249
THE LANCET
Inhalation Fevers
physician always thinks of possible occupational causes for his patient’s symptoms, and there are several disorders which can usually be recognised from a good occupational history. For instance, in farmer’s lung the fever and respiratory response----cough, crepitations, and a restrictive ventilation defect-begin 4-6 hours after inhalation of spores from mouldy hay. Here, precipitins to mouldy hay and to Micropolyspora feeni are present, and the reaction has been categorised as an extrinsic allergic alveolitis, a form of type-III hypersensitivity reaction.l Distinct from this is metal-fume fever, where welders (as during welding of galvanised steel) inhale fumes of zinc or other metals, as oxide particles, and suffer a delayed febrile reaction with malaise and myalgia.2 This reaction includes an unexplained tolerance effect, in which symptoms lessen with repeated daily exposure but are much worse on return to THE alert
work after a break, such as a weekend. Flax and cotton workers with byssinosis likewise have their worst symptoms on Mondays. The alveolar membrane is a huge diffusing surface some fifty times larger in area than the skin. Fortunately it is well protected from larger particles (over 5 pm in diameter) which are deposited in the airways and later removed, but gases, vapours, and small particles can reach the alveoli. If they are soluble they will enter the pulmonary capillaries. Toxic and immunological reactions can occur, and the potential for harmful reactions is high; the lung is indeed subject to a wide variety of disorders, but one might expect them to arise more often than they do. Lately reports have appeared of disorders which seem to fit into the spectrum between the extrinsic allergic alveolitis of farmer’s lung and the febrile and constitutional symptoms of metal-fume fever and byssinosis.3-6 Inall the reports symptoms could be related to inhalation of air contaminated by microorganisms, usually from 1.
Pepys, J. Hypersensitivity Diseases of the Lungs due to Fungi and Organic Dusts. Basle, 1969. 2. Parkes, W.R. Occupational Lung Disorders; p. 476. London, 1974. 3. Banaszak, E. F., Thiede, W. H., Fink, J. N. New Engl. J. Med. 1970, 283, 271. 4. Pickering, C. A.
C., Moore, W. K. S., Lacey, J., Holford-Strevens, V. C.,
Pepys, J.Clin. Allergy, 1976, 6, 451. 5.Friend,
J. A. R., Gaddie, J., Palmer, K. N. V., Pickering, C. A. C., Pepys, J. Lancet, 1977,i, 297. 6.Edwards, J.H., Griffiths, A. J., Mullins, J. Nature, 1976, 264, 438.
humidifiers. The Medical Research Council gathered together many interested parties for a symposium, a report of which has now been published.’ In four different factories, in Nottingham,4 Leeds, Aberdeen,s and Cardiff,6 workers complained of malaise, fever, and myalgia, beginning within 4-8 hours of starting work, usually settling within 24 hours, and worst on Mondays. In three of the factories there was also a respiratory component with cough and breathlessness, and physiological investigations revealed a restrictive ventilatory defect with impaired gas diffusion suggesting an alveolitis. There were none of the X-ray changes seen in farmer’s lung, and no evidence of irreversible lung damage emerged during the period of observation. In Cardiff, where workers did not have respiratory changes, polyuria was a striking symptom.’ There was no obvious airborne dust in any of the outbreaks, but in Aberdeen the disorder was linked to vacuum pumps of "liquid ring" type, which were discharging an aerosol into the factory atmosphere. In the other three factories the illness was associated with humidification systems. In each factory recirculating water used in the humidifiers or vacuum pumps had become contaminated with a heavy mixed growth of bacteria and fungi. Protozoa, including flagellates, ciliates, and amoebae, were also found in Cardiff and Aberdeen, and may also have been present in the other factories. In all the outbreaks there was difficulty in finding a specific responsible organism. Most of the affected workers had serum precipitins to crude extracts of contaminated water, as did a quarter to three-quarters of symptomless workers exposed to the same conditions. When precipitin reactions to individual bacteria or fungi were sought, there were no consistent findings. Similarly, cautious inhalation challenge tests with contaminated-water extracts reproduced the illness in affected workers, but not in normal controls,s and yet when affected workers inhaled extracts of individual organisms there was no reaction.4 In Cardiff, Ncegleria gruberi was present in large numbers, and serum precipitins to this amoeba could be detected in affected workers.6 In the other three outbreaks serum gave high indirect fluorescent-antibody titres to Acanthamaeba species in 13 out of 15 affected workers, organisms of this group having been found in circulating water samples from Leeds and Aberdeen.’7 Is there any evidence that these antibodies are the basis of the clinical illness? As with farmer’s lung, the fact that some exposed workers can have precipitins to antigen, and yet never get symptoms when exposed to it, casts doubt on the attractively simple idea that the precipitin reaction is the basis for the clinical symptoms. The presence of precipitins confirms that an individual has been exposed 7. Medical Research Council Symposium.
