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Chloromycetin in Typhoid Fever
720 sets
in ; eosinophilia, in his view, is
a
good prognostic
sign. RocHE and his colleagues have used the modern wet count of eosinophils, which is much quicker and accurate than indirect estimation from a more differential count on a stained film. They confirmed that a surgical operation is soon followed by a
profound fall, and often a complete disappearance, of eosinophils in the blood. This eosinopenia is most severe 5-8 hours after the operation begins, and it persists for some hours; but usually by 24 hours recovery has begun and the eosinophils rise again, often reaching levels above the normal in the next 7 days. Xow, as a rule the level of eosinophils in the blood at any one time means little ; it is the change in that level under different conditions that matters. But it is clear that if in the period from 4 to 24 hours after the start of a surgical operation the patient’s eosinophil level is very low, it can be assumed that the adrenal cortex is functioning properly, and even if the patient is shocked there is no indication for giving adrenal cortex hormone. The only cautions are that the patient must not have an aplastic bonemarrow, or an allergic eosinophilia. To illustrate their point, RoCHE and his colleagues quote a very striking case. In 12 normally reacting patients, the eosinophil levels in the blood 10 hours after operation The unusual patient was were about 0-5 per c.mm. a man operated on for a suspected lesion of the sigmoid colon who was profoundly shocked afterwards ; his blood eosinophils 10 hours postoperatively were 260 per c.mm. ; the patient died in spite of the administration of adrenal cortex hormones, and at the necropsy he was found to have tuberculosis of both adrenal glands, only a little functioning gland
remaining. It is evidently important that we should know the state of the patient’s adrenocortical reserves before operation. so RocHE and his co-workers have devised two tests to provide this information. The first uses after blood for the eosinophil-count has A.c.T.H. : been taken, 25 mg. of A.C.T.H. is injected intramuscularly and 4 hours later the eosinophil-count is repeated ; the fall must be at least 50% to indicate that -
-
-
attempt to begin the operation failed because of shock caused by the anaesthetic. She was therefore treated for 6 days with large doses of A.C.T.H., by which time the eosinophils in the blood had fallen 75% and the urinary excretion of ketosteroids had increased from 0-9 to 8-9 mg. in 24 hours. The operation was then performed without incident, and, though the patient had a difficult time after the operation, she recovered satisfactorily. The number of cases reported by
ROCHE et al. is small, but their work is sure to be repeated, and if it is confirmed the surgeon will want to know his patients’ eosinophil-counts. Stimulated by the work with A.C.T.H. in rheumatoid arthritis, the technique of eosinophil counting is being improved. Most laboratories use DuNGAR’s method in some form, but this has disadvantages, especially for large-scale use; methods like that of RANDOLPH,3 which use propylene glycol in the diluting fluid, are coming into
use.
Apart from its immediate importance, there are two interesting points about this work. It is one of the first applications of A.C.T.H. and its effects as a "
research toolin conditions other than rheumatoid arthritis. And the results suggest that shock due to failure of adrenal cortical function is likely to be distinctly rare, so that large amounts of adrenal cortical hormone will be saved for the patients who really need it.
in
Fever UNTIL lately typhoid fever had resisted all attempts at chemotherapy. Most of the sulphonamides intro-
Chloromycetin
Typhoid
duced in the past fifteen years have been tried in this disease, but the initially favourable claims for several of them were soon disproved. The same process has been repeated with each of the antibiotics hitherto
tried-penicillin, streptomycin, aerosporin (polymyxin), andAureomycin ’-and even the promising results reported with penicillin and sulphonamides combined have not been repeated. There is good reason, therefore, for caution in interpreting the remarkable clinical effects of chloramphenicol. In the last few months an increasing stream of adrenocortical reserves are normal. The second test clinical reports have appeared in this country and is based on the observation that a small dose-0-3 mg. -of adrenaline will also cause a fall in circulating abroad confirming the original observations of WOODWARD and his 4 with chloromycetin eosinophils ; it is thought that the adrenaline acts in the treatment of colleagues in Malaya. Some typhoid patients on the hypothalamus or the pituitary which in turn have of these been reviewed in these columns.5 already stimulates the adrenal cortex. The test is thus one The action on the constitutional symptoms are drug’s of pituitary-adrenocortical reserves. It is carried so striking that the clinicians are unanimous in out by injecting 0-3 mg. of adrenaline subcutaneously acclaiming its value, even though some failures