Postgrad Med J: first published as 10.1136/pgmj.25.287.413 on 1 September 1949. Downloaded from 413

TYPHOID AND THE PARATYPHOIDS: A REVIEW- By J. C. S. PATERSON, B.Sc., M.B., M.R.C.P. Department of Medicine, Postgraduate Medical School of London

Preliminary reports of the efficacy of chloro- bacillus which he showed to be the true activator mycetin in the treatment of typhoid fever are of the disease. sufficiently encouraging to suggest that a new By i896 Widal and Sicard had demonstrated measure of control may readily be applied to this specific agglutinins in the serum of typhoid disease which is endemic throughout practically patients, making possible an agglutination re- the whole world, and which has carried a mortality action in the diagnosis of the disease, and the rate such as to have played no small part in history. experimental work of Chantemesse and Widal It is worthwhile, therefore, to review at this time (I898) led to the employment of anti-typhoid some of the immense literature which has accumu- inoculation by Wright and Leishman (I900). lated, 'and in particular to note the various approaches that have been made, towards the Clinical treatment and control of typhoid and its related The most comprehensive analysis of the clinical fevers. course and complications of typhoid fever is to be

found in the writings of Osler, Thayer, Flexner, Protected by copyright. Historical Cushing and others in the Johns Hopkins Reports Typhoid fever was prevalent during the of the years i894-95, x895 and I900. These Parliamentary Wars (I642-48), and one of the papers present a detailed account of typhoid earliest descriptions was that left by Thomas fever as it occurred in Baltimore over a period of Willis (i684). Huxham (I739) described the some eight years, and are well worthy of study. At Plymouth epidemic of 1737. There was little dis- the same time, however, it is to be remembered tinction drawn, however, during the I8th century that typhoid fever is a disease of great variability between typhus and typhoid fevers. Petit and in its virulence, its manner of onset and in the Serres described typhoid fever in I813, and severity and duration of its course, varying greatly Trousseau (I826) described the intestinal lesions from one outbreak to the next. Hence no great ' both for the glory of my Master and for science,' benefit is derived from a study of the incidence of on behalf of his chief, Pierre Bretonneau, who symptoms, the duration of the fever, the incidence seems not to have committed himself to print of complications or even of the mortality rate as he did make known his to the these in one this although findings apply any epidemic. Moreover, http://pmj.bmj.com/ Academy. Louis (I829), at La Pitie Hospital also peculiar variability of typhoid fever makes it ex- described the disease and the intestinal lesions, tremely difficult to assess the value of therapeutic and was the first to use the term' fievre typhoide.' procedures. To Gerhard of Philadelphia (i837), who had been For descriptive purposes it is usual to consider a pupil of Louis, must be credited the first clear an invasive phase or period of onset, then to clinical and anatomical descriptions of the two describe the features as they present themselves diseases. Gerhard's work was substantiated from week to week ; the febrile period may last by 'that of Sch6nlein (i839) in Germany one week only or six weeks or even longer. on September 28, 2021 by guest. and of Ritchie (i847) and of Jenner (I849) in Britain. Ritchie introduced the term ' enteric Period of Onset fever.' The incubation period may be from one to three An interesting contribution made before the weeks but usually is about ten days. Willis (I684) bacteriological era was that by Budd (I873) who wrote that ' . .. the first assault is for the most had also studied at La Pitie Hospital. He insisted part accompanied with a shivering or horror .. .' that typhoid fever was spread by contaminated This is not so, for chills are not a pronounced water and milk, the likely contaminant being the feature of the early stage. Headache, often intense, faeces of the convalescent patient. Eberth (I88o) loss of appetite and malaise are most common. discovered the typhoid bacillus although it is Diarrhoea or constipation, usually the former, likely that Klebs had recognized it earlier, and in may be the earliest complaint. Epistaxis, which I884 Gaffky obtained the first pure culture of the may be copious, is frequent, and occurs more often Postgrad Med J: first published as 10.1136/pgmj.25.287.413 on 1 September 1949. Downloaded from 414 POST GRADUATE MEDICAL JOURNAL September 1949 in typhoid fever than in any other infectious movements of the arms and picking at the bed- disease. Bronchitis is usual and dry cough a very clothes are all features of