Farmer's lung disease (FLD), first described by Campbell in 1932, is one of the most prevalent forms of hypersensitivity pneumonitis (HP).1 It is caused by the inhalation of microorganisms from hay and the dust from grain or straw stored in very damp conditions. It is a significant cause of morbidity among farm workers in some countries.2,3 Few studies have been published in Spain,4–6 in contrast to the large series published in other regions with similar climatic conditions to northern Spain.

The exact prevalence of FLD is difficult to determine, since the disease is influenced by many factors, including climate, geographical region, local customs, and differences in the nature and intensity of exposure to antigens.7 Approximately 0.5%–3% of farmers may develop FLD, and the disease is associated with higher mortality rates. More recent studies performed among farmers in Asia described a prevalence of less than 6%,7,8 but few epidemiological studies have been performed in our setting.9

The causative antigens in most cases of HP, including FLD, are bacteria, the most commonly described being thermophilic actinomycetes. This species includes Saccharopolyspora rectivirgula (previously known as Micropolyspora faeni, described as the main FLD antigen), Thermoactinomyces vulgaris, Thermoactinomyces viridis, and Thermoactinomyces sacchari, among others. These organisms reproduce in areas with high levels of humidity and at temperatures of between 40 and 60°C. They are often isolated in contaminated farms (from moldy hay and other types of fodder), milking sheds and compost plants. These bacteria are among most common etiological agents in studies reported in Europe and North America,10,11 but farmers are also exposed to other fungi and fungal fragments that can also cause FLD, such as Alternaria, Aspergillus fumigatus and Botrytis.11,12 FLD, then, is common in farming areas, particularly in the cold, wet seasons, when climatic conditions lead to increased levels of microorganisms in stored hay (Fig. 1).12

Fig. 1.

(A, B) Different methods for storing hay, compacted (A) and covered (B). In this type of storage, certain climatic conditions can induce the growth of the microorganisms which cause farmer's lung disease.

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All HP diseases, including FLD, are caused by repeated exposure to antigenic particles in a susceptible, previously sensitized patient. The characteristics of antigens that determine their ability to induce an immunological response include their size, solubility, nature, resistance to enzymatic degradation, and inflammatory capacity. These antigens are implicated in the formation of antigen-antibody immune complexes, particularly of the IgG type, which intervene in complement activation. Antibody response alone is insufficient to cause disease: a cytotoxic CD8+ lymphocyte response is also required. Lymphocyte mediation is another mechanism involved in the process, particularly Th1 mediation, which is responsible for lymphocyte alveolitis and the formation of granulomas.1,13 Some studies have shown that lymphocytes are also involved in the pathogenesis of FLD, and evidence of lymphocyte stimulation is considered as diagnostic proof of the disease.14 Immediate hypersensitivity reactions, probably caused by IgG4 rather than IgE, may also play a role in the genesis of the immunological response.13,15

Little information is available on the particular host characteristics which determine susceptibility to developing FLD. It is more common in middle-aged men, although this probably reflects differences in exposure levels. It is also more common in non-smokers, probably because tobacco reduces the IgG response to inhaled antigens, affects cytokine production, and alters macrophage function.16,17

Known environmental risk factors include antigen load, duration of exposure, rhythm of exposure (frequency/intermittency), use or non-use of respiratory protection, and the type of working practices.11

FLD is conventionally classified into 3 groups (acute, subacute, and chronic), depending mainly on clinical and radiological findings at the time of diagnosis.18

Several conventional diagnostic criteria have been proposed for FLD, but none have been validated. The major criteria are summarized in Table 1. Like other diffuse interstitial pulmonary diseases (DIPD), the point of departure is clinical suspicion, backed up by a detailed history of workplace and environmental exposure, suggestive clinical symptoms and lung function values, radiological findings, cytological evidence on bronchoalveolar lavage (BAL), and consistent pathology results21,22 (Fig. 2). The following additional testing is then performed:

Fig. 2.

Proposed diagnostic algorithm for farmer's lung disease. BAL: bronchoalveolar lavage; DIPD: diffuse interstitial pulmonary disease; FLD: farmer's lung disease; TBB: transbronchial biopsy. *Respiratory function improvement >20% of FVC, FEV1 and/or DLco. Source: adapted from the algorithm proposed for the diagnosis of HP by Morell et al.28

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Radiology

In acute phases, the chest X-ray can be normal or show diffuse pulmonary infiltrates. In the chronic phases, a bilateral reticular pattern may be observed.

In acute phases, typical chest HCRT findings are diffuse ground glass infiltrates and hyperlucent images (as a result of concomitant bronchiolitis), which together form a pattern of mosaic attenuation.32 Centrilobular nodules are also typical in some disease phases, but they are more common in the acute phases32 (Fig. 3A). Honeycombing is an important feature of chronic forms. Emphysema is observed in 20% of non-smokers with FLD.33,34

Fig. 3.

