IX Typhoid Fever. Malta Fever
Typhoid Fever
The names of Klebs, Eberth, and Koch, are associated with the discovery, in 1880-81, of the bacillus of enteric fever, bacillus typhosus; and it was obtained in pure culture by Gaffky in 1884. It has been studied from every point of view, in man and in animals; in the blood, tissues, and excretions; in earth, air, water, milk, and food; in its distribution, methods of growth, and chemical products. Especially, the study of its chemical products has been directed toward (1) immunisation against the disease, (2) bacteriological diagnosis of the disease at an early stage.
The date of the first protective inoculations against typhoid is July to August 1896: they were made at Netley Hospital, by Professor Wright and Surgeon-Major Semple. The first inoculations in Germany, made by Pfeiffer and Kolle, were published two months later. The story of these famous Netley inoculations is told in the British Medical Journal, 30th January 1897. Eighteen men offered themselves—
“A good deal of fever was developed in all cases, and sleep was a good deal disturbed. These constitutional symptoms had to a great extent passed away by the morning, and laboratory work went on without interruption.... With two exceptions, all these vaccinations were performed upon Medical Officers of the Army or Indian Medical Services, or upon Surgeons on Probation who were preparing to enter those services.”
Good luck attend all eighteen of them, and immunity against typhoid, wherever they are. The doses that they received were estimated in proportion to the dose that would kill a guinea-pig of 350-400 grammes weight; and the protective fluid contained no living bacilli:—
“The advantages which are associated with the use of such ‘dead vaccines’ are, first, that there is absolutely no risk of producing actual typhoid fever by our inoculations; secondly, that the vaccines may be handled and distributed through the post without incurring any risk of disseminating the germs of the disease; thirdly, that dead vaccines are probably less subject to undergo alterations in their strength than living vaccines.”
The first use of the vaccine during an outbreak of typhoid was in October 1897, at the Kent County Lunatic Asylum. The treatment was offered to any of the working staff who desired it:—
“All the medical staff, and a number of attendants, accepted the offer. Not one of those vaccinated—84 in number—contracted typhoid fever: while of those unvaccinated and living under similar conditions, 16 were attacked. This is a significant fact, though it should in fairness be stated that the water was boiled after a certain date, and other precautions were taken, so that the vaccination cannot be said to be altogether responsible for the immunity. Still, the figures are striking.” (Lancet, 19th March 1898; see also Dr. Tew’s paper, in Public Health, April 1898.)
Certainly, they are striking; so is the story of the eight young subalterns on the Khartoum expedition, of whom six were vaccinated, and two took their chance. The six escaped typhoid, the two were attacked by it, and one died. But these figures are too small to be of much value.
The first anti-typhoid inoculations on a large scale were made among British troops in India (Bangalore, Rawal Pindi, Lucknow), when the Plague Commission, of which Professor Wright was a member, was in India, November 1898 to March 1899. These inoculations were voluntary, at private cost, and without official sanction; though the original proposal for them, in 1897, had come from the Indian Government. Pending official sanction, they were stopped. Then, on 25th May 1899, the Indian Government made application to the Secretary of State for India that they should be sanctioned, and should be made at the public cost. The application is as follows:—
“The annual admissions per mille for enteric fever amongst British troops in India have risen from 18.5 in 1890 to 32.4 in 1897, while the death-rate has increased from 4.01 to 9.01; and we are of opinion that every practicable means should be tried to guard against the ravages made by this disease. The anti-typhoid inoculations have been, we believe, on a sufficiently large scale to show the actual value of the treatment, while the results appear to afford satisfactory proof that the inoculations, when properly carried out, afford an immunity equal to or greater than that obtained by a person who has undergone an attack of the disease; further, the operation is one which does not cause any risk to health. In these circumstances, we are very strongly of opinion that a more extended trial should be made of the treatment; and we trust that your Lordship will permit us to approve the inoculation, at the public expense, of all British officers and soldiers who may voluntarily submit themselves to the operation.”
On 1st August, the Secretary of State for India announced in Parliament that this treatment, at the public expense, had been sanctioned.