the typhoid state, and common feature. More unusual but no less im- reminiscent of encephalitis. The skin is hot and portant are the onset with abdominal pain which dry and often loose from loss of weight and de- so easily simulates acute appendicitis, and that hydration. The tongue is dry and dirty and with meningism and photophobia, neck retraction sordes collect on the teeth and at the angles of the and vomiting, even progressing to a purulent mouth. The toxic state may be so great as to meningitis (Stuart, 1948). cause death at this stage, not uncommonly in the first half of the second week. First Week Between the tenth and fourteenth days the During the first week the fever which is now the enlarged Peyer's patches and lymphoid follicles of leading feature of the illness, gradually rises in a the intestine undergo necrosis and slough to form ' staircase ' manner, the evening temperature ulcers. The mesenteric nodes are enlarged, being a degree or so higher than that of the pre- sometimes palpable and tender, and may also vious evening, to reach its fastigium at Io4° or undergo necrosis. The spleen is enlarged and the Io5' F. This is not necessarily so, however, in liver may be palpable and vaguely tender. the case which begins with a chill as the fever may Haemorrhage may occur with the sloughing and reach its fastigium in a matter of hours and often formation of ulcers and is sometimes accompanied has done so by the time the patient takes to bed. by a sharp drop in temperature to a subnormal The pulse is increased in rate but not in proportion level. Necrosis and sloughing may be extensive to the degree of fever and is of characteristic so that the whole of the mucosa of the terminal dicrotic type. The eyes are bright and the face ileum and caecum appears gangrenous and in flushed ; often there is at this early stage a flush such cases there is marked abdominal tenderness; over the chest-typhoid erythema. The tongue it is often a very difficult matter to decide whether Protected by copyright. becomes coated and the abdomen is slightly dis- or not perforation into the peritoneal cavity has tended and vaguely tender. Constipation may occurred. now be the rule rather than diarrhoea. The fever becomes steady with only a small Third Week morning remission and is remarkably resistant to Towards the end of the second week the fever attempts to lower it by means of tepid sponging. has become intermittent in character and now It persists towards the second week at which stage gradually settles by lysis; the pulse, no longer a few crops of' rose spots ' appear on the chest and dicrotic, is more in keeping with the temperature; abdomen. Each crop lasts a day or two and is loss of weight is by now very apparent and the usually seen in approximately 8o per cent. of those patient is weak and exhausted. Though the with fair skins but in not more than a quarter of disease process will often subside, other complica- the dark-skinned. At the same time the antibodies tions are wont to appear at this stage. The sorely- of the infecting organism become demonstrable in tried gut seems paralysed and meteorism may be troublesome and In a severely the serum of the majority of cases. persistent. http://pmj.bmj.com/ cachetic subject femoral and iliac vein thrombosis Second Week and parotitis are not unlikely. Neuritis is common The fever is maintained or may fall to a lower and the 'tender toes of typhoid' seem to be a level though usually still of a remittent character; localized form of neuritis. Mental depression may the pulse is still slow but tends to lose its dicrotic last long into convalescence. character, and the clinical picture depends very In subsequent weeks the temperature may re- much upon the severity of the illness. In a mild main well below normal, the hypothermia of con- case the fever will gradually subside, the tongue valescence common to both typhoid fever and on September 28, 2021 by guest. clean and the appetite return, and one may well malaria. Sometimes, however, the fever may re- imagine that resolution is taking place in the lapse with a fresh invasion of the blood stream by turgid and infiltrated lymphatic tissue of the typhoid bacilli, but often there are rises of tem- intestine. But in the severe cases toxaemia is the perature not accountable in this way, possibly re- dominant feature and a clouding of consciousness, lated to too early physical effort or even to con- which is so typical of typhoid fever as to be im- stipation. plicit in the name itself (Greek xvcpos, a cloud) A persistent irregular fever in the fifth and sixth and makes the victim of the disease so uncom- weeks may be related to localization of the in- plaining, deepens to the much more gross dis- fection as in mastoiditis, periostitis, pyelitis, turbance of consciousness of the 