Radiological characteristics in farmer's lung disease. (A) Chest high-resolution computed tomography in a patient with acute farmer's lung. Ground glass infiltrates and centrilobular nodules can be observed. (B) Chest high-resolution computed tomography in a patient with chronic farmer's lung. Note the reticular pattern in middle fields with low-grade ground glass infiltrate.

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Involvement is typically limited to the middle and upper lung fields, although lower fields cannot be ruled out, which means that at times disease appears on CT primarily in a honeycombing pattern and the radiological image is indistinguishable from that of usual interstitial pneumonia (UIP)35 (Fig. 3B).

Transbronchial Biopsy, Cryobiopsy, and Surgical Lung Biopsy

Transbronchial biopsy (TBB) can be useful in the early stages of the disease.43 TBB by cryoprobe (or cryobiopsy) is a less invasive endoscopic technique than surgical lung biopsy, and may play an important role in the diagnosis of FLD. Recently published studies report a diagnostic yield in DPID of over 70%, with relatively few complications.44–46

Surgical lung biopsy is not usually required to establish a diagnosis of FLD, but it is often vital in differentiating a chronic form of FLD from other interstitial entities, particularly in cases in which no antigen can be identified.28,47 In general, it is rarely required in the acute phases, since the causal relationship is usually easy to establish. The largest series published to date is that of Hariri et al., who described 5 cases of acute HP, although the findings suggest that these may be acute exacerbations of a previous HP, rather than an acute HP as such, since intra-alveolar fibrin with some interstitial eosinophils and neutrophils that occur along with subacute changes, such as lymphocytic bronchiolitis and loose, non-necrotizing granulomas, were observed.48 For this reason, histological findings in the acute phase of the disease are still not fully clarified. Alveolar infiltrates with neutrophils, eosinophils and necrotizing vasculitis of the small vessels have been described.48 In the subacute and chronic forms of the disease, the relationship between the onset of symptoms and causal exposure is less clear, and fibrosing changes may occur in some cases, suggestive of a pattern of usual interstitial pneumonia (UIP) or non-specific interstitial pneumonia (NSIP).49 In general, the typical histological findings (but not the pathognomic findings) are reflected in the conventional triad described by Coleman and Colby,50 which have been described in more detail in some more recent articles, namely: (1) predominantly lymphocytic interstitial pneumonia; (2) chronic bronchiolitis in the form of predominantly lymphocytic peribronchiolar infiltrate with or without fibrosis; and (3) predominantly interstitial, loose, non-necrotizing granulomas51 (Fig. 4). However, it should be taken into account that granulomatous findings may be absent in up to 30% of cases. Some publications even report that the complete triad exists only in 50% of the cases,48 and the presence of peribronchiolar metaplasia has also been described.49

Fig. 4.

Histopathological characteristics in farmer's lung disease. Loose, non-necrotizing granulomas formed by histiocytic aggregates and abundant lymphoplasmacytic infiltrate (hematoxylin-eosin 40×).

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The differential diagnosis is performed basically against other DIPDs. Chronic forms may be similar to idiopathic pulmonary fibrosis (IPF) and fibrotic phase NSIP, with a progressive clinical picture and few symptoms. Even if a surgical lung biopsy is available, differential diagnoses suggested by that specimen can include other entities, ranging as widely as sarcoidosis, drug-induced DIPDs, lymphocytic interstitial pneumonia, and DIPDs due to connective tissue diseases. In advanced chronic forms, it may be difficult to differentiate the histological pattern of UIP from IPF, or from the NSIP pattern, although fibrosis spreading toward the center of the lobule in biopsies with a UIP pattern can indicate the possibility of chronic HP.50–52 Autopsy series have found that fibrosis is more common than granulomas in the chronic forms of the disease.17

The initial lack of specific symptoms in the acute forms may initially suggest an influenza-like process in cases with normal standard chest X-ray, or bacterial pneumonia in patients with pulmonary infiltrates.

Hence, while the most common features can guide diagnosis, the wide range of clinical, radiological and histological presentations require us to establish a strict correlation between them all before reaching a definitive diagnosis.

The treatment of FLD is based mainly on avoiding exposure to the antigen: we will address this approach in more detail in the section on prevention. This is the only measure that has been shown to delay disease progression.

Treatment with glucocorticosteroids accelerates recovery in the acute forms, but it has not been shown to affect the progress of the disease in the long term, and some authors question their role in the chronic forms.13,53 Corticosteroids are traditionally recommended in patients with impaired lung function. The doses are similar to those given for other DIPDs, such as sarcoidosis (30mg/day for 1 month, then 20mg/day, followed by tapering to a maintenance dose of 7.5–15mg/day). No scientific evidence is available for recommending either the use or avoidance of inhaled glucocorticosteroids.

