American Journal of Respiratory and Critical Care Medicine

We evaluated the long-term outcome of farmer's lung (FL) patients and matched control farmers using high-resolution computed tomography (HRCT). The study population consisted of 88 FL patients and 83 control farmers, matched by age, sex, and smoking habits. The mean time after the first diagnosed episode of FL was 14 yr. The great majority, 82%, of the studied subjects were nonsmokers. Clinical studies included HRCT, spirometry, and pulmonary diffusing capacity. Emphysema was found significantly more often (23%) in FL patients than in control farmers (7%) (p = 0.006). The presence of emphysema was 18% in nonsmoking and 44% in smoking FL patients, the respective values being 4% and 20% in control farmers. Patients with recurrent attacks of FL tended to have emphysema more often (p = 0.08) than patients who had experienced only a single attack. Fibrosis was observed in 17% of the FL patients and in 10% of the control farmers (p = 0.2). Miliary changes were found in 12% of the FL patients compared with 4% of the control farmers (p = 0.07). Both emphysematous and fibrotic but not miliary changes correlated significantly with impaired pulmonary function. In conclusion, farmer's lung disease seems to be associated with an increased risk of developing emphysema. Erkinjuntti-Pekkanen R, Rytkönen H, Kokkarinen JI, Tukiainen HO, Partanen K, Terho EO. Long-term risk of emphysema in patients with farmer's lung and matched control farmers.

Previous follow-up studies of farmer's lung (FL) patients have shown that interstitial fibrosis is the most common radiological finding in chest X-rays and emphysema has been suspected to develop in only a few FL patients (1-3). However, a recent study using high-resolution computed tomography (HRCT) suggested that FL may be more likely to cause emphysematous than fibrotic changes (4). As this study was uncontrolled and farmwork itself may carry an increased risk of emphysema (5), a controlled study was needed. We compared HRCT findings in 88 FL patients, an average of 14 yr after the diagnosis of FL, to findings in 83 matched control farmers. We have earlier shown with the same study population that impairment of pulmonary diffusing capacity and an increased risk of airway obstruction are the most important long-term pulmonary function defects of FL (6).

Study Population

Of the 101 FL patients included in a previous study on FL (7), those 97 still living were asked to participate in the present study (6). Seven patients did not participate in the HRCT examination and two patients were excluded due to lack of a suitable control farmer. Thus the present analyses included 88 FL patients.

All FL patients were diagnosed in Kuopio University Hospital during 1977 to 1982. For all the patients, this was their first diagnosed episode of FL and all fulfilled the diagnostic criteria for FL presented by Terho (8). When the present study was performed there had been a mean interval of 14 yr (range 11 to 16 yr) after the initial diagnosis of FL disease.

Control farmers were frequency matched by 5-yr age group, sex, and smoking habits (nonsmokers, ex-smoker, current smoker) at the beginning of the follow-up with control subjects drawn from 2,424 participants of a farmer's health survey done in 1979 in Kuopio University Hospital district (9). Because all FL patients had cattle tending as their main farm operation, only control farmers with the same main farm operation in 1979 were selected. One control to each FL patient was invited to a clinical examination. If a control farmer was unable to attend, a new control farmer from the same stratum was selected; 86 of the 138 invited control farmers (62%) participated in the clinical examinations. Two control farmers were excluded from the analyses; one because her smoking habit was wrongly coded in the initial study in 1979 and another because she had suffered from FL 3 yr earlier. One control farmer did not participate in the HRCT examination. Thus 83 control farmers were included in the present analyses.

High-resolution Computed Tomography

The HRCT examination was performed with a Siemens Somatom Plus-S scanner (Siemens, Erlangen, Germany). For each subject, seven to ten 1-mm-thick slices were obtained at 20-mm intervals from the diaphragm to the lung apex, using a 1-s scanning time, 275 mA, and 137 KvP. The window settings were 1,200 HU/−500 HU and the zoom factor was as large as possible. A high-frequency reconstruction algorithm was used.