On 20th January 1900, Professor Wright published in the British Medical Journal an account of these 1898-99 inoculations in India. “They were undertaken under conditions which were very far from ideal. In particular, there is reason to suppose that the results obtained may have been unfavourably influenced by a weakening of the vaccine, brought about by repeated re-sterilisation.” In no case was reinoculation done. The statistics were compiled from information furnished by officers of the Royal Army Medical Corps actually in charge of troops in the various stations; and were supplemented by reports received from the commanding officers of the various inoculated regiments. They are as follows:—
| Numbers under Observation. | Cases. | Deaths. | Percentage of Cases. | Percentage of Deaths. | |
|---|---|---|---|---|---|
| Inoculated | 2835 | 27 | 5 | 0.95 | 0.2 |
| Uninoculated | 8460 | 213 | 23 | 2.5 | 0.34 |
If the inoculated had been attacked equally with the uninoculated throughout the period of observation, they would have had 71 cases instead of 27.
These inoculations belong to the early part of 1899. During the rest of the year, inoculations were made in India, Egypt, and Malta: the results are given in an appendix to the Report of the Royal Army Medical Department, 1899. (See British Medical Journal, 21st September 1901.) The great majority of the troops tabulated were in India. Of the troops stationed at Malta, 61 were inoculated, 2456 not inoculated; among the former there were no cases, among the latter there were 17 cases and 5 deaths. In Egypt, of 4835 troops, 461 were inoculated; among these there were no cases, among the uninoculated there were 30 cases and 7 deaths. In India, of 30,353 troops, 4502 were inoculated, leaving 25,851 not inoculated; among the inoculated there were 44 cases and 9 deaths, among the non-inoculated 657 cases and 146 deaths. Taking the Indian statistics, and estimating percentage to strength, we find, amongst the inoculated, admissions 0.98, deaths 0.2; amongst the non-inoculated, admissions 2.5, deaths 0.56. The cases which occurred amongst the inoculated men were in the majority of instances of a mild character. Taking Malta, Egypt, and India together, it appears that the inoculated, if they had suffered equally with the non-inoculated, would have had 108 cases and 24 deaths, instead of 44 cases and 9 deaths.
At the end of 1899, this treatment, only just out of the hands of science, was suddenly demanded for the protection of a huge army at war in a country saturated with typhoid. Still, the South African results, and other results during 1899 to 1901, show a good balance of lives saved. The following paragraphs give all results published from the beginning of 1900 to May 1902. They are put in order of publication. Doubtless a few other reports have been overlooked in compilation; but the list includes all that were easily accessible.
1. Manchester, England. The British Medical Journal, 28th April 1900, contains a note by Dr. Marsden, Medical Superintendent of the Monsall Fever Hospital, Manchester, on the inoculation of 14 out of 22 nurses engaged in nursing typhoid patients. Of the remaining 8, 4 had already had typhoid. The inoculations were made in October 1899. The following table shows the subsequent freedom from typhoid of the nursing staff:—
| Year. | Number of Typhoid Patients. | Cases among Nursing Staff. |
|---|---|---|
| 1895 | 229 | 3 |
| 1896 | 238 | 3 |
| 1897 | 302 | 4 |
| 1898 | 426 | 8 |
| To end of September 1899 | 163 | 5 |
| From October 1899 to March 1900 | 146 | 0 |
2. Ladysmith, South Africa. The Lancet, 14th July 1900, contains a short note by Professor Wright, on the distribution of typhoid among the officers and men of the military garrison, during the siege of Ladysmith. The figures are as follows:—
| Number. | No. of Cases. | Proportion of Cases. | No. of Deaths. | Proportion of Deaths. | Case- mortality. | |
|---|---|---|---|---|---|---|
| Not inoculated | 10,529 | 1489 | 1 in 7.07 | 329 | 1 in 32 | 1 in 4.52 |
| Inoculated | 1,705 | 35 | 1 in 48.7 | 8 | 1 in 213 | 1 in 4.4 |
The wide difference between the two groups, as regards the incidence of the disease, is well marked; but the case-mortality is practically the same in each group. (The statistics of the General Hospital, Ladysmith, also tell in favour of the preventive treatment: see Surgeon-Major Westcott’s letter, British Medical Journal, 20th July 1901, in answer to Dr. Melville’s letter, British Medical Journal, 20th April 1901.)
