- Email: [email protected]
Does It Work?
1042
when the diagnosis is based on clinical alone. - Moreover, identification of the infectfindings ing species will guide the clinician in his choice of common
treatment.
About 90% of all cases of actinomycosis are caused by the anaerobic species Actinomyces israeli (syn. A. bovis), which, as LORD /7 showed in 1910 and many mycologists have since confirmed, is often present as a commensal in the healthy mouth, vegetating especially in tonsillar crypts, under the gum margins, and on carious teeth. In artificial culture the species is anaerobic or micro-aerophilic, of delicate habit, and incapable of producing spores or any resistant form. For this reason it cannot survive on natural substrata outside the animal body ; so infection does not occur from external sources but is always autogenous." The principal sites of the primary disease are the cervicofacial region, usually infected by direct extension from the mouth ; the lungs, by aspiration infection ; and the caecal or appendicular region. Bacteriological examination is often necessary to establish the diagnosis of actinomycosis, but it is not always free from errors in interpretation, for the presence of actinomyces filaments or even " grains " in the sputum of a patient with a chronic pulmonary disorder does not necessarily indicate that the disease is pulmonary actinomycosis ; the organism may have been vegetating in the mouth or even saprophytically in a Last year KAY 8 isolated bronchiectatic cavity. A. israeli from the sputum of 109 out of 240 hospital patients with chronic bronchopulmonary disorders, and from 65 of the 109 it was also isolated by bronchoscopic swabbing. Bronchiectasis with varying degrees of pneumonitis was present in 37 of the 65, in 8 others there was moderately severe chronic bronchitis, and the remaining 20 had aspiration pneumonia, lung
abscess,
extensive
pulmonary suppuration. uncommonly present, with other organisms, as a saprophyte in bronchiectatic and other chronic lung cavities, but it may play a more pathogenic role in some cases of chronic bronchitis, aspiration pneumonia, or local abscess, and these foci, from which more extensive disease may develop, should, when identified, be given prompt treatment. Material obtained by bronchoscopy, from draining sinuses, or from lung resection is far more satisfactory for diagnosis than sputum. SCHAIN and co-workers 9 or - more
A. israeli is not
isolated A. israeli from the bone-marrow and occasionally from the blood, cerebrospinal fluid, or liver tissue of four cases of Hodgkin’s disease and three other conditions. None of the seven patients was suffering from actinomycosis, nor was A. israeli the cause of their clinical condition. In 8500 other specimens from various sources, including 1000 blood samples, they could not find this organism. It seems that, in the seven cases where it was found, A. israeli, probably from the mouth, had become a harmless parasite in the hyperplastic reticulo-endothelial tissue. Aerobic actinomycetes belonging to the genus Nocardia are responsible for the remaining 10% of cases of actinomycosis, and the most important of these are the systemic infections, chiefly pulmonary, caused by the - partly acid-fast Nocardia asteroides Lord, F. T. J. Amer. med. Ass. 1910, 55, 1261. Kay, E. B. Amer. Rev. Tuberc. 1948, 57, 322. 9. Schain, P., De Stefano, B. A., Kazlowski, B. S. Med. 1949, 34, 677. 7. 8.