The presence of emphysema on HRCT was graded according to Sanders and coworkers (10) with the following scale: 0—normal; 1— emphysema involving less than 25% of the slice; 2—emphysema involving 25 to 50% of the slice; 3—emphysema involving 50 to 75% of the slice; 4—emphysema involving more than 75% of the slice. Emphysema was defined as a hypovascular area of pulmonary parenchyma unassociated with a fissure, usually lacking a well-defined wall (10). Emphysema related to fibrosis or scarring was not read as emphysema. However, emphysema and fibrosis and miliary changes were recorded to be on the same slice if these abnormalities were in different parts of that slice. The fibrotic and miliary changes on HRCT were graded according to a modified Hapke's classification (1) in which 0 was normal, 1 was minimal, 2 was definite, and 3 was marked changes.

The radiologic score was defined as the sum of the grading of each slice. Thus, the maximal total emphysema score was 40, and the maximal total score for fibrotic and miliary changes was 30. Scores 0–4 were arbitrarily defined as normal, scores ⩾ 5 were defined as definite emphysema, fibrosis, or miliary changes, and scores ⩾ 10 indicated marked changes.

Ten slices were obtained from the great majority (145 of 171, 85%) of the subjects. However, due to a smaller thorax, seven slices were obtained from one subject, eight slices from nine subjects, and nine slices from 16 subjects. As none of these individuals with a lower number of slices had a score of 3 or 4 (which would be comparable to a score of 5 in subjects with 10 slices), the same cutpoint 5 for definite emphysema, fibrosis, or miliary changes was used in these subjects.

HRCT films were viewed independently by two radiologists (HR and KP), who were blinded to the clinical data. The interobserver kappa values (11) for emphysematous, fibrotic, and miliary changes were 0.44, 0.42, and 0.38, respectively. When the interpretations were different, the final decision was reached by consensus.

Pulmonary Function Tests

All pulmonary function measurements were conducted by the same trained nurse according to American Thoracic Society (ATS) guidelines. For spirometry (Model 2200; SensorMedics, Yorba Linda, CA) the reference values were according to Viljanen (12). Measurement of pulmonary diffusing capacity (Dl CO) (Model 2200; SensorMedics) was conducted with a single-breath technique using the reference values according to the European Community for Steel and Coal (13).

Statistical Analyses

All comparisons in HRCT findings between FL patients and control farmers were made using unconditional logistic regression models with SPSS statistical package. The statistical significance of differences between means was tested using analyses of covariance. All comparisons between the study groups were adjusted for sex, smoking at the beginning of the follow-up in three categories (nonsmoker, ex-smokers, current smoker), and age as a continuous variable. All analyses of pulmonary function also included height as a continuous variable. The mean pulmonary function values presented in Table 1 have been adjusted for age, sex, height, and smoking habits using analysis of covariance (SAS statistical package, version 6; SAS Institute, Cary, NC).

Table 1. ASSOCIATION BETWEEN PULMONARY FUNCTION* AND EMPHYSEMA AND FIBROSIS SCORES

VC (L) MeanFEV1(L) MeanFEF50%(L/s) MeanFVC/FEV1(%) MeanDl CO(ml/min/mm Hg) Mean
Emphysema score
0(n = 127)3.75 2.70 2.99 72.425.8
1–4(n = 18)3.77 2.75 3.24 72.925.4
5–9(n = 18)3.59 2.41 2.46 66.521.1
⩾ 10(n = 8)3.43 2.19 1.98 64.820.1
p Value 0.03< 0.001< 0.001< 0.001  < 0.001
Fibrosis score
0(n = 119)3.76 2.66 2.89 70.925.0
1–4(n = 29)3.57 2.52 2.76 70.624.2
5–9(n = 15)3.57 2.45 2.57 69.022.1
⩾ 10(n = 8)3.24 2.31 2.73 72.119.0
 p Value 0.004 0.01 0.5  0.9  < 0.001

*Values are mean values adjusted for age, sex, height, and smoking.

Test for trend, analyses of covariance, adjusted for age, sex, height, and smoking.

The mean age of FL patients and control farmers was 60 yr; 78% of FL patients and 76% of control farmers were women, and 82% of both FL patients and controls were nonsmokers at the beginning of the follow-up. At the time of the present examination, 39% of the FL patients still worked regularly in the cow house, 4% worked occasionally, and 57% did not participate in farmwork. The respective figures for control farmers were 38%, 7%, and 55%. The adjusted mean (± SD) pulmonary function values of the FL patients were: vital capacity (VC) 3.71 ± 0.87 L; FEV1 2.59 ± 0.64 L; FEV1/VC 70.0 ± 6.7%; FEF50 2.70 ± 1.16 L/s; and diffusing capacity of the lungs for carbon monoxide (Dl CO) 23.0 ± 5.94 ml/min/mm Hg and of the control farmers 3.67 ± 0.83, 2.63 ± 0.67, 7.16 ± 7.0, 3.00 ± 1.26, and 26.2 ± 5.0, respectively.

