had been recognized from the outset, but it was not until 1961, when Pepys and colleagues demonstrated the presence of precipitins to antigens of mouldy hay in patients suffering from the disease, that the idea of an allergic aetiology gained general acceptance. These and other investigators showed that the main sources of antigen were contaminating thermophilic actinomycetes, particularly Saccharopolyspora rectivirgula (then known as Micropolyspora faeni) and Thermoactinomyces vulgaris. These thermophilic microbes (which are bacteria, not fungi) colonize fermenting damp vegetable produce as it heats up. When it eventually dries, a respirable dust laden with antigenic microbial spores is left. Symptoms are consequently most common during winters following wet summer harvests, when hay or grain is used for feeding stock, and astonishing numbers of spores (thousands of millions per cubic metre) are released into the air.

For deposition of the dust to occur predominantly in the gas-exchanging tissues, particle size must be largely confined to the range 0.5 to 5 µm. This encompasses the diameters of many antigenic bacterial and fungal spores, and a large number of microbial species are now recognized as causes of extrinsic allergic alveolitis. In addition, the disease has been described following respiratory exposure to a variety of antigens derived from animal, vegetable, and even chemical sources, both in the workplace and in the home. It may also occur because of allergy to ingested agents, chiefly medications, but only inhalant causes will be addressed in this chapter. Drug-induced examples of the disease are discussed in Chapter 18.14.13.

Aetiology, pathology, and pathogenesis


Table lists the various agents, principally organic proteins, reported to cause extrinsic allergic alveolitis. Most are encountered in working environments and so the disease is usually occupational, but some are encountered in the home or during recreation. Intriguing recent reports have additionally incriminated sources of exposure within the community at large—local pigeons and migrating Canada geese. Most causal agents are microorganisms that are found contaminating a variety of vegetable products, buildings, or equipment, but some are derived directly from animal or vegetable sources, and a few are reactive chemicals. The latter are thought to act as haptens, combining with body proteins to produce larger and now antigenic molecules. Although the microorganisms associated with the more celebrated disorders—farmer’s lung, mushroom worker’s lung, and bagassosis—are usually thermophilic, most causing extrinsic allergic alveolitis are not. Even with mouldy hay and farmer’s lung there is evidence that nonthermophilic organisms (e.g. aspergillus) may occasionally be involved.

Table Agents reported to cause extrinsic allergic alveolitis



Appellation (if any)


Acinetobacter iwoffii

Metal-working fluid

Machine worker’s lung


Paper-mill wood pulp

Wood pulp worker’s lung

Aspergillus sp.

Farm produce, maize (corn)

Farmer’s lung

Aspergillus clavatus

Whisky maltings

Malt worker’s lung

Aspergillus fumigatus

Vegetable compost, cork

Farmer’s lung, suberosis

Aspergillus versicolor

Dog bedding (straw)

Dog house disease

Aureobasidium pullulans

Redwood/domestic cellar


Bacillus subtilis

Wood/cleaning preparations

Candida albicans

Heated swimming pool



Sewage worker’s lung

Cryptococcus albidus

Asian homes in humid summers

Summer-type hypersensitivity pneumonitis

Cryptostroma corticale


Maple bark stripper’s lung

Debaryomyces hansenii

Home ultrasonic nebulizer

Eurotium sp.

Metal-working fluid

Machine worker’s lung

Fusarium sp.

Metal-working fluid/home

Machine worker’s lung




Grifola fondosa

Maitake mushrooms

Mushroom worker’s lung

Humicola fuscoatra

Domestic home

Hypsizigus marmoreus


Mushroom worker’s lung

Lentinus edodes


Mushroom worker’s lung




Lyophyllum aggregatum


Mushroom worker’s lung

Merulius lacrymans

Domestic wood

Mucor stolonifer


Paprika splitter’s lung

Mycobacterium sp.

Metal-working fluid

Machine worker’s lung

Paeccilomyces sp. (nivea/variotii)

Hardwood, oil heater

Penicillium camembertiia

Salami production

P. casei


Cheese washer’s lung

P. chrysogenum/cyclopium

Domestic wood

P. citrinum

Enoki mushroom cultivation

P. frequentens



P. nalgiovense

Pork sausage mould

P. verucosum

Gorganzola cheese

Pezizia domiciliana

Flooded basement

El Niño lung

Pleurotus osteatus/ergngi


Mushroom worker’s lung

Pseudomonas fluorescens

Metal-working fluid

Machine worker’s lung

Rhodotorula sp.

Ultrasonic humidifier

Saccharomonspora viridis

Logging plant

Sphingbacterium spiritivorum

Domestic steam iron


Horse barn straw

Streptomyces albus


Thermophilic actinomycetes (Saccharopolyspora rectivirgula, Thermoactinomyces sacchari/vulgaris)

Hay/straw/grain/mushroom compost/bagasse/heated water/domestic cellar/esparto grass

  • Farmer’s lung

  • Mushroom worker’s lung

  • Bagassosis

  • Esparto plasterer’s lung

Trichosporon cutaneum/ovoides

Asian homes in humid summers

Summer-type hypersensitivity pneumonitis

Miscellaneous bacteria/mycobacteria/fungi/amoebae/nematode debris

Air conditioners/humidifiers/tap water/showers/heated pools, saunas, tubs/metal fluids

  • Humidifier lung

  • Ventilation pneumonitis

  • Sauner taker’s lung


Roof thatch

New Guinea lung


Arthropods (Sitophilus granarius)

Grain dust

Wheat weevil disease


?Feather bloom/?excreta

Bird fancier’s lung


Fish meal

Fish meal worker’s lung

Mammal pituitary (cattle, pig)

Pituitary extracts

Pituitary snuff taker’s lung

Mammal hair


Furrier’s lung

Mollusc shell

Nacre-button manufacture

Urine (rodents)

Urinary protein

Rodent handler’s lung



Wood dust


Coffee bean dust

Coffee worker’s lung

Esparto grassb


Esparto plasterer’s lung

Amorphophalus konjak

Konjak flour

Konnyaku maker’s lung

Peat mossc

Peat moss packaging plant


Shimeji cultivators

Tiger nut

Tiger nut dust

Wood (Gonystylus bacanus)

Wood dust

Wood worker’s lung


Bordeaux mixture (fungicide)


Vineyard sprayer’s lung

Cobalt dissolved in solvents

Tungsten carbide grinding

Diphenyl methane diisocyanate

Plastics industry

Hexamethylene diisocyanate

Plastics industry

Methyl methacrylate


Pauli’s reagent


Phthalic (or trimellitic) anhydride

Epoxy polyester powder paint


Insecticide spray


Dry cleaning

Toluene diisocyanate

Plastics industry

Triglycidyl isocyanate

Plastics industry

Trimellitic anhydride

Plastics industry

Vanadium catalyst

Maleic anhydride manufacture


Hijikia fusiforme (algae)

Konjak flour

Konnyaku maker’s lung

Pet fish food

a Alternative possible causes, Penicillium notatum, Aspergillus fumigatus.

b Possibly due to microbial contamination (Aspergillus sp.).

c Possibly due to microbial contamination (Monocillium sp., Penicillium citreonigrum).

d Possibly due to microbial contamination (Cladosporium sphaerospermum, Penicillium frequentens, or Scopulariopsis sp.).