have and counting the blood eosinophils 4 hours later ; also been recorded. Thus, out of 6 severely ill patients again a fall of 50% or more indicates normal reserves. treated in Bombay by PATEL et al.,3 died and 1 These tests were tried on two patients with pituitary in a series of 63 patients treated in and lesions who might well have had a stormy postoperative relapsed ; and his colleaguesthere were 4 CONTI The first patient had had intensive X-ray Italy by course. deaths and 9 relapses. DANA et al. 8 have described 5 therapy of the pituitary gland for Cushing’s syndrome cases treated in Tunis which showed an alarming rise 10 months before she was admitted to hospital for in 3 of these patients died, but the other blood-urea ; a hysterectomy. With both adrenaline and A.C.T.H. 2 improved when the chloramphenicol was stopped tests there was a significant fall in eosinophils, which and they eventually survived. In our correspondence suggested that the operation could be undertaken columns this week Dr. STEPHENS reports a case from without undue risk. The operation was duly performed, and recovery was uneventful. The second patient had 3. Randolph, T. G. J. Lab. clin. Med. 1949, 34, 1696. 4. Woodward, T. E., Smadel, J. E., Ley, H. L., Green, R., Mankikar, a chromophobe adenoma causing visual impairment ; D. S. Ann. intern. Med. 1948, 29, 131. 5. Lancet, 1949, ii, 1001. with the adrenaline test the eosinophils actually rose 6. Patel, J. C., Banker, D. D., Modi, C. J. Brit. med. J. 1919, ii, 908. F., Cassano, A., Monaco, R. Rif. med. 1949, 63, 901. slightly, while with the A.c.T.H. test only a 15% fall 7.8. Conti, Dana, R., Sebag, A., Cohen, J., Borsoni, G. Tunisie med. 1950, was recorded. Difficulties were anticipated and an 38, 190.
721
Northern Rhodesia, in which
an African boy, infected S. rich in Vi antigen, strain of virulent typhi by seemed to be recovering well with chloramphenicol but collapsed suddenly and died in the second week of the disease. But the consensus of opinion is in agreement with Dr. EDGE, who reviews his 16 cases on p. 710 and remarks that the " complete transformation in a few days " can only be fully appreciated by clinicians who recall their own helplessness in the past. In our columns a fortnight age, GooD and MACKENZIE,and RANKIN and GRIMBLE 10 recounted
a
experiences with chloromycetin in typhoid patients, mostly from the small outbreak in Crowthorne, Berks, in April-May, 1949, which affected about 40 people. A trial under controlled conditions was arranged, using a strict " alternate case " method their
of selection. GOOD and MACKENZIE thus had a group of 6 cases receiving chloramphenicol and a control group of 7 cases, though 3 of the controls were later treated with chloramphenicol when they relapsed. The results were not so satisfactory as might have been expected from the first impressions gained the trial, published in a preliminary note by BRADLEY." There were 3 relapses in the original treated group and 3 in the controls, and the only persistent excreter identified in this outbreak was one of the female patients in the’ treated group. Nevertheless, GooD and MACKENZIE, like all’ previous observers, reach the conclusion that chloramphenicol is the most valuable drug we have against typhoid fever. The 18 cases reported by RANKIN and GRIMBLE comprised 10 patients from the Crowthorne outbreak, which was caused by a strain of Vi-phage type El, and 8 sporadic cases treated in the subsequent six months and due to strains of unspecified, and presumably different, Vi-phage types. The virulence of typhoid strains isolated in different outbreaks, and the severity of the -disease they cause, vary so widely that one cannot regard these sporadic cases, which received no chloramphenicol, as satisfactory controls.’’ A similar criticism applies to the report by EL RAMLI 12 from Cairo in the same issue. His series consisted of 200 cases of typhoid fever treated with chloramphenicol at the Abbassia Fever Hospital between May and December, 1949. The average duration of fever after the start of treatment was 3-5 days and the relapserate was 27-5%. Ei, RAMLI did not feel justified in leaving some of the patients without chloramphenicol as controls, so he compared the case-mortality of 6-5% in his treated series with that of all the typhoid cases, treated at the same hospital over the past ten years (9-12%). It must be borne in mind here in the small typhoid outbreaks that occurred among British troops in Egypt during the past few years the fatality-rates, in patients receiving no specific treatment, ranged from nil to well over 25%. EL RAMLI also observed in 7 very severe cases that the temperature did not settle quickly but remained high for eight to twenty-seven days. His general conclusion is that chloramphenicol provides the most efficient specific treatment for typhoid fever so far
during
"
devised, but he hopes
improve the results -by combining chloramphenicol with sulphadiazine treatto
9. Good, R. A., Mackenzie, R. D. Lancet, April 1, p. 611. 10. Rankin. A. L. K., Grimble, A. S. Ibid. p. 615. 11. Bradley, W. H. Ibid. 1949, i, 869. 12. El Ramli, A. H. Ibid, April 1, p. 618.