3. The Portland Hospital: Modder River and Bloemfontein. The British Medical Journal, 10th November 1900, contains an account by Dr. Tooth of the cases of typhoid in this hospital. Concerning the preventive treatment, he says: “The experience of my colleague Dr. Calverley and myself may be of interest, though we fear that the numbers are too few for safe generalisation.
“Personnel of the Portland Hospital. We take first the relation of disease and inoculation among the personnel of the hospital. Twenty-four non-commissioned officers, orderlies, and servants of the Portland Hospital, and 4 of the medical staff, were inoculated on the voyage out. All these showed the local symptoms at the time; that is, pain, stiffness, and local erythema; 17 also presented well-marked constitutional symptoms—general feeling of illness, fever, and headache. Of the orderlies, 9 had enteric fever subsequently. Two had refused inoculation, and both of these had the disease very severely; in fact one died. Of the inoculated cases, 5 had the disease lightly, and 2 fairly severely. One of the sisters had the disease rather severely, and she had not been inoculated.
“Officers and men admitted to the Portland Hospital. We had under treatment at the Portland Hospital 231 cases of enteric fever, most of which came under our care at Bloemfontein. We have not included in these figures a number of patients who came in convalescent for a short time only, and on their way to the base, and who would therefore appear in the admission and discharge book of the hospital. If we did so, of course our percentages would be lower. Of these 231 patients, 53 had been inoculated at home or on the voyage out, and of them 3 died, making a percentage of deaths among the inoculated of 5.6 per cent.; 178 had not been inoculated, of whom 25 died; that is, a mortality among the non-inoculated of 14 per cent. The general mortality in enteric fever with us was 28 deaths out of 231 cases; that is, 12.1 per cent., which seems to compare favourably with the experience of the London hospitals.
“It is interesting to record our experience among the officers taken separately. Thirty-three officers were admitted with enteric fever; 21 had been inoculated; that is, 63.6 per cent.; a much larger percentage than among the men. Only one of these officers died, and he had not been inoculated.
“These figures are small, but such as they are they are significant, and they dispose us to look with favour upon inoculation. So also does our clinical experience with our patients, for among the inoculated the disease seemed to run a milder course.”
4. No. 9 General Hospital, Bloemfontein. The Medical Chronicle for January 1901 contains an account, by Dr. J. W. Smith, of the work of this hospital. He says: “The general impression amongst the medical officers in our hospital was that a single inoculation probably did not confer an immunity lasting very long—the lapse of time differing in individuals—and also that there was a tendency in the cases of enteric in inoculated patients to abort at the end of ten or fourteen days. I should say, however, that a very considerable number of our detachment who had been inoculated suffered from enteric, of whom 4 at least died. Of the medical staff, the only member of the junior staff who had not been inoculated died of enteric.”
5. Scottish National Red Cross Hospital, Kroonstadt. The British Medical Journal, 12th January 1901, contains an account of the work of this hospital by Surgeon-Colonel Cayley, Officer in Charge. He says: “The first section of the hospital, consisting of 61 persons—officers, nursing sisters, and establishment—left Southampton on 21st April 1900. During the voyage out, all except 4 were inoculated twice, at an interval of about ten days; 2 were inoculated once; and 2 (who had had typhoid) were not inoculated. Immediately we reached the Cape, the hospital was sent up to Kroonstadt in the Orange River Colony, and remained there as a stationary hospital till the middle of October. During this period there were always many cases of enteric under treatment in hospital. Further, some of the medical officers and student orderlies had charge of the Kroonstadt Hotel temporary hospital, which was crowded up with enteric cases; and the nursing sisters, for three weeks, did duty in the military hospitals at Bloemfontein in May and June, when enteric fever was at its worst. There was not a single case of enteric among the personnel of this first section of the hospital.
“The second section of the hospital—medical officers, nurses, and establishment, 82 in all—left Southampton in May 1900. On board ship nearly all of them were inoculated, but many of them only once. The material for inoculation had been on board for some time, and was not so fresh as in the first instance. Of this second section, 1 nurse had enteric at Kroonstadt. She was the only one, out of a total of 36 nurses, who suffered from enteric; and she was the only nurse who was not inoculated, excepting the 2 who were protected by a previous attack of enteric. A third section of the hospital, consisting of 4 medical officers and 16 nurses, went out in July; they were all inoculated, and none of them had enteric.