J. Lab. clin.
BENBOW and colleagues 10 referred to 23 pulmonary and 2 peritoneal infections by this group,11 all of which were fatal, and KIRBY and McNATl&HT mentioned 32 cases, of which 28, all pulmonary infections, were fatal. Clinically, the pulmonary disease may resemble tuberculosis, but careful bacteriological examination, including inoculation into guineapigs, should exclude tuberculous infection. N. asteroides is not sufficiently acid-fast to be detected by the ordinary Ziehl-Neelsen staining method, but it is easily stained by Gram’s method and is not difficult to cultivate from morbid material. The older forms of treatment of actinomycosis with iodides, iodine, or thymol have been superseded by the sulphonamides, penicillin, and streptomycin, all of which have been effective in particular cases. In general, A. israeli infections yield, at least temporarily, to treatment with the sulphonamides, of which the most useful seem to be sulphadiazine andSulphatriad ’but sulphonamide treatment must be prolonged, in some cases even for two years, to insure against recurrence, for the early dramatic improvement is often misleading. Penicillin is probably the most effective agent in actinomycosis caused by A. israeli,12 but the initial dosage must be large enough to prevent the development of penicillin-resistance in the parasite. Streptomycin was used with apparent success by ToRRENs and WOOD 13 and by PEMBERTON and HUNTER,14 in four cases of A. israeli infection, three of which had previously been treated unsuccessfully with sulphonamides and penicillin. There have been few published reports on the treatment of N. asteroides infections with antibacterial drugs, but BENBOW and colleagues,’° among others, have found the sulphonamides effective, and the Mayo Clinic workerss point out that N. asteroides is sensitive to the sulphonamides but not to penicillin. In Paris, D’ESHOUGUES and ZAFFRAN 15 report a case of pulmonary actinomycosis (N. asteroides) which recovered on streptomycin after massive doses of penicillin had failed. Many writers emphasise the importance of surgical intervention, when feasible, especially for the drainage of pus, without which chemotherapy may fail. Radiotherapy, accessory chemotherapy, and the general management of symptoms are important secondary
group.
measures.
Does It Work? IN 1947, at the request of the National Foundation for Infantile Paralysis, the therapeutic trials committee of the American Medical Association formed a special subcommittee to investigate the value of moist heat in poliomyelitis. In a preliminary report 16 this subcommittee has set out the principles to be followed by those who undertake to test any new The report therapeutic agent in poliomyelitis. illustrates how extraordinarily difficult and expensive it may be to
assess
the value of treatment in any
10. Benbow, E. P. jun., Smith, D. T., Grimson, K. S. Amer. Rev. Tuberc. 1944, 49, 395. 11. Kirby, W. M. M., McNaught, J. B. Arch. intern. Med. 1946, 78, 578. 12. Walker, J. M., Hamilton, J. W. Ann. Surg. 1945, 121, 373. Hamilton, A. J. C., Kirkpatrick, H. J. R. Brit. med. J. 1945, ii, 728. Arden, F. Med. J. Aust. 1945, i, 540. 13. Torrens, J. A., Wood, M. W. W. Lancet, 1949, i, 1091. 14. Pemberton, H. S., Hunter, W. R. Ibid, p. 1094. 15. d’Eshougues, J. R., Zaffran, A. Bull. Soc. Méd. Hôp., Paris, 1949, 65, 935. 16. Council on Pharmacy and Chemistry, American Medical Association. J. Amer. med. Ass. 1949, 140, 534.
1043
poliomyelitis, has a complex variable and an uncertain termicourse, aetiology, nation. In planning clinical trials of a poliomyelitis remedy many variables must be taken into account besides the unpredictable course and outcome of the disease. These include differences in diagnostic criteria and possible differences in the effects of various types of the causative virus; the results of climate and geographical situation; the age-distribution of the patients ; and the techniques used to measure the extent of paralysis, deformity, and disability caused by the disease. To control these variables adequately the subcommittee believes that at least 750, and preferably 1500, poliomyelitis patients should be under observation for at least two years. This means that the trial must be conducted on a regional or national scale and that a large number of hospitals must collaborate in it. A hospital participating must agree to accept cases strictly in accordance with predetermined diagnostic criteria, to classify them carefully according to the stage of the disease on admission, to assign them to control and test groups in a’ completely random manner, to give identical physical and other treatment-apart from the treatment to be studied-to each group, and to arrange for the collection by experts of data on the progress and outcome of each case in a form which can be analysed statistically. Three main diagnostic criteria are suggested : (1) acute onset of a febrile illness with headache, fever, and a recognisable stiff neck, the fever in general not to exceed 104°F and not to persist longer than six days unless there are obvious complications to account for it or bulbar palsy has developed ; (2) if paralysis