The HRCT detected emphysema significantly more often in FL patients compared with control farmers (23% versus 7%) (Table 2). Of those who had marked emphysema, three of the four FL patients were nonsmokers and had emphysema as their sole abnormality, but two of the four control farmers were smokers, and the other two had marked emphysema together with marked fibrosis. Emphysema was more common in smokers than in nonsmokers in both groups; seven (44%) of the 16 smoking FL patients, and three (20%) of the 15 smoking control farmers had emphysema (p = 0.1), whereas 13 (18%) of the 72 nonsmoking FL patients but only three (4%) of the 68 nonsmoking control farmers had emphysema (p = 0.02). Emphysema was noted in 11 (31%) of the 36 patients with recurrent attacks of FL and nine (17%) of the 52 patients with a single attack of FL (p = 0.08).

Table 2. EMPHYSEMA, FIBROSIS, AND MILIARY SCORES OF FL PATIENTS AND CONTROL FARMERS BASED ON HRCT FINDINGS

FL Patients (n = 88)Control Farmers (n = 83)
n(%)n(%)
Emphysema score*
059(67)68(82)
1–49(10)9(11)
5–916(18)2(2)
⩾ 104(5)4(5)
Fibrosis score
057(65)62(75)
1–416(18)13(15)
5–910(11)5(6)
⩾ 105(6)3(4)
Miliary score
075(85)76(92)
1–43(3)4(5)
5–95(6)1(1)
⩾ 105(6)2(2)

*p = 0.006, odds ratio (OR) 4.21 (95% confidence interval [CI] 1.52–11.65) comparing FL patients with control farmers with definite emphysema (score ⩾ 5).

p = 0.2, OR 1.92 (95% CI 0.74–4.96) comparing FL patients with control farmers with definite fibrosis (score ⩾ 5).

p = 0.07, OR 3.45 (95% CI 0.90–13.25) comparing FL patients with control farmers with significant miliary changes (score ⩾ 5). Adjusted for age, sex, and smoking using logistic regression models in all analyses.

In the presence of fibrosis or miliary changes, no statistically significant differences were noted between the study groups (Table 2). Recurrent episodes of FL did not relate to the presence of definite fibrosis or miliary changes.

In a comparison of HRCT findings and pulmonary function values, a significant inverse association between emphysema score and VC, FEV1, FEF50%, FEV%, and Dl CO values, as well as between fibrosis score and VC, FEV1, and Dl CO was noted (Table 1). No statistically significant associations between miliary score and pulmonary function parameters were observed.

Those 40 FL patients who did not exhibit any abnormal HRCT findings (score = 0) had significantly (an average of 12%, p < 0.001) lower Dl CO values compared with similar controls (n = 51). In this analysis no statistically significant differences in the VC, FEV1, FEF50%, and FEV% values between those FL patients and clinical controls were noted, even though a tendency toward more airway obstruction was seen in FL patients (data not shown).

In our study, the largest difference between the study groups was observed in emphysema. An average of 14 yr after the diagnosis of FL, the HRCT examination revealed that 23% of the FL patients had emphysema compared with only 7% of the control farmers. Quite surprisingly, no significant difference was noted in the prevalence of fibrosis.

Our results agree with those of Lalancette and coworkers (4), who also used HRCT to diagnose emphysema in nine (27%) and fibrosis in three (9%) of the 33 patients in whom a diagnosis of FL had been made at least 6 yr previously. Emphysematous changes have also been demonstrated in 11 of the 24 (44%) patients with chronic bird breeder's lung (14).

Emphysema has been noted only rarely in previous follow-up studies of FL (1, 2). One reason may be the fact that only chest radiographs, which are insensitive for detecting emphysema (15), have been available. In the study of Lalancette (4), only four of the nine subjects with HRCT-detected emphysema also showed emphysematous changes in their chest radiograph, and three of the nine subjects with emphysema revealed by HRCT had a chest radiograph compatible with interstitial fibrosis. Thus, it may be that in the past, emphysema cases have been missed or defined as fibrosis. It is also possible that the outcome of FL has changed during recent years due to improvements in the diagnosis and treatment of the disease, which could be another reason for the observation of less fibrosis. According to the present study, fibrosis seems to be a less common long-term sequela than emphysema in subjects with diagnosed and treated FL.