Thorax, 1977, 32, 653.
250
antigen, but does not incriminate the antigen in the particular illness. PEPYS7 suggested that some immune complexes might form, with complement activation, involving antibodies with a low affinity for antigen; such antibodies might not be demonstrable by conventional precipitin techniques. Clinical reactions might also arise if complement was activated via the alternative pathway. Different types of reaction might also occur with soluble components of antigens, diffusing to produce soluble aggregates with completo an
consumption; less soluble antigens could remain in the alveoli, causing granulomatous foreign-body reactions. Speakers at the M.R.C. symposium suggested that the febrile response could arise from bacterial endotoxins, or from release of lymphocyte pyrogens as a result of the immunological reaction. The role of lymphocytes, which can release chemotactic and other factors ment
(lymphokines) during immune-complex formation, also requires investigation. Such reports of new clinical syndromes raise many interesting clinical and immunological questions, but they should also alert us to the need for preventive action. Recirculating water can easily become contaminated with a mass of microorganisms, especially if it is agitated, aerated, and warm-as is the case in many humidifiers. Usually water is allowed to cascade over baffles or is sprayed at revolving discs, while air is blown through the humidification chamber. The organisms prosper by growing on organic and inorganic substrates, including each other, and become part of an elaborate food chain. In all four factories where illness occurred, cellulose material may also have been a nutrient (three were in the printing and stationery industry, and the other made rayon). Attempts to combat growth of microorganisms by cleaning, filtration, or bactericidal chemicals have been unsuccessful, and chemicals in the water might create additional hazards. With humidifying systems conversion to steam humidification provides a solution, and in Aberdeen, venting of the vacuum-pump effluent put a stop to symptoms in affected workers. Some industrial processes, such as printing, require careful control of humidity as well as comfortable working conditions-and the same can be said of hospital operating-theatres. Control of temperature and humidity is expensive, but energy costs can be reduced by recirculation of air. If the humidification system depends in turn on recirculating water, a serious hazard can then arise through water contamination with microorganisms. This can be dealt with by employing steam humidification instead; the Department of Health and Social Security now recommends steam humidification in all new installations. Older installations and industrial firms may still be equipped with "wet" humidification
systems hazard
employ processes in which inhalation arise. A story of recurrent fevers or ressymptoms should prompt inquiry into the
or
can
piratory occupational possibilities.