Some microbial contamination may occur during growth of the vegetable host, but most of the antigenic load is usually acquired after harvest. Prolonged storage under damp conditions increases the risk of extrinsic allergic alveolitis substantially, and drying to reduce the water content below 30% greatly lessens the risks. Farmer’s lung and bagassosis are not therefore primary disorders of hay/grain or sugar cane harvest. They usually arise months or even years later, when the stored product is used or moved. In the interim, moulding is likely to have involved a series of different microorganisms that colonize the forage material sequentially. As the exothermic process increases the ambient temperature, so thermophilic microbes come to dominate.

Inevitably there are situations where contamination arises with a number of different microbes, and affected subjects show antibodies to several of them. Unless time-consuming inhalation challenge tests are carried out with extracts of the individual microbial species, it is not possible to identify a single responsible agent in a given case or cases, and it is conceivable that several could be relevant in these circumstances. This is a characteristic feature of contaminated water reservoirs in humidifiers and air conditioners, and a great variety of agents have been suggested as possible causes of humidifier lung, including bacteria, mycobacteria, fungi, protozoa (amoebae), and metazoa (nematode debris). Some authors prefer to distinguish extrinsic allergic alveolitis attributable in such circumstances to microorganisms growing in cool or cold water (humidifier lung) from that arising from heated water (ventilation pneumonitis). Additional sources of causal organisms include hot tubs and saunas, containing both thermophilic and nonthermophilic organisms (including nontuberculous mycobacteria), and water-based metal-working fluids. The latter, often contaminated with oil, are recycled during use to lubricate and cool rotating or cutting equipment in the metal-working industry, and may therefore be dispersed as respirable aerosols. The chief microbial contaminants are generally environmental nontuberculous mycobacteria or fungi, but a variety of other organisms may be involved. Although granulomatous responses might be expected from mycobacterial infection, the mechanism of the diffuse pneumonitis resulting from mycobacterial contamination of metal-working fluids (and hot tubs) does seem to depend on hypersensitivity alone.

Hypersensitivity is also presumed to explain the unusual and rare form of diffuse alveolitis associated with cobalt and tungsten (or cobalt and diamond dust)—the constituents of ‘hard metal’ cutting and sharpening tools. It is unusual because of characteristic giant, multinucleated, scavenger macrophages within the alveolar spaces, and because no microbial contaminants are involved; it is rare because of the small population of workers with relevant exposure. Alternative diagnostic labels are ‘hard metal disease’ and ‘giant cell interstitial pneumonia’.

Curiously, contamination with multiple microbial species does not seem to be a feature of Japanese summer-type pneumonitis, which arises seasonally in the hot and humid regions in the south and west of Japan and neighbouring countries. This is the result of the excessive growth of trichosporon (or, occasionally, Cryptococcus albidus) in poorly ventilated homes. Mould contamination of domestic environments (e.g. cellars, ultrasonic nebulizers, steam irons, oil heaters, air conditioners) in other regions is recognized to cause extrinsic allergic alveolitis far less frequently, but there are many convincing case reports of domestic causes.


There has been little opportunity to characterize the acute form of extrinsic allergic alveolitis histologically in humans because biopsies are very rarely taken within 24 to 48 h of a provoking exposure, and because death leading to autopsy is even less common. Initially there is a nonspecific diffuse pneumonitis with inflammatory cellular infiltration of the bronchioles, alveoli, and interstitium, accompanied by oedema and luminal exudation. With ongoing exposure, whether continuous or intermittent, the more familiar appearances of the subacute forms of extrinsic allergic alveolitis evolve. The most characteristic feature is the formation of epithelioid noncaseating granulomas. These are generally less well formed than in sarcoidosis, less profuse, and often evanescent. They can be recognized within 3 weeks of the initiating exposure, and generally resolve within 6 to 12 months. In parallel, fibrosis evolves alongside cellular infiltration of the interstitium with histiocytes, lymphocytes, and plasma cells. Macrophages with foamy cytoplasm may be prominent in the alveolar spaces, and organization of the inflammatory exudate may lead to intra-alveolar fibrosis. Obstruction or obliteration of bronchioles is common. Foreign-body giant cells may reflect the dependence of extrinsic allergic alveolitis on antigens derived from inhaled foreign material, as does a peribronchial predominance of the inflammatory response. Vasculitis is notable by its absence. The typical histological appearance of subacute extrinsic allergic alveolitis is illustrated in Fig.

Fig. Histological appearance: subacute disease. There is bronchocentric interstitial fibrosis and chronic inflammation, with poorly formed interstitial granulomas including giant cells. (Haematoxylin and eosin stain at medium magnification.)

Histological appearance: subacute disease. There is bronchocentric interstitial fibrosis and chronic inflammation, with poorly formed interstitial granulomas including giant cells. (Haematoxylin and eosin stain at medium magnification.)

(Courtesy of Dr T Ashcroft.)

Progressive, widespread, and irreversible fibrosis may occur with continued exposure, leading to disruption of the normal architecture of the lung. In advanced cases honeycombing may develop. Granulomas are no longer characteristic and the overall appearances may differ little from other causes of progressive interstitial pulmonary fibrosis. With extrinsic allergic alveolitis, however, there may be disproportionate fibrosis of the upper lobes.


Immune mechanisms

An outline of the possible immunopathology of extrinsic allergic alveolitis through acute, subacute, and chronic phases is illustrated in Figs. and The presumption that complexes of antigen and complement-activating antibodies are primarily responsible for extrinsic allergic alveolitis is now largely discarded. The evidence for deposition of immune complexes is not convincing, and neither IgG nor IgM antibodies are uniformly demonstrated in the sera of affected subjects unless sensitive detection techniques such as the enzyme-linked immunosorbent assay (ELISA) or radioimmunoassays are used. More importantly, these antibodies are frequently found in subjects who are similarly exposed but clinically unaffected, irrespective of the method of detection. A closer association of disease with the IgG4 antibody subclass has been suggested, but the significance of this is not yet apparent. It is clear, however, that vasculitis—a cardinal feature of the experimental Arthus reaction—is not a characteristic; the inflammatory reaction is dominantly lymphocytic or mononuclear rather than polymorphonuclear, although a transitory polymorphonuclear leucocyte response is typical immediately following exposure. Lung tissue is most commonly examined during subacute phases of the disease, at which time a noncaseating granulomatous response suggesting cell-mediated hypersensitivity is the usual finding.