Smoking is an important etiologic factor for emphysema. In the present study the risk of emphysema was highest in subjects who have had farmer's lung and were ex- or current smokers; nearly half (44%) of them had emphysema. However, 13 of the 20 FL patients with definite emphysema on HRCT were nonsmokers. In the study by Lalancette (4), seven of the nine subjects with emphysema were nonsmokers. Thus, it is evident that FL may lead to emphysema also in nonsmokers.

High-resolution CT has been considered to be superior for demonstrating the type and extent of abnormalities in extrinsic allergic alveolitis (16). The presence and degree of emphysematous changes detected with HRCT have been shown to correlate well with representative pathologic findings (17). In the present study, a strong association between pulmonary function and HRCT findings was noted. Thus, both emphysematous and fibrotic changes noted with HRCT probably represent real emphysema and fibrosis.

We used the same cutoff point of 5 or more in the emphysema score as Lalancette and coworkers (4) to categorize subjects as having definite emphysema. In our study this cutoff separated well between those with and those without impaired Dl CO and airway obstruction. Also a significant inverse correlation between fibrosis score and pulmonary diffusing capacity and vital capacity was noted, but in this analysis the cutoff point of 5 did not discriminate so well between those with higher and lower Dl CO. Thus we repeated our analyses using lower cutoff points (from 1 to 4) for fibrosis, but the results remained similar. In these analyses, the presence of fibrosis increased equally both in FL patients and control farmers, and the largest difference between the study groups remained in the presence of emphysema.

Interestingly, FL patients with normal HRCT findings had significantly, as a mean 12%, lower Dl CO than control farmers, which is the same as the difference between all FL patients and control farmers (6). If the impaired Dl CO had been solely due to fibrosis or emphysema, one would expect the difference in Dl CO between the patients and control farmers to have been smaller after exclusion of subjects with emphysema or fibrosis on HRCT. Therefore, it seems that HRCT is either not sensitive enough for detecting the smallest fibrotic and emphysematous changes or there are some other morphological changes in the lungs that are not radiologically evident, but nonetheless lead to impairment in diffusing capacity.

α1-Antitrypsin levels were not measured, but the low prevalence (1:1,430) of α1-antitrypsin deficiency in Finland (18) makes it a very unlikely candidate for explaining the difference between the study groups in the prevalence of emphysema.

Farmers with pulmonary problems may stop farming. In the present study, we were fortunate to be able to select controls from a survey done close to the same period when the FL patients were diagnosed. Therefore the cases and the controls were comparable at the beginning of the follow-up, which reduces the possibilities for bias. Moreover, the groups were comparable in the extent to which they spent time working in the cow house.

The pathogenesis of emphysema in FL is unknown; it could result from higher exposure and/or FL disease itself, possibly together with individual susceptibility. The most common histopathologic feature of acute FL is interstitial pneumonitis, but inflammatory processes in the distal airways, bronchiolitis, and bronchiolitis obliterans also have been described in about 50% of the cases (19, 20). This inflammation in the distal airways may be the morphological explanation for the development of emphysema as this inflammation may be long-lasting in cases of even low continuing exposure. This is supported by the finding of lower FEF50% in FL patients as compared with control farmers in our study population (6). It is not known whether proteolytic enzymes produced by microbes in organic dust play any role in the development of emphysema (21, 22). Inflammation and tissue damage in the lungs may also be induced by thermophilic actinomycetes (21, 22). Thus, the mechanisms leading to emphysematous changes in FL are probably multifactorial, and it seems that emphysema develops late in the course of FL.

In conclusion, farmer's lung disease seems to be associated with an increased risk of developing emphysema, which is the most common long-term sequela of FL as assessed by HRCT.

The writers thank Mikko Vahteristo, M.Sc., for help with statistical analyses.

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Supported by grants from Farmers' Social Insurance Institution of Finland, Yrjö Jahnsson Foundation, and The Finnish Anti-Tuberculosis Association Foundation.
Correspondence and requests for reprints should be addressed to Riitta Erkinjuntti-Pekkanen, M.D., Department of Pulmonary Diseases, Kuopio University Hospital, FIN-70210 Kuopio, Finland.

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