'typhoid state.' arthritis and liver abscess, to a necrotic mesenteric The eyes sunken but bright and roving, staring lymph node, to secondary pneumonia or to venous but unseeing, delirium only rarely noisy, restless thrombosis. September I949 PATERSON : Typhoid and the Paratyphoids : A Review 415 Postgrad Med J: first published as 10.1136/pgmj.25.287.413 on 1 September 1949. Downloaded from Ambulant Cases Clinical It must be mentioned that occasionally the The paratyphoid fevers may produce a picture sufferer from typhoid fever may never complain similar in all respects to typhoid fever but the or take to bed despite high fever and occasionally tendency to produce necrosis and ulceration of the patients may be admitted to hospital because of lymphoid aggregations in the bowel is much less, intestinal haemorrhage or perforation or some- and is extremely rare in paratyphoid C fever. times because of ruptured recti muscles. The ex- Catarrhal inflammation of the small bowel and planation may be that the clouding of conscious- ulceration of the large bowel, especially the caecum ness, already referred to, is enough to prevent the and ascending colon, are common in paratyphoid patient realizing how ill he is and enables him to B fever and diarrhoea is in consequence a leading make light of his symptoms. feature. The lesser tendency to necrosis and ulceration means also a much diminished in- Paratyphoid Fevers cidence of the compli ations of perforation and Achard and Bensaude (I896) isolated an haemorrhage. organism which was not the typhoid bacillus from The fever pattern is less clear-cut as a rule than an osteomyelitic lesion of the sternoclavicular that of typhoid fever and is frequently of an joint in a case of' typhoid fever,' and introduced irregular and intermittent character. Bradycardia the term paratyphoid fever. Two years later in is not typical as in typhoid fever. On the whole a similar way Gwyn isolated an organism which he the overwhelming toxaemia of the ' typhoid state ' called a paracolon bacillus. Gwyn's organism was is absent except in paratyphoid C fever and in some subsequently isolated by Schottmiiller (I900, I90I) cases of paratyphoid A fever ; rose spots are not and by Brion and Kayser (1902), and was so frequent and the illness is generally less severe. designated Bacillus paratyphosum A. Schott- There is, however, a greater tendency in the para- also isolated the of Achard and miiller organism typhoid fevers, and especially so in paratyphoid C Protected by copyright. Bensaude, and it was termed the B. para- fever, to the development of fixation abscesses typhosum B. In I916 Hirschfeld isolated an from which a pure growth of the paratyphoid organism from the blood of a Serbian soldier who bacillus may often be obtained. The development died of paratyphoid fever, an organism for which of such an abscess causes a recrudescence of the he suggested the name B. paratyphosum C. fever and may by reason of its site determine a These organisms and the typhoid bacillus differ fatal outcome. in their pathogenicity and in the type of disease which they cause in man. The typhoid bacillus Less Common Varieties of Enteric Fever and the paratyphoid A and C bacilli are not Several of the salmonella organisms which natural pathogens of animals though the para- commonly cause gastro-enteritis in man have, on typhoid A bacillus has been isolated from the pig occasion, been recovered from the blood stream in (Broudin, I927); they commonly cause enteric cases of continued fever. fever but not acute gastro-enteritis in man. The S. cholerae-suis and its Kunzendorf variant paratyphoid B bacillus, on the other hand, may give rise to a septicaemia and typhoid-like although mainly a human pathogen has been more fever. Boycott and McNee (I936) record a case http://pmj.bmj.com/ often recovered from animals and birds (Hor- of continued fever with a fatal purulent meningitis. maeche and Salsamendi, 1936, 1939; Bartel, S. cholerae-suis was isolated both from the blood 1938; Edwards and Bruner, I943). In man the stream and from post-mortem material. Harvey organism causes enteric fever but may also cause (I937) published 2I cases admitted to the Johns acute gastro-enteritis. Topley and Wilson (1946), Hopkins Hospital over a period of four years however, point out that there are differences be- and found 50 other cases in the literature. tween the strains causing enteric fever and Schwabacher, Taylor and White (I943) mentioned on September 28, 2021 by guest. gastro-enteritis. a further I7 cases in the literature following In general the dose of paratyphoid organisms Harvey's paper and added two fatal cases of their required to produce infection is greater than the own. They suggest that the comparative rarity of corresponding dose of typhoid organisms. Hence the disease in