Fig. Possible immunopathogenesis: acute phase.

Possible immunopathogenesis: acute phase.

Fig. Possible immunopathogenesis: subacute/chronic phase.

Possible immunopathogenesis: subacute/chronic phase.

It could be argued that these histological appearances merely represent a healing reaction, but the consistent finding of an acute T-lymphocyte response in fluid obtained at bronchoalveolar lavage supports the current consensus that cell-mediated hypersensitivity plays the dominant pathogenic role in extrinsic allergic alveolitis. The results from animal models of the disease are consistent with this, disease being transferred from animal to animal only with sensitized T lymphocytes. This is not to say that other mechanisms play no role, nor that all inflammatory diseases of the gas-exchanging tissues induced by organic dusts share a common mechanism. Indeed, the onset of symptoms within a few hours of exposure, coupled with polymorphonuclear leucocytosis in bronchoalveolar lavage fluid and peripheral blood, favours the participation of an additional (perhaps priming) immunological or toxic process, and B-lymphocyte aggregates have been noted in transbronchial biopsies obtained during the acute phase. Components of a number of organic dusts associated with extrinsic allergic alveolitis are known to activate complement by the alternative pathway and this, with or without humoral hypersensitivity, might also prove to be relevant.

Bronchoalveolar lavage in similarly exposed subjects has shown excess numbers of T lymphocytes, whether they were clinically affected or not, although the proportions of T-cell subpopulations has varied according to disease activity and the circumstances of exposure. Most investigators have detected a relative excess of CD8+ T cells in exposed but asymptomatic subjects, thereby ‘inverting’ the normal CD4+ to CD8+ ratio. The balance appears to be less disturbed in those with disease, and in one sequential study the ratio changed from 0.43 to 1.47 with disease progression. In an intriguing study of an animal model of extrinsic allergic alveolitis, monkeys that developed characteristic reactions to inhalation challenge showed a helper CD4+ cell lymphocytosis in bronchoalveolar fluid and a relative deficiency of suppressor CD8+ cells, compared with the monkeys giving no clinical reaction who showed responses with both CD4+ and CD8+ cells. When the nonreactors were challenged again after low doses of whole-body irradiation had impaired suppressor- more than helper-cell function, characteristic reactions were noted. These observations suggest that a relative impairment of suppressor-cell function, or of its activation following antigenic exposure, is fundamental to the development of extrinsic allergic alveolitis—a situation that has interesting parallels with sarcoidosis. It is also interesting that lymphopenia in peripheral blood is a typical feature of acute exacerbations of the disease, the T lymphocytes migrating from blood to lungs within hours of the provoking exposure. It is small wonder that studies of systemic and local immune responses have given discordant results, and clear that continuing research should address both aspects of the immune response.

It is known that different antigenic determinants from a given inducing microbial source may lead to different immunological responses, and it seems likely that cytotoxic activity and released cytokines (e.g. interleukin (IL)-6 and tumour necrosis factor α‎ (TNFα‎)) play some role, possibly by activating the vascular endothelium and thereby recruiting and activating further macrophages and inflammatory cells. In experimental models interferon-γ‎ has been shown to play a major role (an excess of interferon-γ‎-producing T cells is present in the lungs), and IL-10 ameliorates the disease. There are also increased levels of IL-12 and IL-18, and these cytokines contribute to T-cell polarization towards a Th1-type response. IL-8, a chemotactic factor for neutrophils, and monocyte chemotactic protein-1 (MCP-1) are both elevated in some types of the disease, perhaps accounting for the increase in macrophage and neutrophil recruitment and activation. Serum levels of IL-6 and intercellular adhesion molecule 1 (ICAM-1) are also raised. Bronchoalveolar lavage has also shown that natural killer (NK) cells (CD57+) and mast cells may be prominent additional players in pathogenesis, and there is evidence that the capacity of macrophages to present antigen is enhanced by viral infection and diminished by cigarette smoking. The latter is known to decrease the severity of clinical symptoms as well as the immunological abnormalities.

Cytokines, possibly together with anaphylotoxins from the degradation of complement components (C4, C3, C5), are likely to be responsible for the systemic influenza-like symptoms that are so characteristic of the acute form of extrinsic allergic alveolitis. These symptoms are indistinguishable from those of grain fever in grain workers, ‘Monday fever’ in cotton workers, humidifier fever in subjects exposed to microbially contaminated humidifiers, and metal fume fever in welders. In these situations the febrile disorder is not characteristically associated with clinical alveolitis, raising the possibility that its occurrence with the acute form of extrinsic allergic alveolitis is an independent phenomenon, not an integral part of extrinsic allergic alveolitis itself. In favour of this hypothesis has been the finding of high levels of endotoxin from Gram-negative bacteria (which are known to provoke these symptoms) in grain dust, cotton dust, contaminated humidifiers, and many of the ‘mouldy’ vegetable dusts that cause extrinsic allergic alveolitis. However, neither metal fume nor several other causative agents of extrinsic allergic alveolitis are likely to be contaminated with endotoxin, and so endotoxin-induced release of inflammatory mediators is not an entirely satisfactory explanation. For example, inhalation provocation tests with uncontaminated bird serum in subjects with bird fancier’s lung reproduce both alveolar and influenza-like responses. Evidently the influenza-like response is an integral feature of the acute form of extrinsic allergic alveolitis, but it is relatively nonspecific and can occur in many other situations.

Extrinsic allergic alveolitis occurs in families only sporadically, and few associations with HLA phenotypes have been demonstrated. However, a number of studies have suggested associations between HLA D alleles and pigeon fancier’s lung and Japanese summer-type hypersensitivity pneumonitis. This genetic background is associated with a high production of TNFα‎, and these alleles may exert effects on immune suppression, offering one mechanism by which a genetic predisposition could play a role in the development of extrinsic allergic alveolitis. It has also been suggested that an acute inflammatory episode (from viral infection or the inhalation of microbial toxins or chemicals) may be necessary to disrupt the normal defence equilibrium of surface membrane and local immune responses, thereby permitting antigen to be presented in a fashion that leads to hypersensitivity. Undue ‘leakiness’ of the alveolar membrane can be demonstrated by an increased clearance of inhaled 99Tcm-DTPA, and this has been reported in both the early and continuing phases of extrinsic allergic alveolitis.