is absent there should be, besides fever, a raised protein content and a cell-count of 50-100 per c.mm. in the spinal fluid ; and (3) the paralysis present during the febrile period should be localised and demonstrable-i.e., not merely a generalised muscular weakness. With these criteria, and excluding patients seen later than 28 days from onset (the beginning of fever), the patients should be classified into three categories : (1) preparalytic cases seen during the febrile illness; (2) paralytic cases seen during the febrile state up to 7 days after onset; and (3) paralytic cases seen 8-28 days from onset. For the random assignment of patients to test and control groups the subcommittee has adapted a method originally used in a British Empire Cancer Campaign investigation ; this ensures that in every 20 consecutive admissions 10 patients will be assigned to the test group and 10 to the controls, and that one group can never exceed the other by more than 10 patients. It is neither justifiable nor practicable, in the subcommittee’s view, to withold all treatment from controls. A basic treatment carefully designed to avoid the use of any agent which would confuse or augment the action of the treatment under trial must therefore be decided on and rigidly applied to all test patients as well as controls. For the collection of data on progress and outcome which can be submitted to statistical analysis, the subcommittee recommends that every patient in the trial should be examined and-assessed by a team of experts who are prepared to make frequent visits to each hospital taking part in the trial. This team should, they consider, include an orthopaedic surgeon, a specialist disease which, like a
in physical medicine, a paediatrician, and a neurologist. All its members should be clinically independent of the trial and familiar with the results of orthodox treatment, without, however, having any fixed ideas on or preferences for any particular form of therapy. They should not know at the time of examination whether a particular patient has been in the test or control group. The final interpretation of the data should be the joint work of the hospital clinicians, the team of experts, and a statistician. Reports, all too frequent in the past, of encouraging " results with a new treatment were often based on the hasty assessment of half -a dozen patients and sometimes contributed more to " medical myth and mumpsimus " than to the science of medicine. The way of the assessor in a therapeutic trial is indeed hard and in most respects not immediately rewarding. Statisticians are never satisfied with small numbers and demand from those who undertake to collect data for them an impersonal attitude to patients and a mechanical kind of work which many doctors find insupportable over long periods. Yet the carefully controlled large-scale trial of a therapeutic innovation, tedious and expensive though it may be, seems the only satisfactory way of answering the question " Does it work ? " In the long run the cost of such trials is probably more than offset by the saving they effect by preventing or ending the use of expensive treatments when something cheaper would be just as good. "
Annotations HOSPITAL FINANCE THE drawbacks in the present of financing the hospital service, to which we drew attention last summer,’ have lately been reviewed, from a regional angle, by the North West Metropolitan hospital board ; and representations are being made to the Ministry along the lines of a report by the treasurer. This suggests that the existing methods of estimates submitted by management committees lead to : (1) overstatement of requirements, because each committee tends to provide for unforeseen contingencies ; and (2) guidance or direction from the Ministry.on matters of detail. Furthermore the time-table for submission of estimates, which is dictated by the Parliamentary timeto examine table, gives regional boards the estimates as closely as they should ; and indeed " these committees have not sufficient data on the current rate of spending to be of use to them in preparing their estimates for the board," and they have to proceed with these estimates at the same time as the previous year’s. accounts are being closed. The suggested remedy is that committees should submit forecasts of expenditure f6 the board, which would review these " on a broad basis and pass them to the Ministry of Health in time for the Ministry to decide on the sum to be included in its estimate. Detailed estimates could then be prepared by management committees for submission to the board by, say, the middle of November, and the board would be allowed three months for their examination. This, says the report, would ’give time for any major alteration in the total requirements of the Ministry of Health for the hospital service to be adjusted in the Civil Estimates. After Parliament has approved the estimates the amount
method
regional approving
insufficient time
I
I
management
"
- ,
allocated for the hospital service could be allocated by the Ministry over the regional boards and boards of governors, leaving the regional boards freedom in the utilising of their 1.