as was suggested by EL BOROLOSSY and BUTTLE.13 In view of the extreme degree of toxaemia commonly seen in severe typhoid cases, however, a combination of chloramphenicol and a potent " Vi -)0 anti-typhoid serum, such as that recommended by FELix,1-4 might prove more effective. One aspect of the typhoid problem has received very little attention in the reports on the use of chloramphenicol in the acute disease. Will the new antibiotic prevent the development of the chronic carrier state and thus contribute towards the ultimate goal of eradicating typhoid infection ? This question is of paramount importance and deserves the urgent attention of both public-health officers and laboratory workers. GooiD and MACKENZIE obtained some valuable data by observing the effect of chloramphenicol on the excretion of typhoid bacilli both and after treatment. The findings in their small series were disappointing and recall the observations made on typhoid cases treated with penicillin and sulphathiazole combined.15S It may be concluded that the dosage adopted by GooD and MACKENZIE, which was that originally suggested by WOODWARD and his . colleagues, cannot prevent either clinical relapse or the development of the chronic carrier state. Lately SMADEL and his colleagues 16 have advised that treatment should be continued for about fourteen davs with a total dosage of about 25 g. But they do not say what effect the larger doses given over longer periods have on the excretion of typhoid bacilli in the faeces and urine. That longer treatment is no guarantee against relapse is seen from the experience of RANKIN and GRIMBLE,1o who describe a typical relapse in a patient who had received 37-5 g. of chloromycetin in twenty days. The latest suggestion by WOODWARD (quoted by SMADEL 17), that intermittent short courses of chloramphenicol should be given, was followed in the outbreak at Salford in October, 1949, but the effect on the excretion of typhoid bacilli was no better than that of the original reoimen.18 The closest cooperation between clinician and pathologist is clearly essential in the planning of future therapeutic trials. This cooperation has not been conspicuous in some of those so far carried out here or abroad. The effect of the drug on the bactersemia can be assessed only if the organism is shown to be present in the blood-stream immediately before the drug is exhibited and its presence or absence is checked in blood-cultures taken at regular short intervals afterwards. The effect of the drug on the excretion of the organism can be assessed only if bacteriological examinations of the fseces and urine are begun early in the disease and continued at regular and short intervals until convalescence. These simple rules have not always been observed. When it is intended to conduct a trial under controlled condiselection, and the tions, using ’’alternate case small come from groups infected in different patients localities in an endemic area, equal numbers --of cases infected from the same source must be allotted’ to
ment,
"
during
"
13. El Borolossy, A. W., Buttle, G. A. H. Ibid, 1949, ii, 559. 14. Felix, A. J. Hyg., Camb. 1938, 38, 750. 15. Bevan, G., Sudds, M. V. N., Evans, R., Parker, M. T., Pugh, I., Sladden, A. F. S. Lancet, 1948, i, 545. 16. Smadel, J. E., Woodward, T. E., Bailey, C. A. J. Amer. med. Ass. 1949, 141, 129. 17. Smadel, J. E. Proc. R. Soc. trop. Med. Hyg. 1950 (in the press). 18. Parker, M. T. Unpublished.
722
the treated and the control groups. Single sporadic controlled " trial, cases cannot be included in a because there would then be no control cases from the same source of infection. Vi-phage typing of the strains isolated from the treated and the control cases should be carried out as a routine. The result will confirm or disprove the epidemiological connection "
between alternate cases. Finally, a thorough serological and bacteriological study should be made of the convalescent patients for three to six months after their discharge from hospital, to make certain that they do not become chronic carriers.
Annotations LORD MORAN
of Physicians elected it certainly did not president, foresee that for eight more years his re-election would be an annual event-and an exciting one. Whatever else his critics may say of his nine years’ presidency, they cannot fairly describe it as dull ; nor did it end tamely. Lord Moran is not one of those who hold that because an institution is old it should reduce its activities and live gracefully in the past : he regards prestige as useful rather than ornamental. Since 1941 constructive proposals have come from the college in reports of committees on social and preventive medicine, psychological medicine, medical education, paediatrics, neurology, pathology, dermatology, cardiology, and rheumatic heart-disease, and on problems of demobilisation. The Prophit report on tuberculosis came out in 1948, and an International Conference of Physicians was held in 1947. Internally the members have been given opportunities of meeting to express their views, and representation on the council. Externally the Physicians have joined with the Surgeons and Obstetricians in a standing joint committee ; but they have preferred to remain in Pall Mall rather than form part of an Academy of Medicine in Lincoln’s Inn Fields.