Platelets, Beta-thromboglobulin, and Diabetes Mellitus WHEN tested in vitro, platelets from patients with diabetes mellitus may function abnormally. There are reports of increased adhesiveness,1-4 of
increased tendency to spontaneous aggregation,s and of a heightened sensitivity to aggregating agents such as A.D.P., adrenaline, and collagen.4.6-8 A possible explanation for these findings has now emerged: in the presence of A.D.P., adrenaline, or collagen, diabetic platelets seem unusually active in synthesising a prostaglandin-E-like material; and they also metabolise arachidonic acid to the prostaglandin-E-like material more rapidly than do nondiabetic platelets.9 Could this platelet hyperactivity be clinically important ? In one report4 the enhanced sensitivity to A.D.P. and adrenaline correlated with the activity of retinopathy; in another8 the abnormality was particularly striking in patients with neuropathy; and small-vessel thrombosis has been observed in suralnerve specimens from patients with diabetic neuropathy.10,11 But the hypothesis that diabetic complications are due to platelet abnormalities remains unproven. Platelet technology is laborious, and subtle methodological differences12 (regarded by some as "black platelet magic") lead to conflicting results. It has also been difficult to determine whether the abnormalities demonstrated are a cause or an effect of the complications. And who knows whether these highly artificial in-vitro tests reflect the situation in vivo. In 1975 an Edinburgh groupl3 described the isolation and characterisation of a platelet-specific protein which they named beta-thromboglobulin. p-T.G. has a molecular weight of 36 000 and is released during platelet aggregation; a radioimmunoassay has been devised to quantitate it in bioan
1. Bridges, J. M., Dalby, A. M., Millar, J., Weaver, J. Lancet, 1965, i, 75. 2. Shaw, S., Pegrum, G. D., Wolff, S., Ashton, W. L. J. clin. Path. 1967, 20, 845. 3. Mayne, E. E., Bridges, J. M., Weaver, J. Diabetologia, 1970, 6, 436. 4. Heath, H., Bridgen, W. D., Canever, J. V., Pollock, J., Hunter, P. R., Kelsey, J., Bloom, A. ibid. 1971, 7, 308. 5. Breddin, K., Grun, H., Krzywanek, H. R. Thromb. Hœmostas. 1976, 35, 669. 6. Kwaan, H. C., Colwell, J. A., Cruz, S., Suwanwela, N., Dobbie, J. C. J. Lab. clin. Med. 1972, 80, 236. 7. Sagel, J., Colwell, J. A., Crook, L., Laimins, M. Ann. intern. Med. 1975, 82, 733. 8. O’Malley, B. C., Timperley, W. R., Ward, J. D., Porter, N. R., Preston, F. E. 9.
Lancet, 1975, ii, 1274. Halsushka, P. V., Lurie, D., Colwell, J. A. New Engl. J. Med. 1977, 297, 1306.
10. Fagerburg, S. E. Acta med. scand. 1959, suppl. 345, p. 1. 11. Timperley, W. R., Ward, J. D., Preston, F. E. Diabetologia, 1976, 12, 237. 12. Weiss, H. J. J. Lab. clin. Med. 1976, 87, 909. 13. Moore, S., Pepper, D. S., Cash, J. D. Biochim. biophys. Acta, 1975, 379, 360.
THE LANCET
Inhalation Fevers
physician always thinks of possible occupational causes for his patient’s symptoms, and there are several disorders which can usually be recognised from a good occupational history. For instance, in farmer’s lung the fever and respiratory response----cough, crepitations, and a restrictive ventilation defect-begin 4-6 hours after inhalation of spores from mouldy hay. Here, precipitins to mouldy hay and to Micropolyspora feeni are present, and the reaction has been categorised as an extrinsic allergic alveolitis, a form of type-III hypersensitivity reaction.l Distinct from this is metal-fume fever, where welders (as during welding of galvanised steel) inhale fumes of zinc or other metals, as oxide particles, and suffer a delayed febrile reaction with malaise and myalgia.2 This reaction includes an unexplained tolerance effect, in which symptoms lessen with repeated daily exposure but are much worse on return to THE alert
work after a break, such as a weekend. Flax and cotton workers with byssinosis likewise have their worst symptoms on Mondays. The alveolar membrane is a huge diffusing surface some fifty times larger in area than the skin. Fortunately it is well protected from larger particles (over 5 pm in diameter) which are deposited in the airways and later removed, but gases, vapours, and small particles can reach the alveoli. If they are soluble they will enter the pulmonary capillaries. Toxic and immunological reactions can occur, and the potential for harmful reactions is high; the lung is indeed subject to a wide variety of disorders, but one might expect them to arise more often than they do. Lately reports have appeared of disorders which seem to fit into the spectrum between the extrinsic allergic alveolitis of farmer’s lung and the febrile and constitutional symptoms of metal-fume fever and byssinosis.3-6 Inall the reports symptoms could be related to inhalation of air contaminated by microorganisms, usually from 1.
Pepys, J. Hypersensitivity Diseases of the Lungs due to Fungi and Organic Dusts. Basle, 1969. 2. Parkes, W.R. Occupational Lung Disorders; p. 476. London, 1974. 3. Banaszak, E. F., Thiede, W. H., Fink, J. N. New Engl. J. Med. 1970, 283, 271. 4. Pickering, C. A.