Relation to smoking

The disruptive effect of smoking on the alveolar membrane does not appear to augment the risk for extrinsic allergic alveolitis or to increase its severity: in fact the reverse is true. Although smoking enhances acute phase reactions and IgE production, it diminishes IgA, IgG, and IgM antibody responses, increases circulating CD8+ T-lymphocyte numbers, and probably reduces the incidence and severity of extrinsic allergic alveolitis. However, smokers without IgG antibodies are particularly liable to find their respiratory symptoms attributed to other diseases, and so this negative association between extrinsic allergic alveolitis and smoking may have been exaggerated. That it is real is supported by evidence that smoking may also reduce the risk for other T-cell-mediated immunological disorders such as sarcoidosis, ulcerative colitis, and some types of occupational asthma (generally those associated with low-molecular-weight chemicals). The key cell in a complex series of interactions is probably the alveolar macrophage, which is critical in presenting antigen to CD4+ T lymphocytes and so to activating cellular immune mechanisms. Although smoking increases macrophage numbers and their metabolic activity, the activated cells show impairment of both the expression of surface major histocompatibility (MHC) class 2 antigens and the production or release of IL-1 and inflammatory mediators derived from arachidonic acid metabolism (leukotriene B4, prostaglandin E2, thromboxane B2). It is also argued that the increased macrophage numbers down-regulate pulmonary immune responses in a purely nonspecific fashion by impairing antigen access to more effective blood monocytes.

Relation to coeliac disease

Reports that cryptogenic fibrosing alveolitis (now known, depending on histological characteristics, as ‘usual interstitial pneumonia’ and ‘nonspecific interstitial pneumonia’) and extrinsic allergic alveolitis (and particularly bird fancier’s lung) might be associated with coeliac disease led to the interesting hypothesis that in some cases absorbed food antigens from the disrupted bowel mucosa might play a role in the pathogenesis of the lung disorder; i.e. the lung disorder might be a ‘metastatic’ complication of the bowel disease. Alternatively, systemic hypersensitivity to a common inhaled and ingested avian antigen might give rise to similar immune reactions and diseases in the relevant target organs. The avian IgG antibody response seen in coeliac disease is, however, distinct from that associated with bird fancier’s lung and seems to be a response to dietary egg. It is not related to environmental exposure to birds but does correlate with the activity of the bowel disorder. Subsequent experience suggests a much less strong association between these bowel and lung disorders that, if real, is probably a consequence of their dependence on similar immunological mechanisms and host susceptibility to them. The association is not sufficiently strong that the one disorder should stimulate investigation for the other.


Extrinsic allergic alveolitis is an uncommon but not rare disease, but its comparative scarcity limits epidemiological knowledge, as does the use of different methods of investigation. For every case of extrinsic allergic alveolitis there may be 100 cases of ‘extrinsic allergic’ asthma, but there is even greater geographical variation than with asthma, reflecting the much larger dependence of extrinsic allergic alveolitis on occupational causes and climate. As a consequence, its incidence and its principal causes vary considerably from country to country, and from region to region.


Experience over 3 years with the Surveillance of Work-related and Occupational Respiratory Disease (SWORD) project indicated that extrinsic allergic alveolitis of occupational origin accounted for 2% of occupational lung diseases in the United Kingdom. Asthma, the most common, accounted for 26%. This does, of course, ignore extrinsic allergic alveolitis of nonoccupational origin, which is much less easily assessed. It also disguises the absolute risk, since few workers encounter relevant occupational exposures. Almost 50% of reported cases involved farmers or farm workers, followed by 15% affecting workers in material, metal, or electrical processing trades. Among the farmers, the average incidence was 41 per million per year, though this approached 100 in some regions, and has been estimated at 3000 in Quebec, Canada. However, the estimated incidences are crude and must vary considerably according to the prevailing weather. They may be compared with 200 to 700 per million per year among working groups at greatest risk of developing occupational asthma in the United Kingdom. Contaminating microorganisms underlie over 50% of the cases of extrinsic allergic alveolitis reported to SWORD, followed in order of importance by animal antigens in 6% and chemicals in 5%. In 27% of reports a suspected agent was not specified.


Figures for prevalence are more readily available than those for incidence, and demonstrate quite marked national differences. In developed countries, humidifier lung is being recognized with increasing frequency both in the workplace and in the home, and remarkable prevalences of 15 to 70% have been suggested in populations from contaminated offices in North America. Bird fancier’s lung may be more prevalent at present over the whole of the United Kingdom, simply because of the great popularity of keeping budgerigars (known as parakeets in North America) and pigeons. Budgerigars are kept in some 12% of British homes, and it has been estimated that 0.5 to 7.5% of the population involved are likely to have extrinsic allergic alveolitis as a consequence, albeit mildly in most cases. Pigeon keeping is 40 times less common, and the measured prevalence of pigeon fancier’s lung among pigeon keepers has been a good deal more varied (0–21%). This may reflect both true differences between groups of pigeon breeders as exposure levels vary, for instance, according to number of birds, duration of exposure, loft ventilation, and cleaning habits, and artefactual differences arising as a result of selection bias and variable compliance. The avian antigen responsible and its precise source have yet to be identified, but bloom from the feathers containing oil, saliva, and secretory IgA is currently favoured over dust emanating from dried droppings.

In areas of high rainfall where ‘traditional’ farming methods are used, the prevalence of farmer’s lung may reach 10%. This is likely to be the commonest cause of extrinsic allergic alveolitis in developing countries. In developed countries, where modern farming methods are used, prevalences rarely exceed 2 to 3% and are usually a good deal less. Furthermore, the farming population at risk represents a mere 1 to 2% of the population at large, although there are marked regional variations. Even smaller populations are employed making whisky from germinating barley (maltings), raising mushrooms on a variety of antigenic composts, or handling bagasse (the fibrous stem that remains when sugar is extracted from sugar cane), but within some of these populations extrinsic allergic alveolitis was a common problem until excessive exposure levels were controlled. Extrinsic allergic alveolitis associated with animals other than birds is extremely uncommon, as is the case with chemical-induced extrinsic allergic alveolitis.

In Japan, the seasonal summer growth of T. cutaneum in the home is by far the commonest cause of extrinsic allergic alveolitis where the remarkable ‘summer-type hypersensitivity pneumonitis’ accounts for about 75% of all cases of extrinsic allergic alveolitis. It is approximately 10 times as common as farmer’s lung and 20 times as common as bird fancier’s lung.

The important risk of extrinsic allergic alveolitis from metal-working fluids varies substantially according to the degree and nature of microbial contamination, and the ease with which aerosols of the fluids are released into the working environment. Up to one-third of exposed occupational populations have become affected.


Once extrinsic allergic alveolitis is recognized in one individual, the environment concerned should be assessed for the risk it poses to others. In many circumstances this will be well known already, and exposure levels will be within the range considered acceptable. In others, neither the risk nor the precise causative agent (nor its level of exposure) will be known, and in such unfamiliar circumstances there may be a need to survey the exposed population at risk. Questionnaires and serological tests are most convenient for this, at least as a screening procedure. When large populations are involved, comprehensive investigation is sensible before major modifications are considered to the working environment.