WHEN in 1941 the Sir Charles Wilson
__
Royal College
as
Lord Moran’s qualities are admired most, perhaps, by those who know him best ; but even those who deny the wisdom of his policies must be impressed by the-courage with which he has pursued them. To his successor, Dr. Russell Brain, he leaves a difficult task, but one whose responsibility he has enhanced. NEW LIGHT ON ENDOTOXINS IT has been recognised for some time that the toxic properties of the colon-typhoid-dysentery group, with the probable exception of Shigella shigce, are attributable to a nitrogen-containing polysaccharide complex. Some authors call this substance a somatic antigen and others It has been extracted from bacterial an endotoxin. bodies with trichloracetic acid (Boivin and Mesrobeanu 1933), by tryptic digestion (Ra,istrick and Topley 1934), and with diethylene glycol (Morgan 1937). It is antigenic ; it produces a pathological picture in which the fundamental change is a terminal circulatory hypertension ; it causes hyperthermia, transient hyperglycaemia
In the preliminaries to the National Health Service, the attitude of the Royal College of Physicians, expressed, and to some extent formed, by Lord Moran, was that the creation of a service was inevitable and that their duty was to help in fashioning it, so that avoidable mistakes might be avoided. Probably it would be correct to say that if the senior college had taken a different line, the profession would have refused to work the service, unless or until compelled to do so. On the narrower issue of the future of consultant practice, Lord Moran believed that grave harm would be done to the whole profession if the highest incomes open to doctors in the service were to be no more than the :t2500 a year paid to medical professors ; and his arguments in the House of Lords led to the formation of the Spens Committee on the remuneration of consultants, of which he was a member. This committee’s report, and its acceptance by the Government, has created confusion wherever medical men are publicly employed ; but in the end the whole quality of public service is likely to gain by the committee’s stand against the old tradition that public servants must be poorly paid. The committee’s further proposal that the highest salaries should be awarded only for special merit, as judged by a man’s peers, has led to what we regard as a most important experiment in the technique of public service under the new conditions. For the fact that this experiment is being made, and that the profession has not accepted a conventional system of remuneration on Civil Service lines, we have to thank both Lord Moran and the Minister, both men of
imagination.
(followed by hypoglycsemia), placental haemorrhage with abortion, and haemorrhage in implanted tumours; and its toxicity appears to be less in animals injected with adrenal cortical extract. When endeavouring to explain the toxicity to guineapigs of some heat-killed saline suspensions of Bacterium coli, Roberts1 found that the toxic substance was a polysaccharide complex, or endotoxin, and that it was present in filtrates of heated suspensions. The high susceptibility of guineapigs (but not mice) and the presence of endotoxin in the filtrate of heated saline suspensions, seemed to conflict with accepted knowledge, and further investigation was therefore undertaken. Bact. coliwas grown in a synthetic medium vigorously agitated by aeration, and viable counts of 25,000 million cells per ml. were obtained. When these suspensions of Bact. coli were heated at 80°C for one hour, almost all the endotoxin entered the suspending fluid and could be recovered from the filtrate. On purification it proved to have the physical, chemical, and biological properties associated with the endotoxins of salmonella and
dysentery organisms. These observations were made by employing guineapigs to detect the endotoxin. Experiments on purified endotoxic complex showed that even when guineapigs were injected subcutaneously and mice intravenously, the guineapigs were, weight for weight, 17-5 times more susceptible than mice. It is possible that guineapigs may be more susceptible to Bact. coli endotoxin, and more uniform in their response to it, than to the endotoxins of other enteric bacteria. The gross appearance of lesions in guineapigs suggested capillary haemorrhage, but microscopical examination did not indicate whether the lesion was due to extravasation or to hypertension. When the trypan-blue technique of Menkin (1938) was applied, no evidence of increased capillary permeability could be obtained. The results thus supported the view that the lesion was a terminal hypertension. These simplified methods of producing large quantities of Bact. coli in synthetic medium and of obtaining the endotoxin will no doubt stimulate further studies in this field. It also looks as though much work on antigenic analysis may need re-examination, because the bacterial suspensions have often been killed by heat, which evidently removes the antigen from the bacterial bodies. Though an active immunity was demonstrated in surviving guineapigs, there appears to be no immediate likelihood of developing a method of detoxifying endotoxin for purposes of immunisation; and, as bacterial cells are as effective as the complex in stimulating immunity, there is no obvious advantage in using endotoxin instead of bacterial suspensions as 1. Roberts, R. S.