man is related to the relative in- epidemics of paratyphoid fever are less commonly ability of the organisms to establish themselves in water-borne than are epidemics of typhoid fever. the small numbers usually ingested. S. bareilly Infected food and flies are the means whereby was isolated from cases of enteric fever in India paratyphoid fevers are spread. Paratyphoid A by Bridges and Scott (I93I). S. enteritidis was fever is the commoner- in the Middle and Far isolated from cases of enteric fever during the East and paratyphoid B in Western Europe. Chaco War by Savino and Menendez (I934) and Paratyphoid C fever is practically confined to the was a relatively common cause of enteric fever Middle and Far East. during the Japanese Campaign (1942-45). Smith 416 POST GRADUATE MEDICAL JOURNAL September 1949 Postgrad Med J: first published as 10.1136/pgmj.25.287.413 on 1 September 1949. Downloaded from and Scott (I93o) described three cases of con- rise in titre is of no diagnostic significance. On tinued fever in Aberdeen, the infecting organism the other hand the presence of' 0 'agglutinins to being S. dublin. This organism also caused a titre of I/Ioo six months after inoculation is enteric fever as did S. typhimurium amongst suggestive particularly when the titre continues to troops engaged in the recent campaign in Assam rise. In the rare cases in which both 'H' and and Burma. Kerrin, et al., in 1935, and more '0' agglutinins are absent from the blood recently Partington and Cooper (1948) have each throughout the course of the disease, the reported a case of septicaemia due to S. orianen- Vi agglutination reaction may prove helpful burg. (Monthly Bull. Emerg. Publ. Hlth. Lab. Service, These organisms can give rise to enteric fever I943). of varying degree of severity and in some there Leucopenia is usual in typhoid fever and may be may be intestinal ulceration comparable to typhoid of additional assistance in the early stages of the fever. In addition there is a marked tendency to disease, but is by no means the rule in the para- such complications as abscess formation, arthritis typhoid fevers where even a polymorphonuclear and purulent meningitis. leucocytosis may be found. Diagnosis Treatment The first' essential towards early diagnosis of There is considerable controversy in the past typhoid fever is awareness that the disease is literature on how the victim of typhoid fever ought endemic in most countries of the world and hence to be fed ; severely restricted diets and ample cases are liable to be met at any time. Further, diets have both had their proponents. However, enteric fever should be suspected in any case of since the disease lasts for two or three weeks or sustained fever, otherwise inadequately explained even longer and there is no means of foretelling after three and blood culture the and days' duration, how long it may last in individual case, Protected by copyright. carried out. For primary culture a fairly heavy since exhaustion becomes so marked a feature of inoculum of blood into a broth medium contain- the later stages there is now some measure of ing 'liquoide' to eliminate the effect of com- agreement that it is necessary to persuade the plement is probably the best method. Blood patient to take a diet of at least 2,500 calories per culture will generally be positive in the first week day. The diet should be easily digestible with of the disease and with decreasing frequency roughage reduced to a minimum. Glucose, milk, thereafter. At the same time, but with an in- fruit juice, bread and butter, mashed potatoes, creasing frequency of positive results in the minced meat and milk puddings may all be given. subsequent weeks, urine and faeces should be cul- Dehydration tends readily to occur but is obviated tured, ideally using several enrichment media for if the fluid intake exceeds the urinary output by a the latter. Sometimes in the later stages of the litre and a half per day. Relief of symptoms, paratyphoid fevers the organism can be isolated especially cough, headache and hyperpyrexia, from the pus aspirated from an abscess, and very good nursing and the efficient disposal of excreta often in fatal cases of enteric fever of all types, are implicit in good management. from the contents of the gall bladder. Of the complications, meteorism is often most http://pmj.bmj.com/ Isolation of the causative organism thus re- troublesome, but is often relieved by the applica- mains the method of choice not only in establish- tion of heat to the abdominal wall (Jenner's ing an early diagnosis but also as the certain turpentine stupe is surprisingly effective in many method of differentiation between the varieties of cases). In more resistant cases, pituitrin, eserine enteric fever. In convalescence, culture of the and duodenal suction through a Miller-Abbott faeces and urine, and possibly of the duodenal tube may be 'tried. Where haemorrhage occurs