Immunosuppressive treatments have been tested in refractory forms of other HPs, such as bird fancier's lung, but not in FLD. In these patients, the few published cases have reported improved functional progress with rituximab.54,55

Lung transplantation is indicated in cases of progressive disease with respiratory failure, despite the treatments mentioned above. A recent study found improved 5-year survival in patients transplanted due to HP, compared to those transplanted for IPF.56

There are 3 ways of reducing repeated inhalation of organic particles by FLD patients, in order to prevent the disease progressing to a fibrosing, and hence irreversible, process: (a) definitive withdrawal of the patient from the farming environment, which in most cases is unfeasible for financial reasons; (b) development of new techniques for drying the hay, and ventilation and mechanization of stock feeding; and (c) use of respiratory protective equipment to prevent the antigens entering the respiratory tree.

One of the main preventive measures consists of improving hay storage methods. Drying or heating the fodder during storage has proven to be beneficial in reducing antigen levels.57 Keeping the fodder in loosely packed square bales also hinders the growth microorganisms, but these methods are disappearing, due to the high cost and heavy labor burden, and are being replaced by round bales (Fig. 1). These bales are easy to store and handle, but they contain high humidity levels due to greater compaction of the hay.58 It is also important that silos are emptied more slowly to reduce the amount of dust in the air (and thus the antigen levels), and the time of exposure. Moreover, special care must be taken to keep the storage space well ventilated, with the creation of continuous flow systems to reduce CO2 and bioaersol levels.59 However, these installations are costly, making widespread implementation unlikely.

In some regions, traditional practices, such as salting the hay, are employed for preventing the proliferation of microorganisms, but these are ineffective.58–60 Commercially available additives can also be applied to the fodder to improve storage conditions, but they tend to be very corrosive acids which damage farm machinery, so arable and pastoral farmers are reluctant to use them.

The use of protective respiratory equipment is a prevention method which requires no suspension of farming activity (Fig. 5). In 1971, the clinical observations of Gourley and Braidwood61 confirmed the efficacy of protective masks in patients with a diagnosis of acute FLD. The filters used retained particles of 0.8μ with a 98% efficacy. Kusaka et al.62 studied a cohort of 21 patients with a diagnosis of FLD who used protective respiratory devices for a period of 2 years during their usual farming activities, particularly when handling hay. During the study period, a significant reduction in symptoms of acute exposure was observed, compared to symptoms suffered in the previous 4 years, and only 1 patient had severe acute symptoms requiring hospitalization and/or corticosteroid treatment. However, the efficacy of respiratory protection in the prevention of chronic disease has not yet been confirmed in other studies.

Fig. 5.

Barrier methods. Different models of masks and filters effective in preventing antigen exposure in FLD.

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Some types of respiratory protection may be uncomfortable to use, leading to poor compliance. In the above-mentioned study, of the 21 patients who received protective respiratory devices, 17 (80%) tolerated them for a period of 2 years; the 4 patients who abandoned them did so due to discomfort and lack of symptoms when working without protective systems.62 Tolerance of protective respiratory devices is probably related with prevention of the acute symptoms triggered by exposure and the fact that the only other alternative is changing jobs. When educating patients in the use of these devices, it is important to (1) select the most comfortable and effective device against the antigen to be avoided, and (2) provide advice on care and maintenance.

The progress of FLD varies widely and depends fundamentally on time and antigen load. Even so, in some patients, the disease continues to progress for as yet unknown reasons, despite the use of appropriate avoidance techniques.

The acute phase of FLD is generally reversible, but continuous exposure or several subacute episodes of hypersensitivity to the allergen can cause fibrotic forms to develop, causing irreversible changes in lung structure and function.36,63 Up to 20% of acute forms progress to chronicity. A Finnish study estimated mean 17-year survival after the appearance of symptoms at 9%–17%.64 Factors associated with greater mortality in FLD are a fibrotic pattern in the chest CT65 and significant pulmonary arterial hypertension.66

In summary, FLD is a disease that may possibly be underdiagnosed in the north of Spain, although no precise epidemiological studies are available. Data on the long-term efficacy of corticosteroid treatment and other immunosuppressants is also scant, and no regional antigen panels are available for diagnostic purposes. More awareness of a suspected diagnosis is needed, taking into account that presentation may not fulfill the conventional criteria for DIPD (e.g., obstructive ventilatory changes and emphysema on chest HRCT). Patients with a diagnosis of FLD should be encouraged to follow a strict strategy for preventing antigen exposure, including, in particular, the proper use of protective respiratory equipment.

The authors state that they have no conflict of interests.