Modifications can always be made to the environment to lessen the level of exposure, but their extent will be limited by expense and should be justified by need. Dry storage and adequate ventilation are the two most important factors when vegetable produce is involved, and in some farming areas there is benefit in drying produce artificially after harvest. An alternative is some form of ‘pickling’, so that the produce is preserved chemically. With silage, for example, newly cut grass is kept under impervious covering in relatively sealed conditions. Initial enzymic and moulding processes use up available oxygen, and produce aldehydes and other preservative chemicals. These create nearly anaerobic conditions and protect the produce until it is used. Similarly, hay may be sealed in plastic bags, or grain or bagasse may be treated with propionic acid.

When ventilation and humidification systems are themselves responsible for extrinsic allergic alveolitis, major mechanical alterations may be necessary and the methods of humidification and temperature control may need to be changed. The crucial need is to reduce the ease with which normal airborne microbial contaminants are able to proliferate in stagnant, reservoir, collections of water. For this there may be a role for ‘biocide’ sterilizing agents, but these are also likely to become airborne and respirable and so must have low intrinsic toxicity and sensitizing potency. For one such biocide (isothiazolinone) there have been reports of occupational dermatitis and asthma, though not of extrinsic allergic alveolitis.

An industrial need for rapid air changes coupled with close control of humidity and temperature poses formidable problems. The use of recirculated filtered air is the most economical, but effective filters are expensive and can become contaminated themselves, increasing rather than decreasing the load of respirable microbial antigens. The use of heat exchangers minimizes the cost of temperature control if contaminated exhaust air is not recirculated, but does not conserve water.

Clinical features

Acute extrinsic allergic alveolitis

The acute form of extrinsic allergic alveolitis is the most easily recognized because symptoms are often distressing and incapacitating and have a high degree of specificity. Following a sensitizing period of exposure, which may vary from weeks to years, the affected subject experiences repeated episodes of an influenza-like illness accompanied by cough and undue breathlessness some hours (usually 3–9 h) after commencing exposure to the relevant organic dust. The systemic influenza-like symptoms generally dominate those that are respiratory, and the affected subject complains most of malaise, fever, chills, widespread aches and pains (particularly headache), anorexia, and tiredness. They are unlikely to feel like exercising and may well put themselves to bed, therefore remaining unaware of undue shortness of breath, though likely to develop a dry cough without wheeze and to have some difficulty taking deep, satisfying breaths. Occasionally there is an asthmatic or bronchitic response and wheezing or productive cough becomes an additional feature.

Despite the delay in onset after exposure begins, affected subjects soon learn to associate symptoms with the causative environment, especially if they follow a period away from the causal exposure. Recognition is particularly easy for groups such as farmers and pigeon fanciers for whom these risks are well known. However, in some cases there may be a tendency to deny such a relationship for fear of compromising the ability to pursue a livelihood or hobby, and the clinical history may appear much less convincing than it should.

The severity and duration of symptoms depend critically on exposure dose and individual susceptibility. With low levels of acute exposure, symptoms are mild and persist for a few hours only. When occupation is responsible, the affected worker may feel unwell only at home during the following evening or night, and be fully recovered by the next morning, hence obscuring the relevance of the workplace. When severe responses follow particularly heavy exposures the relation of the one to the other will be more obvious, and complete remission may require several days or even weeks.

In exceptionally severe cases, life-threatening respiratory failure may develop and emergency admission to hospital becomes necessary. Death is not unknown. Respiratory distress at rest with fever and gravity-dependent crackles are the main physical signs, with breathing being fast but shallow. Clubbing is very rarely seen. Hypoxaemia is typically accompanied by hypocapnia, and the chest radiograph shows a diffuse alveolar filling and interstitial pattern. Supplemental oxygen may be required, and in rare cases there may be a brief need for mechanical ventilatory support. Spontaneous recovery can be expected to begin within 12 to 24 h, and can be accelerated with corticosteroids.

Most subjects recover fully from each acute exacerbation, and if the cause is recognized and further exposure avoided there is little risk of persisting pulmonary dysfunction. However, it is not always realistic to expect affected individuals to avoid further exposure, particularly among farming communities, and there is some risk that continuing exposure and repeated acute exacerbations will eventually lead to permanent impairment of lung function.

Chronic extrinsic allergic alveolitis

In some patients extrinsic allergic alveolitis presents in a much less dramatic but potentially more serious way. Exercise tolerance is gradually lost due to shortness of breath, but without systemic upset aside from (in some cases only) prominent loss of weight. This is the result of diffuse pulmonary fibrosis, which has often been progressing for years before the individual seeks advice: the slower the progression, the longer the delay and the greater the likely degree of permanent fibrotic damage. Eventually hypoxaemia and pulmonary hypertension may supervene, and the right heart fails. There are no acute exacerbations, and each day and each month is much like any other. The clinical features are similar to those of other varieties of pulmonary fibrosis, although clubbing is uncommon, and it may prove extremely difficult to distinguish this form of extrinsic allergic alveolitis from usual interstitial pneumonia, nonspecific interstitial pneumonia, sarcoidosis, or other slowly progressive forms of pulmonary fibrosis. There may also be asthmatic or bronchitic symptoms, but these are best regarded as independent airway manifestations of hypersensitivity to the causal agent.

The chronic form of extrinsic allergic alveolitis is typically seen in the person who keeps a single budgerigar in the home. The level of antigenic exposure to avian dust is comparatively trivial compared with that of the farm worker forking bales of heavily contaminated hay in a poorly ventilated barn, but it is encountered almost continuously, particularly if the affected individual is housebound. Differing exposure patterns are largely responsible for these distinct forms of extrinsic allergic alveolitis, although differences in host responsiveness exert an important additional influence, hence there may consequently be considerable variability in clinical features among individuals affected by the same source of antigenic exposure.

Recent reports have suggested that farmer’s lung may additionally be complicated by emphysema, even in never-smokers, although this has not so far been recognized to contribute to the natural history of other types of extrinsic allergic alveolitis. Of possible relevance has been the additional recognition from high-resolution CT that extrinsic allergic alveolitis is associated in a few cases with thin walled cysts together (unsurprisingly) with evidence of bronchiolar obstruction.

Intermediate forms

The acute and chronic forms of extrinsic allergic alveolitis represent the extremes of a continuous spectrum. Individual cases are distributed widely over this spectrum, hence it can be argued that few fall comfortably into one extreme form or the other and that the classification into ‘acute’ or ‘chronic’ has limited practical value. It is important to recognize the marked clinical variability that may occur between cases, and the changes that may occur within cases with the passage of time. The fact that the acute form of extrinsic allergic alveolitis can be produced by inhalation provocation tests in subjects with the chronic form of the disease emphasizes the major role that dose exerts in determining the clinical nature of the response that occurs. Depending on exposure dose and host responsiveness, affected subjects will come to lie at different points on the spectrum at different times. It is possible for acute exacerbations to occur in subjects manifesting predominantly the chronic form of the disease, and for a limited degree of recovery to follow cessation of exposure.