“Of the second section, 5 orderlies had enteric fever at Kroonstadt, of whom 2 died. Of these 5, there were 2 inoculated (once) and 3 non-inoculated. Of the 2 who died, 1 had been once inoculated, the other had not been inoculated.”
6. Meerut, India. The British Medical Journal, 9th February 1901, gives a short note by Professor Wright on inoculations in the 15th Hussars. He says: “Through the kindness of Lieutenant-General Sir George Luck, commanding the Bengal Army, I am permitted to publish the following officially compiled statistics, dealing with the effects of anti-typhoid inoculations in the case of the 15th Hussars:—
From 22nd October 1899 to 22nd October 1900.
| Strength. | Inoculated. | Cases. | Deaths. | Not Inoculated. | Cases. | Deaths. | |
|---|---|---|---|---|---|---|---|
| Officers | 22 | 19 | 0 | 0 | 3 | 0 | 0 |
| N.C.O. and Men | 481 | 317 | 2 | 1 | 164 | 11 | 6 |
| Women | 36 | 24 | 0 | 0 | 12 | 0 | 0 |
It would thus appear that the incidence of enteric in the inoculated was represented by 0.55 per cent., and the mortality by 0.27 per cent.; while the incidence in the uninoculated was 6.14 per cent., and the death-rate 3.35 per cent.”
If the inoculated had suffered equally with the uninoculated, they would have had 22 cases with 11 deaths, instead of 2 cases with 1 death.
7. The Edinburgh Hospital, South Africa. The Scottish Medical and Surgical Journal, March 1901, contains an account of the work of the Edinburgh Hospital, by Dr. Francis Boyd. Of the staff, 58 were inoculated (27 once, and 31 twice). Among these 58, there were 9 cases of typhoid fever, with I death, in a patient who had old mitral disease. “Our experience has been that, while inoculation appears to modify the disease, completely modified attacks are met with in the uninoculated. Again, very severe attacks, with complications and relapse, occur in those who have been inoculated. One cannot from this conclude that inoculation has been valueless, for had not the patient been inoculated, the attack might have been still more severe.”
8. Egypt and Cyprus. The British Medical Journal, 4th May 1901, gives a short note by Professor Wright on inoculations during 1901 in Egypt and Cyprus. He says: “I am indebted to the kindness of Colonel W. J. Fawcett, R.A.M.C., Principal Medical Officer in Egypt, for the following statistics dealing with the incidence of enteric fever, and the mortality from the disease, for the year 1900, in the inoculated and uninoculated among the British troops in Egypt and Cyprus:—
| Average Annual Strength. | Cases. | Deaths. | Percentage of Cases. | Percentage of Deaths. | |
|---|---|---|---|---|---|
| Uninoculated | 2669 | 68 | 10 | 2.50 | 0.40 |
| Inoculated | 720 | 1 | 1 | 0.14 | 0.14 |
These figures testify to a nineteen-fold reduction in the number of attacks of enteric fever, and to a threefold reduction in the number of deaths from that disease, among the inoculated.... The only case which occurred among the inoculated was that of a patient admitted to hospital on the thirty-third day after inoculation. It would seem that the disease was in this case contracted before anything in the nature of protection had been established by the inoculation.”
9. Imperial Yeomanry Hospital, Pretoria. Dr. Rolleston, Consulting Physician to this hospital, writes in the British Medical Journal, 5th October 1901: “Among the personnel of the hospital (17 medical officers, 50 nursing sisters, 83 orderlies, etc.), total, 150, there were 22 cases of enteric fever, or an incidence of 14.6 per cent. Of the 150, 35 were inoculated, and of these, 6, or 17 per cent., suffered from enteric; while, of 115 non-inoculated members of the personnel, 16, or 13.9 per cent., suffered from enteric fever; the percentage is therefore higher among the inoculated. There were 2 deaths, both in non-inoculated patients. In 100 cases of enteric fever among non-commissioned officers and men, taken mainly from convalescent patients, only 8 had been previously inoculated; there were 3 fatal cases, all among non-inoculated patients. Among 42 officers who had enteric, no fewer than 19 had been previously inoculated; 6 of these 19 cases were severe in character, but none were fatal; of the 23 non-inoculated cases, 7 were severe, and of these 7, 3 ended fatally. The interval between inoculation and the subsequent incidence of enteric fever varied between one and twenty-one months, but in only four instances was the interval less than six months. The average interval between inoculation and the onset of enteric fever in these 19 cases was thirty-eight weeks.