C., Moore, W. K. S., Lacey, J., Holford-Strevens, V. C.,
Pepys, J.Clin. Allergy, 1976, 6, 451. 5.Friend,
J. A. R., Gaddie, J., Palmer, K. N. V., Pickering, C. A. C., Pepys, J. Lancet, 1977,i, 297. 6.Edwards, J.H., Griffiths, A. J., Mullins, J. Nature, 1976, 264, 438.
humidifiers. The Medical Research Council gathered together many interested parties for a symposium, a report of which has now been published.’ In four different factories, in Nottingham,4 Leeds, Aberdeen,s and Cardiff,6 workers complained of malaise, fever, and myalgia, beginning within 4-8 hours of starting work, usually settling within 24 hours, and worst on Mondays. In three of the factories there was also a respiratory component with cough and breathlessness, and physiological investigations revealed a restrictive ventilatory defect with impaired gas diffusion suggesting an alveolitis. There were none of the X-ray changes seen in farmer’s lung, and no evidence of irreversible lung damage emerged during the period of observation. In Cardiff, where workers did not have respiratory changes, polyuria was a striking symptom.’ There was no obvious airborne dust in any of the outbreaks, but in Aberdeen the disorder was linked to vacuum pumps of "liquid ring" type, which were discharging an aerosol into the factory atmosphere. In the other three factories the illness was associated with humidification systems. In each factory recirculating water used in the humidifiers or vacuum pumps had become contaminated with a heavy mixed growth of bacteria and fungi. Protozoa, including flagellates, ciliates, and amoebae, were also found in Cardiff and Aberdeen, and may also have been present in the other factories. In all the outbreaks there was difficulty in finding a specific responsible organism. Most of the affected workers had serum precipitins to crude extracts of contaminated water, as did a quarter to three-quarters of symptomless workers exposed to the same conditions. When precipitin reactions to individual bacteria or fungi were sought, there were no consistent findings. Similarly, cautious inhalation challenge tests with contaminated-water extracts reproduced the illness in affected workers, but not in normal controls,s and yet when affected workers inhaled extracts of individual organisms there was no reaction.4 In Cardiff, Ncegleria gruberi was present in large numbers, and serum precipitins to this amoeba could be detected in affected workers.6 In the other three outbreaks serum gave high indirect fluorescent-antibody titres to Acanthamaeba species in 13 out of 15 affected workers, organisms of this group having been found in circulating water samples from Leeds and Aberdeen.’7 Is there any evidence that these antibodies are the basis of the clinical illness? As with farmer’s lung, the fact that some exposed workers can have precipitins to antigen, and yet never get symptoms when exposed to it, casts doubt on the attractively simple idea that the precipitin reaction is the basis for the clinical symptoms. The presence of precipitins confirms that an individual has been exposed 7. Medical Research Council Symposium.
Thorax, 1977, 32, 653.
250
antigen, but does not incriminate the antigen in the particular illness. PEPYS7 suggested that some immune complexes might form, with complement activation, involving antibodies with a low affinity for antigen; such antibodies might not be demonstrable by conventional precipitin techniques. Clinical reactions might also arise if complement was activated via the alternative pathway. Different types of reaction might also occur with soluble components of antigens, diffusing to produce soluble aggregates with completo an
consumption; less soluble antigens could remain in the alveoli, causing granulomatous foreign-body reactions. Speakers at the M.R.C. symposium suggested that the febrile response could arise from bacterial endotoxins, or from release of lymphocyte pyrogens as a result of the immunological reaction. The role of lymphocytes, which can release chemotactic and other factors ment
(lymphokines) during immune-complex formation, also requires investigation. Such reports of new clinical syndromes raise many interesting clinical and immunological questions, but they should also alert us to the need for preventive action. Recirculating water can easily become contaminated with a mass of microorganisms, especially if it is agitated, aerated, and warm-as is the case in many humidifiers. Usually water is allowed to cascade over baffles or is sprayed at revolving discs, while air is blown through the humidification chamber. The organisms prosper by growing on organic and inorganic substrates, including each other, and become part of an elaborate food chain. In all four factories where illness occurred, cellulose material may also have been a nutrient (three were in the printing and stationery industry, and the other made rayon). Attempts to combat growth of microorganisms by cleaning, filtration, or bactericidal chemicals have been unsuccessful, and chemicals in the water might create additional hazards. With humidifying systems conversion to steam humidification provides a solution, and in Aberdeen, venting of the vacuum-pump effluent put a stop to symptoms in affected workers. Some industrial processes, such as printing, require careful control of humidity as well as comfortable working conditions-and the same can be said of hospital operating-theatres. Control of temperature and humidity is expensive, but energy costs can be reduced by recirculation of air. If the humidification system depends in turn on recirculating water, a serious hazard can then arise through water contamination with microorganisms. This can be dealt with by employing steam humidification instead; the Department of Health and Social Security now recommends steam humidification in all new installations. Older installations and industrial firms may still be equipped with "wet" humidification
systems hazard
employ processes in which inhalation arise. A story of recurrent fevers or ressymptoms should prompt inquiry into the
or
can
piratory occupational possibilities.