Differential diagnosis

Acute extrinsic allergic alveolitis is not the only disorder characterized by systemic influenza-like symptoms and respiratory distress to follow an unusually heavy exposure to microbially contaminated vegetable produce. In 1986 an international symposium considered a further disorder that occurs within hours of heavy respiratory exposure to dusts containing fungal toxins, especially those released on decapping silos. It is the result of direct toxicity rather than hypersensitivity and the term ‘organic dust toxic syndrome’ was recommended to describe it. Its effects are usually mild and self-limiting, but severe respiratory embarrassment can occur and there is a small risk of ongoing, and potentially fatal, fungal invasion of the lungs. This risk could be enhanced if corticosteroid treatment is given, and death has occurred in subjects who appear to have been fully immunocompetent. Not only does organic dust toxic syndrome occur in circumstances which favour the occurrence of extrinsic allergic alveolitis (particularly silos and swine/poultry confinement buildings), but its clinical features have much in common with extrinsic allergic alveolitis, and to a lesser extent with nitrogen dioxide toxicity, which may also affect silo workers. Indeed, there is so much overlap that it can be very difficult indeed to distinguish one disorder from the others (Table

Table Characteristics of nitrogen dioxide toxicity (silo filler’s disease), organic dust toxic syndrome, and acute farmer’s lung

Nitrogen dioxide toxicity

Organic dust toxic syndrome

Acute farmer’s lung

Susceptibility in smokers




Relation to time of harvest


Months to years

Months to years

Microbial decomposition of harvest product




Confined exposure space




Previous episodes




Dry cough









Systemic upset





Basal crackles








Time of onset after beginning exposure

1–10 h

1–10 h

1–10 h


Hours to days

Hours to days

Hours to days






Radiograph–small irregular opacities, alveolar shadows




Restricted ventilation




Reduced gas transfer








Fungi from secretions/biopsy





Serum precipitins

+ (?– in smokers)

Response to steroids



Life threatening

Not uncommonly



The acute form of extrinsic allergic alveolitis can only be the result of an acute and recent (a matter of hours) exposure to the relevant causal antigen. This limits the opportunity for diagnostic error, although the circumstances of an unusually heavy exposure may be subtle. For example, a pigeon fancier might spend rather less time than usual with his birds, but much more time than usual in the more hazardous dusty car he uses regularly to transport racing birds for training exercises.

Just as acute and heavy exposures to organic dusts may cause disorders other than extrinsic allergic alveolitis, they may also be quite irrelevant and purely coincidental to the acute respiratory disorder with which the patient presents. Consequently the differential diagnosis should include consideration of other acute disorders of the lung parenchyma and interstitium, such as infections, other immunological disorders, drug reactions, and even paraquat poisoning, which sometimes occurs accidentally in farm workers. In bird keepers the diagnosis of viral, mycoplasmal, and chlamydial infection may itself be confounded by false-positive microbial antibody tests. This is the result of pre-existing avian antibodies cross-reacting with egg protein in the microbial cultures used to provide the test agents.

When subacute or chronic forms of extrinsic allergic alveolitis are encountered, the differential diagnosis lies with other diffuse infiltrative and fibrotic disorders of the lung. Those most frequently resembling extrinsic allergic alveolitis include usual interstitial pneumonia, nonspecific interstitial pneumonia, sarcoidosis, pneumoconiosis, tuberculosis, and metastatic cancer, although a huge variety of less common disorders may also need to be considered.

Clinical investigation

Establishing a diagnosis of extrinsic allergic alveolitis involves three areas of investigation: the lungs, the exposure, and the evidence for hypersensitivity.


In many cases extrinsic allergic alveolitis is first suspected after the presence of diffuse alveolitis or progressive pulmonary fibrosis is established. With the acute form of the disease the chest radiograph commonly shows no abnormality unless symptoms are moderately severe. When the radiograph is abnormal, there is a widespread ground-glass appearance or an alveolar filling pattern, particularly in the lower and mid-zones. This may resolve within a mere 24 to 48 h once exposure has ceased. In more subacute forms small reticular opacities, simulating asbestosis, are seen within the same distribution: these may persist for several weeks despite cessation of exposure and, if exposure continues, honeycombing may develop. Occasionally a more nodular pattern occurs. In contrast to the distribution of acute and subacute radiological abnormalities, the upper zones are predominantly affected by the irreversible fibrotic process that characterizes the chronic form of disease. This may simulate sarcoidosis or even tuberculosis, and may lead to considerable shrinkage and distortion. In practice, the radiographic appearances vary considerably from patient to patient and correlate poorly with the clinical severity of the disease.

CT provides a much clearer picture of the type of radiographic abnormality and of its extent, particularly when thin-section high-resolution techniques are used, but no single feature or pattern is pathognomonic (Fig. Again, investigation within hours of exposure has been limited and experience is largely confined to patients with subacute and chronic disease. Increased ground-glass density of the lung parenchyma is the most prominent finding in the subacute form, followed almost equally by reticular or nodular infiltration, more uniform involvement of the lung fields being demonstrated than is obvious from plain radiographs. At end expiration a mosaic pattern is characteristic, reflecting patchy bronchiolar involvement and the different degrees by which residual gas can be expelled from distal lobules. The attenuated areas may then be normal, the translucent areas indicating gas retention. Lymph node enlargement and/or pleural involvement are not characteristic. With chronic forms, the CT scan shows a similar pattern of fibrosis and disruption to the plain radiograph, but again is considerably more sensitive.

Fig. (a) CT scan of a woman aged 44 years who had never smoked whose lung biopsy showed the typical appearances of subacute extrinsic allergic alveolitis. She kept two budgerigars in her home and had serum precipitins to avian antigens. The scan shows marked ground glass attenuation of the lung parenchyma, which is nodular in some areas due to characteristic peribronchiolar (and centrilobular) foci. In other areas there is increased translucency because of bronchiolar obstruction and air trapping. Both the ground glass attenuation and the increases in translucency are exaggerated in the expiratory film (b), giving a ‘mosaic’ pattern. She recovered fully after the birds left her home.

(a) CT scan of a woman aged 44 years who had never smoked whose lung biopsy showed the typical appearances of subacute extrinsic allergic alveolitis. She kept two budgerigars in her home and had serum precipitins to avian antigens. The scan shows marked ground glass attenuation of the lung parenchyma, which is nodular in some areas due to characteristic peribronchiolar (and centrilobular) foci. In other areas there is increased translucency because of bronchiolar obstruction and air trapping. Both the ground glass attenuation and the increases in translucency are exaggerated in the expiratory film (b), giving a ‘mosaic’ pattern. She recovered fully after the birds left her home.