J. comp. Path. 1949, 59, 245.
in ; eosinophilia, in his view, is
a
good prognostic
sign. RocHE and his colleagues have used the modern wet count of eosinophils, which is much quicker and accurate than indirect estimation from a more differential count on a stained film. They confirmed that a surgical operation is soon followed by a
profound fall, and often a complete disappearance, of eosinophils in the blood. This eosinopenia is most severe 5-8 hours after the operation begins, and it persists for some hours; but usually by 24 hours recovery has begun and the eosinophils rise again, often reaching levels above the normal in the next 7 days. Xow, as a rule the level of eosinophils in the blood at any one time means little ; it is the change in that level under different conditions that matters. But it is clear that if in the period from 4 to 24 hours after the start of a surgical operation the patient’s eosinophil level is very low, it can be assumed that the adrenal cortex is functioning properly, and even if the patient is shocked there is no indication for giving adrenal cortex hormone. The only cautions are that the patient must not have an aplastic bonemarrow, or an allergic eosinophilia. To illustrate their point, RoCHE and his colleagues quote a very striking case. In 12 normally reacting patients, the eosinophil levels in the blood 10 hours after operation The unusual patient was were about 0-5 per c.mm. a man operated on for a suspected lesion of the sigmoid colon who was profoundly shocked afterwards ; his blood eosinophils 10 hours postoperatively were 260 per c.mm. ; the patient died in spite of the administration of adrenal cortex hormones, and at the necropsy he was found to have tuberculosis of both adrenal glands, only a little functioning gland
remaining. It is evidently important that we should know the state of the patient’s adrenocortical reserves before operation. so RocHE and his co-workers have devised two tests to provide this information. The first uses after blood for the eosinophil-count has A.c.T.H. : been taken, 25 mg. of A.C.T.H. is injected intramuscularly and 4 hours later the eosinophil-count is repeated ; the fall must be at least 50% to indicate that -
-
-
attempt to begin the operation failed because of shock caused by the anaesthetic. She was therefore treated for 6 days with large doses of A.C.T.H., by which time the eosinophils in the blood had fallen 75% and the urinary excretion of ketosteroids had increased from 0-9 to 8-9 mg. in 24 hours. The operation was then performed without incident, and, though the patient had a difficult time after the operation, she recovered satisfactorily. The number of cases reported by
ROCHE et al. is small, but their work is sure to be repeated, and if it is confirmed the surgeon will want to know his patients’ eosinophil-counts. Stimulated by the work with A.C.T.H. in rheumatoid arthritis, the technique of eosinophil counting is being improved. Most laboratories use DuNGAR’s method in some form, but this has disadvantages, especially for large-scale use; methods like that of RANDOLPH,3 which use propylene glycol in the diluting fluid, are coming into
use.
Apart from its immediate importance, there are two interesting points about this work. It is one of the first applications of A.C.T.H. and its effects as a "
research toolin conditions other than rheumatoid arthritis. And the results suggest that shock due to failure of adrenal cortical function is likely to be distinctly rare, so that large amounts of adrenal cortical hormone will be saved for the patients who really need it.
in
Fever UNTIL lately typhoid fever had resisted all attempts at chemotherapy. Most of the sulphonamides intro-
Chloromycetin
Typhoid
duced in the past fifteen years have been tried in this disease, but the initially favourable claims for several of them were soon disproved. The same process has been repeated with each of the antibiotics hitherto
tried-penicillin, streptomycin, aerosporin (polymyxin), andAureomycin ’-and even the promising results reported with penicillin and sulphonamides combined have not been repeated. There is good reason, therefore, for caution in interpreting the remarkable clinical effects of chloramphenicol. In the last few months an increasing stream of adrenocortical reserves are normal. The second test clinical reports have appeared in this country and is based on the observation that a small dose-0-3 mg. -of adrenaline will also cause a fall in circulating abroad confirming the original observations of WOODWARD and his 4 with chloromycetin eosinophils ; it is thought that the adrenaline acts in the treatment of colleagues in Malaya. Some typhoid patients on the hypothalamus or the pituitary which in turn have of these been reviewed in these columns.5 already stimulates the adrenal cortex. The test is thus one The action on the constitutional symptoms are drug’s of pituitary-adrenocortical reserves. It is carried so striking that the clinicians are unanimous in out by injecting 0-3 mg. of adrenaline subcutaneously acclaiming its value, even though some failures have and counting the blood