contents after aspiration through a Miller-Abbott the patient should be kept quiet and comfortable on September 28, 2021 by guest. tube, serves to discover which cases become with as little sedation as is necessary. Transfusion transient or chronic carriers (about 2 to 3 per cent. should not be resorted to unless the haemorrhage cases). is gross and continuing. Where perforation The Widal agglutination reaction generally is suspected laparotomy should be carried becomes positive at the end of the first week, but out although it is not often a life saving pro- can only be a contributory diagnostic procedure. cedure. In a patient with no history of inoculation or of During the past ten years efforts have been previous infection a titre of I/50 for 'H' made on a world-wide scale to discover some more agglutinins or of I/Ioo for ' O ' agglutinins in the specific means of treatment and there has been first ten days affords strong presumptive evidence considerable encouragement in the development of infection. In the previously inoculated, 'H' of serum and bacteriophage therapy, of chemo- agglutinins may remain in the blood and even a therapy and of the use of antibiotics. September 949 PATERSON : Typhoid and the Paratyphoids : A Review 4X7 Postgrad Med J: first published as 10.1136/pgmj.25.287.413 on 1 September 1949. Downloaded from Serum Therapy Lister Institute and dispensed in 33 cc. and 66 cc. Grasset and Gory immunized guinea-pigs, quantities. Administration was by intramuscular rabbits and horses and studied the immune sera injection or intravenously in the more toxic cases. at the Pasteur Institute in Paris (Grasset and Gory, 1927a, I927b ; Gory and Grasset, 1928). Grasset Bacteriophage Therapy (1930) then used the immune serum prepared from In I926 D'Herelle suggested the use of bacterio- the horse in a therapeutic trial at Johannesburg, phage in the treatment of typhoid fever, but where he found it of advantage to use local strains though some excellent results were obtained they of the typhoid bacillus in preparing the serum and were, on the whole, variable (Bower, I938). to concentrate the immune serum. Using this Craigie and Brandon (I936a, I936b) then demon- serum he found that in a series of 35 cases treated strated not only specific Vi-anti-typhoid bacterio- during the first 12 days of the disease, 32 showed phage but that there were several such bacterio- considerable remission of fever and decrease of phages, and later Craigie and Yen (1938) showed toxaemic symptoms, and that I9 of 24 cases in that serologically identical strains of S. typhi could which the serum treatment was commenced after be differentiated by the use of specific phages. the twelfth day showed similar though less marked Fisk (I938) and Ward (I943) showed that mice improvement. By 1931 (Grasset, I93i) he was experimentally infected with S. typhi could be using a polyvalent (TABC) serum and had treated successfully by means of parenteral in- treated over 6oo cases, and by 1938 (Grasset, jection of type-specific phage. Knouf and his 1938) was able to report that he had reduced the colleagues (I946) continued Bower's work at Los mortality rate from 20o per cent. to io per cent., Angeles using type-specific bacteriophage in the having treated about 3,500 cases. Furthermore, treatment of 56 patients ; I mi. of the Craigie and where serum had been administered in the first Yen type II phage diluted to 500 ml. with 5 per three days of the disease, the mortality rate fell to cent. glucose was given by slow intravenous drip. Protected by copyright. 3 per cent. Since not all strains are sensitive to this phage and Felix and Pitt (i934) conducted experiments on several days are occupied in testing them, Desran- mice and concluded that a serum having a high leau (I948) used a polyphage (types I to IV) in titre of ' O0' and ' Vi' antibodies was the most 20 cases. effective therapeutic agent. Felix (I935) extended The results were very promising, particularly his investigation to human cases of typhoid fever where treatment was given in the early stages. in Palestine and found a very striking amelioration There is a rigor with a fall in blood pressure and of the toxaemic symptoms following serum in- rise in temperature for a few hours after injection. jection. He attributed this to the ' O' antibodies, The temperature falls to normal within 24 to 48 but was unable to demonstrate that the 'Vi' hours and the 'typhoid state' disappears. Blood antibodies effectively suppressed bacterial in- cultures became negative but three of Desran- vasion -6 he had hoped. A therapeutic serum leau's cases given phage late in the disease became containing both antibodies prepared according to carriers.