Lung function studies vary according to severity and recent activity. As with asthma, they may be unremarkable in the acute form of the disease when there has been little recent exposure. When lung function is impaired, the pattern suggests parenchymal and interstitial disease but is otherwise nonspecific. There is impaired carbon monoxide gas transfer (diminished TLco and Kco) with restricted ventilation (i.e. forced vital capacity (FVC) is diminished as much as forced expiratory volume in 1 s (FEV1) or more so, with respect to predicted values), decreased compliance, and (in more severe cases) arterial hypoxaemia and hypocapnia, particularly on exercise. Although total lung capacity is reduced, residual volume is often increased, suggesting air trapping as a result of bronchiolar involvement. Occasionally there is also obstruction of the large airways, but this implies a coincidental asthmatic or bronchitic effect. Serial measurements of lung function may be particularly useful in demonstrating that impairment is closely related to the relevant exposure.

Bronchoscopy is useful in demonstrating that there is no macroscopic abnormality, apart from the occasional presence of mucosal inflammation, and bronchoalveolar lavage fluid may usefully show that no microbial growth occurs on culture. If lavage fluid, or induced sputum, is obtained within a matter of hours of exposure, a polymorphonuclear leucocyte response may dominate, simulating usual interstitial pneumonia, but this is followed by an accumulation of lymphocytes over the following 24 to 48 h. In the subacute and chronic forms of the disease, T lymphocytes represent 10 to 20% or more of recovered cells, although the absolute numbers of macrophages are generally increased also. This characteristic cellular picture is not specific for extrinsic allergic alveolitis, but it strongly supports the diagnosis if other suggestive features are present. Other inflammatory granulomatous disorders, such as sarcoidosis and tuberculosis, hypersensitivity reactions to drugs, and a number of rare lymphoid infiltrative disorders are also associated with a lymphocytosis in lavage fluid, but in practice sarcoidosis is generally the most plausible alternative diagnosis.

In sarcoidosis, B-lymphocyte numbers are decreased and the excess T lymphocytes are typically CD4+ helper cells, with the CD4+ to CD8+ ratio normally exceeding 1 and so exaggerated. By contrast, the ratio is typically reversed in extrinsic allergic alveolitis, CD8+ cells outnumbering CD4+ cells, and B-lymphocyte numbers are not decreased. Lymphocyte markers may therefore help distinguish sarcoidosis from extrinsic allergic alveolitis. Unfortunately, the pattern favouring extrinsic allergic alveolitis does not distinguish so readily between subjects with exposure and symptoms and those with exposure but no symptoms. Both T-cell types show increased numbers if there is exposure, and the number of CD8+ cells tends to show a relatively greater, not lesser, increase in asymptomatic subjects, as described above. The absolute value of the CD4+ to CD8+ ratio therefore provides limited diagnostic benefit in identifying active disease, but this is rarely a relevant issue outside a research setting. A number of cytokines can also be recovered from the lavage fluid, but these are of research rather than diagnostic interest.

Inflammatory activity may also be detected by measurements of exhaled nitric oxide. Although different patterns over the period of exhalation in relation to different speeds of exhalation may allow a parenchymal source to be distinguished from an airway source, the procedure has no diagnostic specificity for alveolar responses that are allergic in origin. It may, however, be more useful as a monitoring tool by showing that particular periods of exposure are associated with pulmonary inflammatory responses. Transbronchial or video-assisted thoracoscopic lung biopsy may occasionally be indicated when other diagnostic procedures do not distinguish extrinsic allergic alveolitis from other diffuse infiltrative or fibrotic disorders of the lung. Biopsy is more likely to be needed in the subacute or chronic forms of the disease when hypersensitivity is less obvious, or acutely when there has been an unduly heavy exposure to microbial spores and there is suspicion of microbial invasion.

Environmental exposure

In many cases the history alone provides the evidence of relevant exposure, but this is not always reliable and an independent account of the exposures involved can be invaluable. Ideally, industrial hygiene measurements are made (particularly from personal samplers) so that respirable agents can be recognized and quantified, and microbiological techniques are used to identify specific microbial contaminants. These are sophisticated investigations and usually indicated only when extrinsic allergic alveolitis is first suspected in an environment not previously associated with the disease, particularly in industries where many individuals may be at risk and where modification of the plant and its respirable environment may be a costly matter.


The demonstration of a serum IgG antibody response to the inducing organic dust is the most widely used method of ‘confirming’ hypersensitivity (saliva may be used more conveniently in children), but this has proved to be unsatisfactory. Although affected subjects tend to have higher antibody levels than those who are exposed but unaffected, the antibody response tends to correlate more closely with exposure than with disease. If the more sensitive ELISA is used, rather than the traditional Ouchterlony double-gel diffusion test, even higher rates of false-positive results are obtained. In practice the absence of an IgG precipitin response is extremely uncommon in subjects eventually proved to have extrinsic allergic alveolitis, providing they are nonsmokers. This is of considerable value in that a negative test generally excludes the diagnosis. The limited value of a positive test is to be expected in view of the current belief that cellular, not humoral, immunity provides the principal mechanism underlying the disease. It is unfortunate that practicable tests for cellular hypersensitivity are not readily available.

When the diagnosis remains in doubt, some form of inhalation challenge test may be necessary. The simplest method involves comparison of experimental periods spent away from the suspected causative environment with similar periods of continuing exposure. The acute form of the disease is likely to be recognized in this way, though the procedure can be time consuming and there may be practical problems of compliance. When a definitive diagnosis is particularly important, laboratory-based inhalation challenge tests can be used. These employ a variety of techniques, ranging from nebulizing soluble extracts to recreating natural environmental exposures in an exposure chamber. The influenza-like component of positive reactions is often uncomfortable, and if excessive doses are administered these tests can be hazardous. Furthermore, objective evidence for positive reactions may be difficult to obtain from conventional lung function tests, hence tests of this nature should be restricted to centres with special expertise. Personal experience of evaluating objective changes in body temperature, circulating neutrophil and lymphocyte numbers, forced vital capacity, and exercise studies from 144 inhalation challenge tests is summarized in Table Together they provide high specificity and high sensitivity. Auscultation, chest radiography, measurements of gas transfer, and arterial blood gas analyses are often too insensitive to provide useful diagnostic information.