“As far as these scanty figures go, they point to the conclusion (1) that anti-typhoid inoculation does not absolutely protect against a future attack of typhoid fever; (2) that when enteric occurs in an inoculated person, there is, as a rule, an interval of about six months; (3) that inoculation protects against a fatal termination to the disease.”
10. Richmond Asylum, Dublin. The British Medical Journal, 26th October 1901, contains a note by Professor Wright on an outbreak of typhoid in this asylum during August to December 1900. Inoculations were begun on 6th September, by Dr. Cullinan, and by 30th November 511 persons were inoculated. After careful criticism of all doubtful cases, Professor Wright gives the following figures:—
Comparative Incidence of Typhoid Fever in Inoculated and Non-Inoculated, calculated upon the average strength of the representative groups during the period intervening between the commencement of the inoculations and the termination of the epidemic.
| Average Strength. | Cases. | Deaths. | Percentage of Cases. | Percentage of Deaths. | |
|---|---|---|---|---|---|
| Uninoculated | 298 | 30(-1?) | 4 | 10.1 | 1.3 |
| Inoculated | 339 | 5(+1?) | 1 | 1.3 | 0.3 |
“It may be noted,” he says, “that the result is in conformity with that of all the statistical returns of anti-typhoid inoculation which have reached me.”
11. Deelfontein. The Lancet, 18th January 1902, contains a paper by Dr. Washbourn and Dr. Andrew Elliot, on 262 cases of typhoid fever in the Imperial Yeomanry Hospital at Deelfontein during the year March 1900 to March 1901. (See Dr. Washbourn’s earlier letter, Brit. Med. Jour., 16th June 1900.) They say: “In 211 of our cases, it was definitely recorded whether the patient had been inoculated or not: 186 of these cases had not been inoculated, with 20 deaths, or a mortality of 10.7 per cent.; 25 had been inoculated, with 4 deaths, or a mortality of 16 per cent. The mortality was thus higher among the inoculated than among the non-inoculated.” Of the personnel of the hospital, there were 59 inoculated, with 4 cases, and 25 not inoculated, with 4 cases.
12. Winburg. The Lancet, 5th April 1902, contains a short note by Professor Wright, on the 5th Battalion, Manchester Regiment. He says: “In view of the dearth of statistics bearing on the incidence of typhoid fever in South Africa in inoculated and uninoculated persons respectively, the following, for which I am indebted to Lieutenant J. W. West, R.A.M.C., Winburg, Orange River Colony, may not be entirely without interest. The statistics here in question give the results obtained in the case of the 5th Battalion, Manchester Regiment, for the six months which have elapsed since their landing in South Africa. The figures, which relate to a total strength of 747 men and officers under observation, are as follows:—
| Number. | Cases. | Deaths. | Percentage of Cases. | Percentage of Deaths. | |
|---|---|---|---|---|---|
| Uninoculated | 547 | 23 | 7 | 4.2 | 1 in 3.3 |
| Inoculated | 200 | 3 | 0 | 1.5 | 0 |
“The three attacks in the inoculated are reported to have been of exceptionally mild type, contrasting in a striking manner with the severe attacks which occurred in the uninoculated. At the time of sending in the report, some of the uninoculated patients were ‘not yet out of danger.’”
Certainly, these instances show a good balance of lives saved, not only under the adverse conditions of the war, but also in Egypt, India, and the United Kingdom. But the bacteriological work on typhoid fever has been directed also to the working out of a very different problem: and that is the method of diagnosis which is called “Widal’s reaction.” The practical uses of this reaction are of the utmost importance. It is the outcome of work in different parts of the world—by Wright and Semple and Durham in England, Chantemesse and Widal in France, Pfeiffer and Kolle and Grüber in Germany, and many more. The first systematic study of it was made by Durham and Pfeiffer; and Widal’s name is especially associated with the application of their work to the uses of practice. Admirable accounts of the whole subject are given by Dr. Cabot in his book, The Serum-Diagnosis of Disease (Longmans, 1899), and by Mr. Foulerton in the Middlesex Hospital Journal, October 1899 and July 1901.