eosinophils 4 hours later ; also been recorded. Thus, out of 6 severely ill patients again a fall of 50% or more indicates normal reserves. treated in Bombay by PATEL et al.,3 died and 1 These tests were tried on two patients with pituitary in a series of 63 patients treated in and lesions who might well have had a stormy postoperative relapsed ; and his colleaguesthere were 4 CONTI The first patient had had intensive X-ray Italy by course. deaths and 9 relapses. DANA et al. 8 have described 5 therapy of the pituitary gland for Cushing’s syndrome cases treated in Tunis which showed an alarming rise 10 months before she was admitted to hospital for in 3 of these patients died, but the other blood-urea ; a hysterectomy. With both adrenaline and A.C.T.H. 2 improved when the chloramphenicol was stopped tests there was a significant fall in eosinophils, which and they eventually survived. In our correspondence suggested that the operation could be undertaken columns this week Dr. STEPHENS reports a case from without undue risk. The operation was duly performed, and recovery was uneventful. The second patient had 3. Randolph, T. G. J. Lab. clin. Med. 1949, 34, 1696. 4. Woodward, T. E., Smadel, J. E., Ley, H. L., Green, R., Mankikar, a chromophobe adenoma causing visual impairment ; D. S. Ann. intern. Med. 1948, 29, 131. 5. Lancet, 1949, ii, 1001. with the adrenaline test the eosinophils actually rose 6. Patel, J. C., Banker, D. D., Modi, C. J. Brit. med. J. 1919, ii, 908. F., Cassano, A., Monaco, R. Rif. med. 1949, 63, 901. slightly, while with the A.c.T.H. test only a 15% fall 7.8. Conti, Dana, R., Sebag, A., Cohen, J., Borsoni, G. Tunisie med. 1950, was recorded. Difficulties were anticipated and an 38, 190.
721
Northern Rhodesia, in which
an African boy, infected S. rich in Vi antigen, strain of virulent typhi by seemed to be recovering well with chloramphenicol but collapsed suddenly and died in the second week of the disease. But the consensus of opinion is in agreement with Dr. EDGE, who reviews his 16 cases on p. 710 and remarks that the " complete transformation in a few days " can only be fully appreciated by clinicians who recall their own helplessness in the past. In our columns a fortnight age, GooD and MACKENZIE,and RANKIN and GRIMBLE 10 recounted
a
experiences with chloromycetin in typhoid patients, mostly from the small outbreak in Crowthorne, Berks, in April-May, 1949, which affected about 40 people. A trial under controlled conditions was arranged, using a strict " alternate case " method their
of selection. GOOD and MACKENZIE thus had a group of 6 cases receiving chloramphenicol and a control group of 7 cases, though 3 of the controls were later treated with chloramphenicol when they relapsed. The results were not so satisfactory as might have been expected from the first impressions gained the trial, published in a preliminary note by BRADLEY." There were 3 relapses in the original treated group and 3 in the controls, and the only persistent excreter identified in this outbreak was one of the female patients in the’ treated group. Nevertheless, GooD and MACKENZIE, like all’ previous observers, reach the conclusion that chloramphenicol is the most valuable drug we have against typhoid fever. The 18 cases reported by RANKIN and GRIMBLE comprised 10 patients from the Crowthorne outbreak, which was caused by a strain of Vi-phage type El, and 8 sporadic cases treated in the subsequent six months and due to strains of unspecified, and presumably different, Vi-phage types. The virulence of typhoid strains isolated in different outbreaks, and the severity of the -disease they cause, vary so widely that one cannot regard these sporadic cases, which received no chloramphenicol, as satisfactory controls.’’ A similar criticism applies to the report by EL RAMLI 12 from Cairo in the same issue. His series consisted of 200 cases of typhoid fever treated with chloramphenicol at the Abbassia Fever Hospital between May and December, 1949. The average duration of fever after the start of treatment was 3-5 days and the relapserate was 27-5%. Ei, RAMLI did not feel justified in leaving some of the patients without chloramphenicol as controls, so he compared the case-mortality of 6-5% in his treated series with that of all the typhoid cases, treated at the same hospital over the past ten years (9-12%). It must be borne in mind here in the small typhoid outbreaks that occurred among British troops in Egypt during the past few years the fatality-rates, in patients receiving no specific treatment, ranged from nil to well over 25%. EL RAMLI also observed in 7 very severe cases that the temperature did not settle quickly but remained high for eight to twenty-seven days. His general conclusion is that chloramphenicol provides the most efficient specific treatment for typhoid fever so far
during
"
devised, but he hopes
improve the results -by combining chloramphenicol with sulphadiazine treatto
9. Good, R. A., Mackenzie, R. D. Lancet, April 1, p. 611. 10. Rankin. A. L. K., Grimble, A. S. Ibid. p. 615. 11. Bradley, W. H. Ibid. 1949, i, 869. 12. El Ramli, A. H. Ibid, April 1, p. 618.