the method of Felix and Petrie (1938) and http://pmj.bmj.com/ standardized by Felix' (1938) technique was Chemotherapy and Antibiotics adopted by a League of Nations Commission in Buttle, et al. (I937) demonstrated that sul- 1938 as a standard serum. phanilamide inhibited the growth of S. typhi in With Felix' serum Robertson and Yu (I936) normal blood in vitro though not in broth, and treated 52 patients in Shanghai. Twenty showed that mice could be protected from multiple lethal a decrease in toxaemic symptoms and decrease of doses of S. typhi and S. paratyphi B by its use. pyrexia, and seven a decrease in toxaemic symp- However the sulphonamide drugs alone have not toms only. Cookson and Facey (I937) treated proved to be of value in the treatment of typhoid on September 28, 2021 by guest. 73 cases at Poole, McSweeney (I937) 6i cases at and paratyphoid fevers in man (Medical Research Dublin, Hodgson (I944) 57 cases of whom 25 Council Report, I943). cases had serum, at Liverpool, Pijper and Crocker Bigger (1946) found that the combination of (I939) 36 cases at Pretoria and Landor (194I) penicillin and sulphathiazole had a pronounced used serum at Singapore in a number of cases, bactericidal effect on S. typhi and suggested though he was unable to supervise personally all making use of this synergistic action in treatment. the cases being treated. All of these observers McSweeney (I946) tried this method in six cases confirmed Felix's view as to the value of serum of typhoid fever in Dublin and reported dramatic therapy and Pijper and Crocker considered that improvement. He gave ten.million units of peni- there is a definite relation between the course of cillin and about 34 gm. sulphathiazole in four days the disease and the titre of' Vi' antibodies in the and a second similar course after an interval of two patient's serum. The serum was prepared by the days. Pyrexia subsided, toxic symptoms dis- 418 POST GRADUATE MEDICAL JOURNAL September 1949 Postgrad Med J: first published as 10.1136/pgmj.25.287.413 on 1 September 1949. Downloaded from appeared and the organisms were cleared from the Levi and Willen (I941) reported the cure of a blood, faeces and urine. Parsons (I948) reported chronic typhoid carrier with sulphaguanidine, and on a trial of this method on cases of typhoid fever Loewenthal and Corfield (I943) found this drug in British Military Hospitals in the Middle East, effective in a chronic carrier of B. paratyphosum. but was unable to confirm McSweeney's results. Cutting and Robson (1942), however, failed to Reimann and his colleagues (1945) reported the produce any effect in six chronic carriers after trial of streptomycin in five cases of typhoid fever treatment with iodophthalein, sulphonamides and and considered that it had exerted some bacteri- phenothiazine. cidal effect. They recommended its administra- Bigger's method of employing the synergistic tion by both parenteral and oral routes. action of penicillin and sulphathiazole was applied Chloromycetin, originally isolated from Strepto- to two carriers by Comerford, Richmond and myces venezuelae by Erhlich et al. (I947), was Kay (1946, I947) with success. Fry and his found to be active against rickettsiae, and used colleagues (1948) tried the method on a larger therapeutically in typhus fever due to R. prowa- series of cases but did not have encouraging re- zeki by Smadel and his colleagues (1948). sults though they considered that penicillin was Smadel's group then proceeded to try its effect on excreted in the bile in adequate amount. Rumball scrub typhus fever in Malaya and in so doing and Moore (I949a) cleared a chronic carrier using a accidentally treated and observed its effect on combination of penicillin and sulphamerazine and typhoid fever. Woodward, Smadel and others suggest that it is necessary to maintain the ' blood (1948) reported the first ten cases of typhoid fever sulpha' level at over io mgm. per Ioo ml. in treated with chloromycetin. There is an im- order to obtain the full synergistic effect of mediate improvement in the patient's general penicillin. condition, a lessening of toxicity and a rapid fall Rustein et al. (I945) studied the effect of of temperature. Given orally there is a rapid dis- streptomycin. Parenterally administered strepto-Protected by copyright. appearance of bacilli from the faeces. Murgatroyd mycin had little or no bacteriostatic effect on (I949) reports a case of typhoid fever in which the typhoid bacilli in the faeces, and given orally in favourable outcome may well have been due to capsules the effect was only transitory. chloromycetin therapy, and Bradley (I949) in a Chloromycetin has been used recently in a preliminary communication on the use of chloro- chronic typhoid carrier by Rumball and Moore mycetin in a recent outbreak of typhoid fever (I949b), but although the organism was sensitive to comments on the dramatic relief of symptoms and chloromycetin in vitro, it was not cleared from the pyrexia. Chloromycetin has recently been syn- faeces after chloromycetin had been given in doses thesized and named cbloramphenicol (Brit. Med. of 30 mgm./Kg. body weight for seven days. The J. 1949). The synthetic product is effective in authors state that this dose was about three times typhus, in lymphogranuloma venereum and greater than the calculated therapeutic dose for the in psittacosis, and reports of its use in typhoid acute disease and suggest that even heavier dosage fever are awaited. may'be required for the chronic carrier.

Treatment of Carriers Prevention http://pmj.bmj.com/ The control of the chronic carrier is a trouble- Hygiene. The decline in the incidence of some problem and where the occupation of the enteric fever in this country dates from the passage individual has involved the handling of food, of the Public Health Act of I875, together with subsidies and even threats have been amongst the the abatement of the grosser nuisances. At about many measures to which resort has been made. the same time Max von Pettenkofer had all but It is of small wonder that numerous medical and rid the city of Munich from typhoid by the pro- surgical procedures have been advocated in order vision of a' proper drainage system. Pure water on September 28, 2021 by guest. to rid the unfortunate carrier of his organism. supplies, efficient sewage and garbage disposal, Laxatives, biliary disinfectants, vaccines and and the maintenance of standards of cleanliness phages have generally proved unsatisfactory. for food production and distribution still provide Cholecystectomy, originally suggested by Dehler the best means of limiting the disease. Notification (1907), is in some cases effective (Bigelow and of the disease when it occurs and the search for Anderson, 1933 ; Coller and Forsbeck, I937). and control and treatment of carriers are other Appendicectomy and nephrectomy have also been indispensable measures. carried out. Immunization. The practicability of inoculation Iodophthalein, a biliary antiseptic, was suggested was demonstrated by Wright (Wright and Semple, by Onodera et al. (193I), and several successes I897; Wright, 1902), and he inoculated over have been reported (Saphir and Howell,' 1940; 3,000 troops inIndia