Non-infectious fever: inhalation fever or toxic alveolitis?
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Biomedical subjects
Publications and source records attributed to P Malmberg.
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Pulmonary function measurements, bronchoalveolar lavage (BAL), and analyses of precipitating antibodies in blood were performed in 12 farmers wtih no symptoms from the airways and 12 farmers who were admitted to the hospital due to acute symptoms of alveolitis (all nonsmokers). In addition, a bronchial methacholine provocation test was performed in the asymptomatic farmers. In 11 of the 12 symptomatic farmers but in none of the asymptomatic farmers, precipitating antibodies against one or more of the microorganisms which usually occur in a farmer's environment were found. In the farmers with symptomatic alveolitis, a restrictive impairment of pulmonary function was found, while pulmonary function was normal in all asymptomatic farmers. Findings in the BAL fluid showed increased concentrations of total cells, lymphocytes, and neutrophils and elevated levels of albumin, fibronectin, and angiotensin-converting enzyme in asymptomatic farmers compared with our own reference group. The same analyses in BAL fluid from the symptomatic farmers revealed a further increase in all parameters compared with the asymptomatic farmers. The BAL fluid from asymptomatic farmers had normal levels of hyaluronic acid (hyaluronan) and procollagen 3 N-terminal peptide, while these levels were significantly increased in the symptomatic group. We conclude that inflammation in the alveolar space and signs of activation of alveolar macrophages are present in farmers regardless of respiratory symptoms, although these findings are more pronounced in the presence of symptoms of acute alveolitis; however, the findings of impaired pulmonary function and the occurrence of precipitins and elevated levels of hyaluronic acid and procollagen 3 N-terminal peptide in BAL fluid were exclusively found in the farmers with airways symptoms. We postulate the hyaluronic acid, due to its pronounced ability to immobilize water, may be of importance in the development of the pulmonary function impairment observed in farmer's lung disease.
Testing of lung function and bronchial reactivity, bronchoalveolar lavage (BAL), and a skin prick test with a standard panel and six "swine" extracts obtained from swine and swine environment were performed in 20 randomly selected nonsmoking swine confinement workers. In addition, blood samples for detection of antibodies by the diffusion in gel-enzyme-linked immunosorbent assay (DIG-ELISA) technique and precipitating antibodies were drawn. Air samples for measurement of dust and endotoxin levels were collected. All the farmers regarded themselves as healthy. The results were compared with reference groups consisting of urban nonsmoking subjects who had not been exposed to pig farming environment. The pig farmers had normal lung function and the bronchial reactivity was not different from the reference group. In the BAL fluid of the farmers, the concentration of total cells and granulocytes was increased while the concentrations of lymphocytes and macrophages were normal. The BAL fluid concentrations of albumin, fibronectin, and hyaluronan were elevated in the farmers. Skin prick tests with swine extracts were negative in all farmers. Antibodies (assessed by DIG-ELISA) against swine dander, swine dust, and pig feed were increased and precipitating antibodies against swine dander were found in 14, against pig food in five, and against swine confinement dust in three of the 20 pig farmers. The concentration of airborne total dust was 7.4 mg/cu mm and the endotoxin concentration was 37 (22 to 60) ng/cu mm during tending the pigs and increased, during feeding, to 13.8 mg/cu mm and 315 (194 to 716) ng/cu mm, respectively. There was no correlation between exposure and lung function or lavage findings. In conclusion, randomly selected pig farmers had signs of airway inflammatory reaction and activation of the immune system without alteration in lung function and bronchial reactivity.
A simple device aiming to increase deposition of nebulized methacholine in the lower airway was studied. The device controlled inspiratory flow and volume and dried the aerosol. The effect of drying on deposition in the throat and lower airways was studied in six subjects given an aerosol of 99mTechnetium-diethylenetriamine pentaacetate (DTPA) in saline with the device and with a reference device giving the same inspiratory flow and volume but no drying. Drying reduced throat deposition from 46 (range 26-61) to 13 (range 6-22)% (p less than 0.05) of the inhaled and retained dose. The effect of drying on the biological effect of nebulized methacholine was studied in 21 subjects who underwent three provocation tests on different days with doubling concentrations of methacholine from 0.5 to a maximum of 64 mg.ml-1, one with the reference device and two with the drying device. The percentage change in forced expiratory volume in one second (%FEV1) per cumulative dose of methacholine changed from -1.0 (2.6) %FEV1.mumol-1 (geom. mean and SD) with the reference device to -1.6 (3.6) with the drying device p less than 0.02. In an additional study 20 subjects underwent four provocation tests on different days, two with a different version of the drying device and two with the reference device. The slope changed from -1.1 (3.1) to -1.6 (3.3), p less than 0.02. The reproducibility of duplicate measurements did not improve with the drying device. Thus, the drying device decreased throat deposition and increased the biological effect of nebulized methacholine.