as was suggested by EL BOROLOSSY and BUTTLE.13 In view of the extreme degree of toxaemia commonly seen in severe typhoid cases, however, a combination of chloramphenicol and a potent " Vi -)0 anti-typhoid serum, such as that recommended by FELix,1-4 might prove more effective. One aspect of the typhoid problem has received very little attention in the reports on the use of chloramphenicol in the acute disease. Will the new antibiotic prevent the development of the chronic carrier state and thus contribute towards the ultimate goal of eradicating typhoid infection ? This question is of paramount importance and deserves the urgent attention of both public-health officers and laboratory workers. GooiD and MACKENZIE obtained some valuable data by observing the effect of chloramphenicol on the excretion of typhoid bacilli both and after treatment. The findings in their small series were disappointing and recall the observations made on typhoid cases treated with penicillin and sulphathiazole combined.15S It may be concluded that the dosage adopted by GooD and MACKENZIE, which was that originally suggested by WOODWARD and his . colleagues, cannot prevent either clinical relapse or the development of the chronic carrier state. Lately SMADEL and his colleagues 16 have advised that treatment should be continued for about fourteen davs with a total dosage of about 25 g. But they do not say what effect the larger doses given over longer periods have on the excretion of typhoid bacilli in the faeces and urine. That longer treatment is no guarantee against relapse is seen from the experience of RANKIN and GRIMBLE,1o who describe a typical relapse in a patient who had received 37-5 g. of chloromycetin in twenty days. The latest suggestion by WOODWARD (quoted by SMADEL 17), that intermittent short courses of chloramphenicol should be given, was followed in the outbreak at Salford in October, 1949, but the effect on the excretion of typhoid bacilli was no better than that of the original reoimen.18 The closest cooperation between clinician and pathologist is clearly essential in the planning of future therapeutic trials. This cooperation has not been conspicuous in some of those so far carried out here or abroad. The effect of the drug on the bactersemia can be assessed only if the organism is shown to be present in the blood-stream immediately before the drug is exhibited and its presence or absence is checked in blood-cultures taken at regular short intervals afterwards. The effect of the drug on the excretion of the organism can be assessed only if bacteriological examinations of the fseces and urine are begun early in the disease and continued at regular and short intervals until convalescence. These simple rules have not always been observed. When it is intended to conduct a trial under controlled condiselection, and the tions, using ’’alternate case small come from groups infected in different patients localities in an endemic area, equal numbers --of cases infected from the same source must be allotted’ to
ment,
"
during
"
13. El Borolossy, A. W., Buttle, G. A. H. Ibid, 1949, ii, 559. 14. Felix, A. J. Hyg., Camb. 1938, 38, 750. 15. Bevan, G., Sudds, M. V. N., Evans, R., Parker, M. T., Pugh, I., Sladden, A. F. S. Lancet, 1948, i, 545. 16. Smadel, J. E., Woodward, T. E., Bailey, C. A. J. Amer. med. Ass. 1949, 141, 129. 17. Smadel, J. E. Proc. R. Soc. trop. Med. Hyg. 1950 (in the press). 18. Parker, M. T. Unpublished.
722
the treated and the control groups. Single sporadic controlled " trial, cases cannot be included in a because there would then be no control cases from the same source of infection. Vi-phage typing of the strains isolated from the treated and the control cases should be carried out as a routine. The result will confirm or disprove the epidemiological connection "
between alternate cases. Finally, a thorough serological and bacteriological study should be made of the convalescent patients for three to six months after their discharge from hospital, to make certain that they do not become chronic carriers.
Annotations LORD MORAN
of Physicians elected it certainly did not president, foresee that for eight more years his re-election would be an annual event-and an exciting one. Whatever else his critics may say of his nine years’ presidency, they cannot fairly describe it as dull ; nor did it end tamely. Lord Moran is not one of those who hold that because an institution is old it should reduce its activities and live gracefully in the past : he regards prestige as useful rather than ornamental. Since 1941 constructive proposals have come from the college in reports of committees on social and preventive medicine, psychological medicine, medical education, paediatrics, neurology, pathology, dermatology, cardiology, and rheumatic heart-disease, and on problems of demobilisation. The Prophit report on tuberculosis came out in 1948, and an International Conference of Physicians was held in 1947. Internally the members have been given opportunities of meeting to express their views, and representation on the council. Externally the Physicians have joined with the Surgeons and Obstetricians in a standing joint committee ; but they have preferred to remain in Pall Mall rather than form part of an Academy of Medicine in Lincoln’s Inn Fields.