Leading article, Lancet, July 9, p. 61.
when the diagnosis is based on clinical alone. - Moreover, identification of the infectfindings ing species will guide the clinician in his choice of common
treatment.
About 90% of all cases of actinomycosis are caused by the anaerobic species Actinomyces israeli (syn. A. bovis), which, as LORD /7 showed in 1910 and many mycologists have since confirmed, is often present as a commensal in the healthy mouth, vegetating especially in tonsillar crypts, under the gum margins, and on carious teeth. In artificial culture the species is anaerobic or micro-aerophilic, of delicate habit, and incapable of producing spores or any resistant form. For this reason it cannot survive on natural substrata outside the animal body ; so infection does not occur from external sources but is always autogenous." The principal sites of the primary disease are the cervicofacial region, usually infected by direct extension from the mouth ; the lungs, by aspiration infection ; and the caecal or appendicular region. Bacteriological examination is often necessary to establish the diagnosis of actinomycosis, but it is not always free from errors in interpretation, for the presence of actinomyces filaments or even " grains " in the sputum of a patient with a chronic pulmonary disorder does not necessarily indicate that the disease is pulmonary actinomycosis ; the organism may have been vegetating in the mouth or even saprophytically in a Last year KAY 8 isolated bronchiectatic cavity. A. israeli from the sputum of 109 out of 240 hospital patients with chronic bronchopulmonary disorders, and from 65 of the 109 it was also isolated by bronchoscopic swabbing. Bronchiectasis with varying degrees of pneumonitis was present in 37 of the 65, in 8 others there was moderately severe chronic bronchitis, and the remaining 20 had aspiration pneumonia, lung
abscess,
extensive
pulmonary suppuration. uncommonly present, with other organisms, as a saprophyte in bronchiectatic and other chronic lung cavities, but it may play a more pathogenic role in some cases of chronic bronchitis, aspiration pneumonia, or local abscess, and these foci, from which more extensive disease may develop, should, when identified, be given prompt treatment. Material obtained by bronchoscopy, from draining sinuses, or from lung resection is far more satisfactory for diagnosis than sputum. SCHAIN and co-workers 9 or - more
A. israeli is not
isolated A. israeli from the bone-marrow and occasionally from the blood, cerebrospinal fluid, or liver tissue of four cases of Hodgkin’s disease and three other conditions. None of the seven patients was suffering from actinomycosis, nor was A. israeli the cause of their clinical condition. In 8500 other specimens from various sources, including 1000 blood samples, they could not find this organism. It seems that, in the seven cases where it was found, A. israeli, probably from the mouth, had become a harmless parasite in the hyperplastic reticulo-endothelial tissue. Aerobic actinomycetes belonging to the genus Nocardia are responsible for the remaining 10% of cases of actinomycosis, and the most important of these are the systemic infections, chiefly pulmonary, caused by the - partly acid-fast Nocardia asteroides Lord, F. T. J. Amer. med. Ass. 1910, 55, 1261. Kay, E. B. Amer. Rev. Tuberc. 1948, 57, 322. 9. Schain, P., De Stefano, B. A., Kazlowski, B. S. Med. 1949, 34, 677. 7. 8.