Exposure to farm dust may cause asthma, rhinitis, allergic alveolitis, organic dust toxic syndrome, and chronic bronchitis. Febrile reactions to inhaled dusts are common and are usually of a toxic rather than an allergic type. Some evidence indicates that dairy farmers may have an increased prevalence of chronic bronchitis, allergic asthma, rhinitis, and chronic airflow limitation, but this has not been conclusively shown. Storage mites and cow dander are important allergens in dairy farming. Inflammation of airways may in part be caused by immediate or delayed hypersensitivity. Other mechanisms, such as activation of inflammatory cells from toxic agents or high exposure levels, may be of considerable importance in causing airway and lung disease.
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Lung function tests, tests of working capacity with gas exchange, and computed tomography (CT) with density measurements with the patient supine and prone were performed in 23 males with asbestos-related bilateral pleural lesions. Two had pulmonary asbestosis grade 1/0 or more; all the others had normal lung parenchyma. On x-ray, the pleural lesions were divided into plaques involving only the parietal pleura There was a and diffuse pleural fibrosis of various degrees involving the visceral pleura. There was a good correlation between the findings at plain chest roentgenography and CT, but more lesions were seen on the CT scan. However, a few pleural plaques seen on conventional films were not observed at CT. Individuals with plaques had slightly lowered lung function compared to reference subjects. Bilateral diffuse pleural fibrosis was associated with a marked decrease in pulmonary function. The two patients with radiologically evident pulmonary asbestosis were found in this group. Decreased lung function was also observed in subjects with pleural fibrosis of only grade 1 (involving less than one fourth of the hemithorax) and a normal exercise capacity. The study shows the importance of differentiation between various asbestos-related pleural lesions.
All visitors to a general health survey in 1979, 17,140 men and 14,371 women, completed a questionnaire on smoking habits, exposure to asbestos, silica and welding fumes, and diseases such as pleural effusion, pneumonia, cough, asthma and diabetes. Seven per cent of the men reported exposure to asbestos, 10% to welding fumes, and 6% to silica. Among those who reported work related dust exposure there was a higher proportion of smokers, and smokers exposed to dust smoked more tobacco per day than non exposed smokers. In the group of men 30-59 years of age, who did not indicate exposure to occupational pollutants 2.7% reported previous pleural effusions. However, among asbestos exposed men of the same ages, the prevalence was more than doubled (5.7%, p less than 0.01). This finding was highly significant in a logistic regression model where age and smoking habits were included. The data indicate that 10% or more of diagnosed cases of pleurisy could be associated with previous asbestos exposure.
The endotoxin concentration in air was measured in farms where 11 farmers had experienced febrile reactions or allergic alveolitis and in a random sample of farms with 17 symptomless farmers. Samples were obtained during normal dairy farming in eight reference farms (background samples) and in all farms during the handling of material which had probably caused symptoms or disease or, in reference farms, maximal spore exposure (worst case samples). In addition, parallel samplers were used in reference farms, one with a cyclone (5 microns cutoff) and one without, to measure the dust and endotoxin concentrations in the respirable fraction and total dust. The endotoxin worst case values varied from less than 0.01 to greater than 50 micrograms/m3 in symptom farms (median 6.4 micrograms/m3, geometric mean 2.2 micrograms/m3) and from less than 0.01 to greater than 50 micrograms/m3 in reference farms (median 42 micrograms/m3, geometric mean 29 micrograms/m3). This difference was not statistically significant. The background values in reference farms were 1.3 (median) and 0.4 (geometric mean) micrograms/m3. The differences between samples with and without cyclone and between background and worst case samples were statistically significant (p less than 0.02). About 75% of the activity was found in the non-respirable fraction. No correlation was found between exposure to endotoxin and symptoms in farmers. There were weak, but statistically significant, correlations between endotoxin concentrations and total spore count or dust concentrations. The surprisingly high endotoxin values in the respirable fraction of air from environments which apparently did not cause symptoms raises the concern that the Limulus amebocyte assay might be sensitive to other components in the dust rather than endotoxin.