Widal’s reaction is surely one of the fairy tales of science. The bacteriologist works not with anything so gross as a drop of blood, but with a drop of blood fifty or more times diluted; one drop of this dilution is enough for his purpose. Take, for instance, an obscure case suspected to be typhoid fever: a drop of blood taken from the finger is diluted fifty or more times, that the perfect delicacy of the test may be ensured; a drop of this dilution is mixed with a drop of nutrient fluid containing living typhoid bacilli, and a drop of this mixture of blood and bacilli is watched under the microscope:—
“The motility of the bacilli is instantaneously or very quickly arrested, and in a few minutes the bacilli begin to aggregate together into clumps, and by the end of the half-hour there will be very few isolated bacilli visible. In less marked cases, the motility of the bacilli does not cease for some minutes; while in the least marked ones the motility of the bacilli may never be completely arrested, but they are always more or less sluggish, while clumping ought to be quite distinct by the end of the half-hour.”
The result of this clumping is also plainly visible to the naked eye, by the subsidence of the agglutinated bacteria to the bottom of the containing vessel: and thus an easy practical mode of diagnosis is afforded by it.
As with typhoid, so with Malta fever, cholera, and some other infective diseases. And the unimaginable fineness of this reaction goes far beyond the time of the disease. Months, even years, after recovery from typhoid, a fiftieth part of a drop of the blood will still give Widal’s reaction: and it has been obtained in an infant whose mother had typhoid before it was born. A drop of dried blood, from a case suspected to be typhoid, may be sent a hundred miles by post to be tested; and typhoid, like diphtheria, may now be submitted to the judgment of an expert far away, and the answer telegraphed back. It would be difficult to exaggerate the practical importance of this reaction for the early diagnosis of cases of typhoid fever, especially those cases that appear, at the onset, not severe.
Malta Fever
The specific organism of Malta fever (Mediterranean fever), the bacillus Melitensis, was discovered in 1887 by Surgeon-Major David Bruce, of the Army Medical Staff. Its nature and action were proved by the inoculation of monkeys. The use of Widal’s reaction is of great value in this disease:—
“The diagnosis of Malta fever from typhoid is, of course, a highly important practical matter. It is exceedingly difficult in the early stages.” (Manson, loc. cit.)
As with typhoid, so with Malta fever, Netley led the way to the discovery of an immunising serum. In the course of the work, one of the discoverers was by accident infected with the disease:—
“He was indisposed when he went to Maidstone to undertake anti-typhoid vaccination, and after fighting against his illness for some days, he was obliged to return to Netley on 9th October. Examination of blood-serum (Widal’s reaction) showed that he was suffering from Malta fever. It appears that he had scratched his hand with a hypodermic needle on 17th September, when immunising a horse for the preparation of serum-protective against Malta fever; and his blood, when examined, had a typical reaction on the micrococcus of Malta fever in 1000-fold dilution. The horse, which has been immunised for Malta fever for the last eight months, was immediately bled, and we are informed that the patient has now had two injections, each of 30 cub. cm. of the serum. He is doing well, and it is hoped that the attack has been cut short.” (British Medical Journal, 16th October 1897.)
About fifty cases had up to September 1899 been treated at Netley “with marked benefit: whereas they found that all drug-treatment failed, the antitoxin treatment had been generally successful.”36 A good instance of the value of the serum-treatment of Malta fever is published in the Lancet, 15th April 1899. For a later account of this treatment and of its efficacy, see the Philadelphia Medical Journal, 24th November 1900.
Another point is noted by Sir Patrick Manson, in his recent Lane Lectures (Constable, 1905). “For some time back,” he says, “a commission of experts, working under the direction of the Royal Society, has been studying this disease in Malta. The commission has accumulated much detailed information; but the most important observation it has published is the fact that a large percentage of the goats in Malta are infected with Micrococcus melitensis, and that the milk of the infected goats contains the bacterium. May not this account for the great prevalence of Mediterranean fever there and in other places having perhaps a similar milk-supply?”