Table Diagnostic features of positive inhalation challenge tests

Diagnostic changes within 36 h of challenge exposure

Sensitivity (%)

Increase in body temperature to >37.2° C


Increase in circulating neutrophils by ≥2.5 × 109/litre


Decrease in circulating lymphocytes by ≥0.5 × 109/litre, with lymphopenia (<1.5 × 109/litre)


Decrease in forced vital capacity by ≥15%


Increase in exercise minute volume by ≥15%


Increase in exercise respiratory frequency by ≥25%


The data were taken from a series of 144 antigen and control challenge tests in 31 subjects. Diagnostic endpoints were chosen to produce specificities of approximately 95% after mean changes associated with positive challenge tests were shown to be highly significant. When each monitoring parameter was given a score of 1 for a significant result, a total score of 2/6 or more was associated with a specificity of 100% and a sensitivity of 78% for the 144 challenge tests.

Criteria for diagnosis

In the hope of avoiding a need for biopsy or other invasive investigation, the United States-led Hypersensitivity Pneumonitis Study Group recently concluded that five features across these three domains, plus weight loss, are generally sufficient to make a diagnosis: recurrent (relevant) symptoms, inspiratory crackles, exposure to a recognized inducer, symptoms arising within 4–8 h of exposure onset, and precipitating antibodies to the putative causal agent.


Management of the individual first demands that the diagnosis is secure and then centres on reducing any further exposure to a minimum. There is no place for desensitization. Ideally, the affected individual changes the relevant working, domestic, or recreational environment completely, but this may mean a profound loss in income or great expense, and is often unrealistic. Nor is it fully justified on purely medical grounds, since continued exposure does not lead inevitably to progressive disease.

The affected individuals who continue to work in the occupation responsible for their disease can often reduce their exposure substantially by changing the pattern of their particular duties. An alternative is the use of industrial respirators, which filter out 98 to 99% of respirable dust from the ambient air. These are especially valuable when exposures are intermittent and short, but may be uncomfortably hot when worn for long periods or when there is heavy work, and so compliance with their use may be poor.

Whatever course is followed, continuing exposure should be accompanied by regular medical surveillance. If there is no progression, it is reasonable for some exposure to continue. When there is progressive disease, exposure should cease. This may involve a loss of earnings and may entitle the affected worker to compensation. Rarely, the individual with progressive disease will refuse to change their occupation or hobby, and the physician must weigh the possible advantages of long-term, or pulsed, corticosteroid therapy against the risks. An additional medication, pentoxifylline, is currently under investigation, since it interferes with a number of macrophage functions of probable relevance and diminishes macrophage release of TNFα‎ and IL-10.

Compensation of industrial causes

In the United Kingdom, industrial injuries legislation provides compensation from central government for disability in employees (but not employers) from extrinsic allergic alveolitis of occupational origin. The level of disability, and hence compensation, is assessed following examination by a ‘medical board’. State benefits are limited to a maximum figure, which is adjusted from time to time according to inflation. Acceptance of state compensation in the United Kingdom no longer debars the recipient from seeking redress additionally in the civil courts, which is the primary mechanism of compensation in many countries.


No further exposure

As with occupational asthma the risk of continuing active disease following cessation of exposure increases with duration of the exposure period. With the acute form of extrinsic allergic alveolitis the exposure period is generally short and the disorder usually resolves without sequelae once the diagnosis is made and exposure ceases, but serial bronchoalveolar lavage and clearance studies suggest continuing inflammation and membrane leakiness for periods up to 15 years. The significance of this is unclear since the subjects involved generally remained asymptomatic and gave normal results on radiographic and lung function studies. Cessation of exposure in the more chronic cases has a less obvious beneficial effect, but usually prevents further progression.

Continuing exposure

There is greater concern when exposure continues. This may lead not only to recurrent acute attacks but to progressive and permanent fibrotic damage—i.e. to the chronic form of the disease. While concern for the risk of progressive fibrosis is undoubtedly justified, and while the chronic form of the disease certainly carries a greater risk of long-term morbidity or mortality, chronic disease occurs in only a minority of affected subjects. A 2- to 40-year follow-up survey of 92 farm workers presenting with acute farmer’s lung showed that while most continued to live on farms, only some developed radiographic evidence of pulmonary fibrosis (39%) or impairment of carbon monoxide gas transfer (30%), but as many as 28% gave histories of chronic productive cough and 25% had airway obstruction. A similar 10-year outcome has been reported in pigeon fanciers with acute extrinsic allergic alveolitis; again, most elected to continue their antigenic exposures despite medical advice to the contrary.

Therefore, in some cases—perhaps most—important protective mechanisms emerge that lead to tolerance of the effects of further acute exposures, or at least prevent the development of damaging fibrosis. A history of similar increasing tolerance is occasionally noted with occupational asthma, and tolerance not progressive disease is the rule rather than the exception in most animal models of extrinsic allergic alveolitis. However, with both asthma and extrinsic allergic alveolitis some affected subjects give clear accounts of increased responsiveness to a given level of exposure months or years after initial antigen exclusion, which suggests that protective mechanisms may be downgraded more quickly than the causal mechanisms.

As with sarcoidosis, there is debate as to whether the use of corticosteroids for acute episodes confers any long-term benefit. The answer is not clear, but one recent investigation failed to demonstrate any long-term functional differences between groups randomized to treatment with corticosteroids or placebo for the initial acute episode of farmer’s lung. Although the corticosteroid group recovered more quickly from the acute episode, there was the suspicion, already voiced by other investigators, that early steroid therapy carries a greater risk of long-term recurrence. It is possible that the initial response to steroids encouraged less care over subsequent exposures. Alternatively, steroid therapy may have induced a different equilibrium between immunological responses, perhaps interfering disproportionately with the development of protective mechanisms.

Further reading

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Braun SR, et al. (1979). Farmer’s lung disease: long-term clinical and physiologic outcome. Am Rev Respir Dis, 119, 185–91.Find this resource:

Churg A, et al. (2006). Chronic hypersensitivity pneumonitis. Am J Surg Pathol, 30, 201–8.Find this resource:

Cormier Y, et al. (2000). High-resolution computed tomographic characteristics in acute farmer’s lung and in its follow-up. Eur Respir J, 16, 56–60.Find this resource:

Erkinjuntti-Pekkanen R, Rytkonen H, Kokkarinen JI, Tukiainen HO, Partanen K, Terho EO (1998). American Journal of Respiratory & Critical Care Medicine, 158, 662–5.Find this resource:

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Lacasse Y, et al. (2003). Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med, 168, 661–70.Find this resource:

Martinez FJ, Keane MP (2006). Update in diffuse parenchymal lung diseases 2005. Am J Respir Crit Care Med, 173, 1066–71.Find this resource:

Meredith SK, Taylor VM, McDonald JC (1991). Occupational respiratory disease in the United Kingdom 1989: a report to the British Thoracic Society and the Society of Occupational Medicine by the SWORD project group. Br J Indust Med, 48, 292–8.Find this resource:

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Pepys J, et al. (1963). Farmer’s lung. Thermophilic actinomycetes as a source of ‘farmer’s lung hay’ antigens. Lancet, ii, 607–11.Find this resource:

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