Air samples from 79 farms with 10(5) to 10(11) microorganisms/m3 were analyzed by scanning electron microscopy (SEM), fluorescence microscopy (FM), and the culture method. The total exposure to microorganisms (particularly actinomycetes) was underestimated when assessed as colony-forming units (cfu). The average cfu count was one-sixth of the total count according to SEM or FM, and the individual variability was great. This occurrence was partly explained by the aggregation of spores. Single spores accounted for 2-65% of all spores in 35 samples. There was an average of three spores/particle, and 93 (range 67-100)% of the spores were single or in aggregates of respirable size. Aggregation was more pronounced for actinomycetes and at high spore counts. Actinomycetes and bacteria could not be distinguished by FM. Bacteria (other than actinomycetes) were not detected by SEM, yet the total count of microorganisms was similar for FM and SEM. Most particles were spores from actinomycetes and fungi of the genera Aspergillus or Penicillium.
The incidence of allergic alveolitis (AA) and of febrile reactions (FR) to inhaled mold dust in those who did not meet the criteria of AA was investigated in Swedish farmers, and the findings were related to farming methods and exposure type. A questionnaire was completed by 6,702 farmers. A stratified sample of 390 farmers underwent examination comprising spirometry, a skin-prick test, blood tests for precipitating antibodies and total IgE and an interview concerning symptoms, exposure and farming methods. The yearly incidence of AA was 2-3/10,000 farmers. The incidence of FR was 30-50 times higher (1/100 farmers) and the majority of these reactions was of a toxic rather than allergic type (organic dust toxic syndrome). Among farmers with recent FR or AA there was a higher frequency of positive precipitin reactions (p less than 0.05). Exposures to moldy grain, straw, wood chips and hay were associated with both AA and FR. A major difference in exposure between 17 farmers with AA and 80 with FR was that AA appeared to require repeated exposure, while FR was associated with occasional heavy exposure to mold dust.
Lung function, bronchial reactivity, serum antibody levels, bronchoalveolar lavage (BAL) fluid and the magnitude of exposure to airborne microorganisms during farm work were studied in 10 healthy farmers with no respiratory symptoms. Lung function and bronchial reactivity were not altered. An increase in the amount of antibodies against several microorganisms could be demonstrated but precipitating antibodies were observed only in two subjects. In the BAL fluid the nonsmoking farmers had elevated proportion of lymphocytes and elevated levels of albumin, fibronectin and angiotensin-converting enzyme while the levels of hyaluronan and procollagen III N-terminal peptide were within normal limits. The lung function, bronchial reactivity, serum antibody levels and BAL findings were not correlated with the exposure to airborne microorganisms. We conclude that healthy farmers, exposed to mold dust, may exhibit signs of alveolitis including albumin leakage, accumulation of inflammatory cells and alveolar macrophage activation.
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Static and dynamic spirometric tests were performed in 21 healthy subjects (21-61 years old, 8 smokers and 9 ex-smokers) on 3 different days within 2 weeks. The design of the study allowed separation of the influence of learning and diurnal changes between 09.00 and 17.00 h. In addition, the reproducibility of the tests and the effect of inhalation of 2.5 mg of terbutaline sulphate were studied. No learning effect was observed. There were slight, but statistically significant differences between morning, noon and afternoon measurements. Thus, the residual volume and flow in the early phase of forced expiration were highest in the afternoon, while maximal voluntary ventilation was lower at noon than in the afternoon or morning. The intraindividual variabilities (defined as standard deviation of difference between first and second measurement) of total lung capacity, vital capacity and forced expiratory volume in 1 s (FEV1) were about 3% of the predicted values. The ratio of intra- to interindividual variability was 0.2-0.3. The remaining tests showed higher variability and a higher intra- to interindividual variability ratio. Terbutaline inhalation caused a significant increase in most forced expiratory flow variables. A 10% increase in FEV1 corresponded to a 50-60% increase in endexpiratory flow. In spite of this, the endexpiratory flow and mean transit time were better discriminators of the effects of bronchodilation in normal subjects.
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The ability to detect early lung disease with different combinations of lung function tests was assessed by discriminant analysis. A number of lung function tests were performed in 224 never-smokers, 232 smokers, 111 pneumoconiotic subjects and 137 asthmatic patients. The discriminatory capacities of different combinations of test variables are presented. For detecting lung damage induced by tobacco smoke, a combination of the transfer factor and the slope of the alveolar plateau (phase III) increased the sensitivity from 18% to 32% at a specificity of 95%, compared with phase III alone. Dynamic spirometry did not add to the discriminatory capacity. Patients with asthma could be separated from reference subjects by airway resistance, Phase III or a combination of variables in dynamic spirometry. Pneumoconiotic subjects were best identified by a combination of the transfer factor, volumic compliance and phase III. Closing capacity divided by total lung capacity (TLC) and FEV1/TLC further improved the discrimination between different subgroups.
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