J. Lab. clin.
BENBOW and colleagues 10 referred to 23 pulmonary and 2 peritoneal infections by this group,11 all of which were fatal, and KIRBY and McNATl&HT mentioned 32 cases, of which 28, all pulmonary infections, were fatal. Clinically, the pulmonary disease may resemble tuberculosis, but careful bacteriological examination, including inoculation into guineapigs, should exclude tuberculous infection. N. asteroides is not sufficiently acid-fast to be detected by the ordinary Ziehl-Neelsen staining method, but it is easily stained by Gram’s method and is not difficult to cultivate from morbid material. The older forms of treatment of actinomycosis with iodides, iodine, or thymol have been superseded by the sulphonamides, penicillin, and streptomycin, all of which have been effective in particular cases. In general, A. israeli infections yield, at least temporarily, to treatment with the sulphonamides, of which the most useful seem to be sulphadiazine andSulphatriad ’but sulphonamide treatment must be prolonged, in some cases even for two years, to insure against recurrence, for the early dramatic improvement is often misleading. Penicillin is probably the most effective agent in actinomycosis caused by A. israeli,12 but the initial dosage must be large enough to prevent the development of penicillin-resistance in the parasite. Streptomycin was used with apparent success by ToRRENs and WOOD 13 and by PEMBERTON and HUNTER,14 in four cases of A. israeli infection, three of which had previously been treated unsuccessfully with sulphonamides and penicillin. There have been few published reports on the treatment of N. asteroides infections with antibacterial drugs, but BENBOW and colleagues,’° among others, have found the sulphonamides effective, and the Mayo Clinic workerss point out that N. asteroides is sensitive to the sulphonamides but not to penicillin. In Paris, D’ESHOUGUES and ZAFFRAN 15 report a case of pulmonary actinomycosis (N. asteroides) which recovered on streptomycin after massive doses of penicillin had failed. Many writers emphasise the importance of surgical intervention, when feasible, especially for the drainage of pus, without which chemotherapy may fail. Radiotherapy, accessory chemotherapy, and the general management of symptoms are important secondary
group.
measures.
Does It Work? IN 1947, at the request of the National Foundation for Infantile Paralysis, the therapeutic trials committee of the American Medical Association formed a special subcommittee to investigate the value of moist heat in poliomyelitis. In a preliminary report 16 this subcommittee has set out the principles to be followed by those who undertake to test any new The report therapeutic agent in poliomyelitis. illustrates how extraordinarily difficult and expensive it may be to
assess
the value of treatment in any
10. Benbow, E. P. jun., Smith, D. T., Grimson, K. S. Amer. Rev. Tuberc. 1944, 49, 395. 11. Kirby, W. M. M., McNaught, J. B. Arch. intern. Med. 1946, 78, 578. 12. Walker, J. M., Hamilton, J. W. Ann. Surg. 1945, 121, 373. Hamilton, A. J. C., Kirkpatrick, H. J. R. Brit. med. J. 1945, ii, 728. Arden, F. Med. J. Aust. 1945, i, 540. 13. Torrens, J. A., Wood, M. W. W. Lancet, 1949, i, 1091. 14. Pemberton, H. S., Hunter, W. R. Ibid, p. 1094. 15. d’Eshougues, J. R., Zaffran, A. Bull. Soc. Méd. Hôp., Paris, 1949, 65, 935. 16. Council on Pharmacy and Chemistry, American Medical Association. J. Amer. med. Ass. 1949, 140, 534.
1043
poliomyelitis, has a complex variable and an uncertain termicourse, aetiology, nation. In planning clinical trials of a poliomyelitis remedy many variables must be taken into account besides the unpredictable course and outcome of the disease. These include differences in diagnostic criteria and possible differences in the effects of various types of the causative virus; the results of climate and geographical situation; the age-distribution of the patients ; and the techniques used to measure the extent of paralysis, deformity, and disability caused by the disease. To control these variables adequately the subcommittee believes that at least 750, and preferably 1500, poliomyelitis patients should be under observation for at least two years. This means that the trial must be conducted on a regional or national scale and that a large number of hospitals must collaborate in it. A hospital participating must agree to accept cases strictly in accordance with predetermined diagnostic criteria, to classify them carefully according to the stage of the disease on admission, to assign them to control and test groups in a’ completely random manner, to give identical physical and other treatment-apart from the treatment to be studied-to each group, and to arrange for the collection by experts of data on the progress and outcome of each case in a form which can be analysed statistically. Three main diagnostic criteria are suggested : (1) acute onset of a febrile illness with headache, fever, and a recognisable stiff neck, the fever in general not to exceed 104°F and not to persist longer than six days unless there are obvious complications to account for it or bulbar palsy has developed ; (2) if paralysis is absent there should