WHEN in 1941 the Sir Charles Wilson
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Royal College
as
Lord Moran’s qualities are admired most, perhaps, by those who know him best ; but even those who deny the wisdom of his policies must be impressed by the-courage with which he has pursued them. To his successor, Dr. Russell Brain, he leaves a difficult task, but one whose responsibility he has enhanced. NEW LIGHT ON ENDOTOXINS IT has been recognised for some time that the toxic properties of the colon-typhoid-dysentery group, with the probable exception of Shigella shigce, are attributable to a nitrogen-containing polysaccharide complex. Some authors call this substance a somatic antigen and others It has been extracted from bacterial an endotoxin. bodies with trichloracetic acid (Boivin and Mesrobeanu 1933), by tryptic digestion (Ra,istrick and Topley 1934), and with diethylene glycol (Morgan 1937). It is antigenic ; it produces a pathological picture in which the fundamental change is a terminal circulatory hypertension ; it causes hyperthermia, transient hyperglycaemia
In the preliminaries to the National Health Service, the attitude of the Royal College of Physicians, expressed, and to some extent formed, by Lord Moran, was that the creation of a service was inevitable and that their duty was to help in fashioning it, so that avoidable mistakes might be avoided. Probably it would be correct to say that if the senior college had taken a different line, the profession would have refused to work the service, unless or until compelled to do so. On the narrower issue of the future of consultant practice, Lord Moran believed that grave harm would be done to the whole profession if the highest incomes open to doctors in the service were to be no more than the :t2500 a year paid to medical professors ; and his arguments in the House of Lords led to the formation of the Spens Committee on the remuneration of consultants, of which he was a member. This committee’s report, and its acceptance by the Government, has created confusion wherever medical men are publicly employed ; but in the end the whole quality of public service is likely to gain by the committee’s stand against the old tradition that public servants must be poorly paid. The committee’s further proposal that the highest salaries should be awarded only for special merit, as judged by a man’s peers, has led to what we regard as a most important experiment in the technique of public service under the new conditions. For the fact that this experiment is being made, and that the profession has not accepted a conventional system of remuneration on Civil Service lines, we have to thank both Lord Moran and the Minister, both men of
imagination.
(followed by hypoglycsemia), placental haemorrhage with abortion, and haemorrhage in implanted tumours; and its toxicity appears to be less in animals injected with adrenal cortical extract. When endeavouring to explain the toxicity to guineapigs of some heat-killed saline suspensions of Bacterium coli, Roberts1 found that the toxic substance was a polysaccharide complex, or endotoxin, and that it was present in filtrates of heated suspensions. The high susceptibility of guineapigs (but not mice) and the presence of endotoxin in the filtrate of heated saline suspensions, seemed to conflict with accepted knowledge, and further investigation was therefore undertaken. Bact. coliwas grown in a synthetic medium vigorously agitated by aeration, and viable counts of 25,000 million cells per ml. were obtained. When these suspensions of Bact. coli were heated at 80°C for one hour, almost all the endotoxin entered the suspending fluid and could be recovered from the filtrate. On purification it proved to have the physical, chemical, and biological properties associated with the endotoxins of salmonella and
dysentery organisms. These observations were made by employing guineapigs to detect the endotoxin. Experiments on purified endotoxic complex showed that even when guineapigs were injected subcutaneously and mice intravenously, the guineapigs were, weight for weight, 17-5 times more susceptible than mice. It is possible that guineapigs may be more susceptible to Bact. coli endotoxin, and more uniform in their response to it, than to the endotoxins of other enteric bacteria. The gross appearance of lesions in guineapigs suggested capillary haemorrhage, but microscopical examination did not indicate whether the lesion was due to extravasation or to hypertension. When the trypan-blue technique of Menkin (1938) was applied, no evidence of increased capillary permeability could be obtained. The results thus supported the view that the lesion was a terminal hypertension. These simplified methods of producing large quantities of Bact. coli in synthetic medium and of obtaining the endotoxin will no doubt stimulate further studies in this field. It also looks as though much work on antigenic analysis may need re-examination, because the bacterial suspensions have often been killed by heat, which evidently removes the antigen from the bacterial bodies. Though an active immunity was demonstrated in surviving guineapigs, there appears to be no immediate likelihood of developing a method of detoxifying endotoxin for purposes of immunisation; and, as bacterial cells are as effective as the complex in stimulating immunity, there is no obvious advantage in using endotoxin instead of bacterial suspensions as 1. Roberts, R. S.
J. comp. Path. 1949, 59, 245.