Platelets, Beta-thromboglobulin, and Diabetes Mellitus WHEN tested in vitro, platelets from patients with diabetes mellitus may function abnormally. There are reports of increased adhesiveness,1-4 of
increased tendency to spontaneous aggregation,s and of a heightened sensitivity to aggregating agents such as A.D.P., adrenaline, and collagen.4.6-8 A possible explanation for these findings has now emerged: in the presence of A.D.P., adrenaline, or collagen, diabetic platelets seem unusually active in synthesising a prostaglandin-E-like material; and they also metabolise arachidonic acid to the prostaglandin-E-like material more rapidly than do nondiabetic platelets.9 Could this platelet hyperactivity be clinically important ? In one report4 the enhanced sensitivity to A.D.P. and adrenaline correlated with the activity of retinopathy; in another8 the abnormality was particularly striking in patients with neuropathy; and small-vessel thrombosis has been observed in suralnerve specimens from patients with diabetic neuropathy.10,11 But the hypothesis that diabetic complications are due to platelet abnormalities remains unproven. Platelet technology is laborious, and subtle methodological differences12 (regarded by some as "black platelet magic") lead to conflicting results. It has also been difficult to determine whether the abnormalities demonstrated are a cause or an effect of the complications. And who knows whether these highly artificial in-vitro tests reflect the situation in vivo. In 1975 an Edinburgh groupl3 described the isolation and characterisation of a platelet-specific protein which they named beta-thromboglobulin. p-T.G. has a molecular weight of 36 000 and is released during platelet aggregation; a radioimmunoassay has been devised to quantitate it in bioan
1. Bridges, J. M., Dalby, A. M., Millar, J., Weaver, J. Lancet, 1965, i, 75. 2. Shaw, S., Pegrum, G. D., Wolff, S., Ashton, W. L. J. clin. Path. 1967, 20, 845. 3. Mayne, E. E., Bridges, J. M., Weaver, J. Diabetologia, 1970, 6, 436. 4. Heath, H., Bridgen, W. D., Canever, J. V., Pollock, J., Hunter, P. R., Kelsey, J., Bloom, A. ibid. 1971, 7, 308. 5. Breddin, K., Grun, H., Krzywanek, H. R. Thromb. Hœmostas. 1976, 35, 669. 6. Kwaan, H. C., Colwell, J. A., Cruz, S., Suwanwela, N., Dobbie, J. C. J. Lab. clin. Med. 1972, 80, 236. 7. Sagel, J., Colwell, J. A., Crook, L., Laimins, M. Ann. intern. Med. 1975, 82, 733. 8. O’Malley, B. C., Timperley, W. R., Ward, J. D., Porter, N. R., Preston, F. E. 9.
Lancet, 1975, ii, 1274. Halsushka, P. V., Lurie, D., Colwell, J. A. New Engl. J. Med. 1977, 297, 1306.
10. Fagerburg, S. E. Acta med. scand. 1959, suppl. 345, p. 1. 11. Timperley, W. R., Ward, J. D., Preston, F. E. Diabetologia, 1976, 12, 237. 12. Weiss, H. J. J. Lab. clin. Med. 1976, 87, 909. 13. Moore, S., Pepper, D. S., Cash, J. D. Biochim. biophys. Acta, 1975, 379, 360.