be, besides fever, a raised protein content and a cell-count of 50-100 per c.mm. in the spinal fluid ; and (3) the paralysis present during the febrile period should be localised and demonstrable-i.e., not merely a generalised muscular weakness. With these criteria, and excluding patients seen later than 28 days from onset (the beginning of fever), the patients should be classified into three categories : (1) preparalytic cases seen during the febrile illness; (2) paralytic cases seen during the febrile state up to 7 days after onset; and (3) paralytic cases seen 8-28 days from onset. For the random assignment of patients to test and control groups the subcommittee has adapted a method originally used in a British Empire Cancer Campaign investigation ; this ensures that in every 20 consecutive admissions 10 patients will be assigned to the test group and 10 to the controls, and that one group can never exceed the other by more than 10 patients. It is neither justifiable nor practicable, in the subcommittee’s view, to withold all treatment from controls. A basic treatment carefully designed to avoid the use of any agent which would confuse or augment the action of the treatment under trial must therefore be decided on and rigidly applied to all test patients as well as controls. For the collection of data on progress and outcome which can be submitted to statistical analysis, the subcommittee recommends that every patient in the trial should be examined and-assessed by a team of experts who are prepared to make frequent visits to each hospital taking part in the trial. This team should, they consider, include an orthopaedic surgeon, a specialist disease which, like a
in physical medicine, a paediatrician, and a neurologist. All its members should be clinically independent of the trial and familiar with the results of orthodox treatment, without, however, having any fixed ideas on or preferences for any particular form of therapy. They should not know at the time of examination whether a particular patient has been in the test or control group. The final interpretation of the data should be the joint work of the hospital clinicians, the team of experts, and a statistician. Reports, all too frequent in the past, of encouraging " results with a new treatment were often based on the hasty assessment of half -a dozen patients and sometimes contributed more to " medical myth and mumpsimus " than to the science of medicine. The way of the assessor in a therapeutic trial is indeed hard and in most respects not immediately rewarding. Statisticians are never satisfied with small numbers and demand from those who undertake to collect data for them an impersonal attitude to patients and a mechanical kind of work which many doctors find insupportable over long periods. Yet the carefully controlled large-scale trial of a therapeutic innovation, tedious and expensive though it may be, seems the only satisfactory way of answering the question " Does it work ? " In the long run the cost of such trials is probably more than offset by the saving they effect by preventing or ending the use of expensive treatments when something cheaper would be just as good. "
Annotations HOSPITAL FINANCE THE drawbacks in the present of financing the hospital service, to which we drew attention last summer,’ have lately been reviewed, from a regional angle, by the North West Metropolitan hospital board ; and representations are being made to the Ministry along the lines of a report by the treasurer. This suggests that the existing methods of estimates submitted by management committees lead to : (1) overstatement of requirements, because each committee tends to provide for unforeseen contingencies ; and (2) guidance or direction from the Ministry.on matters of detail. Furthermore the time-table for submission of estimates, which is dictated by the Parliamentary timeto examine table, gives regional boards the estimates as closely as they should ; and indeed " these committees have not sufficient data on the current rate of spending to be of use to them in preparing their estimates for the board," and they have to proceed with these estimates at the same time as the previous year’s. accounts are being closed. The suggested remedy is that committees should submit forecasts of expenditure f6 the board, which would review these " on a broad basis and pass them to the Ministry of Health in time for the Ministry to decide on the sum to be included in its estimate. Detailed estimates could then be prepared by management committees for submission to the board by, say, the middle of November, and the board would be allowed three months for their examination. This, says the report, would ’give time for any major alteration in the total requirements of the Ministry of Health for the hospital service to be adjusted in the Civil Estimates. After Parliament has approved the estimates the amount
method
regional approving
insufficient time
I
I
management
"
- ,
allocated for the hospital service could be allocated by the Ministry over the regional boards and boards of governors, leaving the regional boards freedom in the utilising of their 1.
Leading article, Lancet, July 9, p. 61.