and the British Forces in the Enwright, I941 ; Saphir et al., I942). South African War. Russell (I9I3) continued and September x949 PATERSON: Typhoid and the Paratyphoids: A Review 419 Postgrad Med J: first published as 10.1136/pgmj.25.287.413 on 1 September 1949. Downloaded from extended this work in America. Greenwood and BIBLIOGRAPHY Yule demonstrated the lower in- ACHARD, C., and BENSAUDE, R. (x896), Bull. Mim. Soc. Mid. (19I5) markedly HMP., Paris, 13, 8zo. cidence of typhoid fever in a statistical analysis of ANDERSON, E. S., and RICHARDS, H. G. H. (I948), J. Hyg., Camb., 46, x64. the data of the Antityphoid Committee (I913). BARTEL H. (I938), Tieraztl. Rdsch., 44, 6ox. in an account of the BIGELOV, G. H., and ANDERSON, G. W. (I933), Y. Am. Med. Boyd (1943a), experiences Ass.. Iol, 349. gained in P.O.W. Camps near Benghazi where BIGGER, J. W. (1946), Lancet, I, 83 BOWER, A G. (1938), Mil. Surgeon, 3, 70. sanitary conditions were of a very low order, BOYCOTT, J., and McNEE, J. W. (1936), Lancet, 2, 741. evidence of the effectiveness of the BOYD, J. S. K. (I943a), Brit. Med. 3., I, 719. provides strong BOYD J. S. K. (43b), Ibid.,'2, I178. TAB vaccine used by the British Army and BRADLEY, W. H. (I949), Lancet, x, 869. BRIDGES, R. F., and SCOTT, W. M. (I93I), J. Roy. Army Med. demonstrates its superiority to that used by the Cps., 56, 241. Italians. In one where there were about BRION, A., and KAYSER, H. (I902), Munch. med. Wschr., 49, camp 6xi. 24,000 British troops there was an absence of Brit. Med. 3. (I949), Annotation, x, 672. BROUDIN, L. (1927), C.R. Soc. Biol., 97, IS89. enteric fever although it was present among their BUDD W. (I873), ' Typhoid Fever,' London, Longman. Italian captors. In the other camp with Italian BULMER, E. (I943) Brit. Med. 3., , 374. BUTTLE, G. A. H. PARISH, H. J., McLEOD, M., and prisoners, enteric fever was not controlled by their STEPHENSON b. (I937), Lancet, I, 681. CHANTEMESSE, A., and WIDAL, G. F. I. (I888), Ann. de own vaccine but diminished strikingly after the l'Inst. Pasteur, Paris, 2, 54. prisoners had been inoculated with the British COLLER, F. A., and FORSBECK, F. C. (I937), Ann. Surg., O05, 791. Army vaccine. COMERFORD, C. H., RICHMOND, H., and KAY, W. W. (I946), Lancet, 343. An efficient vaccine must be prepared from COMERF6RD, C. H., RICHMOND, H., and KAY, W. W. (I947), virulent strains under standard and controlled Ibid. 2, 808. COOKSON, H., and FACEY, R. V. (1937), Brit. Med. J., x, IOOo. conditions. The British Army TAB was a heat- CRAIGIE, J., and BRANDON, K. F. (I936a), Canad. Publ. Hlt.3., 27, I65. killed, phenol-preserved vaccine. Grasset (x935) CRAIGIE, J., and BRANDON, K. F. (1936b), J. Path. Bact., 43, in South Africa prepared an endotoxoid vaccine 233. CRAIGIE, J., and YEN, C. H. Canad. Publ. Hlth. 3., (1938), 29, Protected by copyright. which was used in South African troops in the 448, 484. CUTTING, W. C., and ROBSON, G. B. (1942), 3. Am. Med. North African Campaign with a protective effect Ass., Ix8, 1447. to that used the British DEHLER (1907), Munch. med. Wschr., 54, 779, 2134. Cited by equal by Army (Boyd, BIGELOW and ANDERSON. I943b). Felix (1941) prepared an alcoholized DESRANLEAU, J. (1948), Canad. Publ. Hlth. J., 39, 317. D'HERELLE, F. (I926), 'Le Bact6riophage et son Comporte- vaccine in which the Vi antigen is destroyed to a ment,' Masson, Paris. lesser extent than in a heat-killed vaccine. EBERTH, C. J. (I88o), Arch. path. Anat., 8i, 58. EDWARDS, P. R., and BRUNER, D. W. (I943), J. Infect. Dis., Although this vaccine has not been used in a field 72, 58. trial on a wide scale, there is no reason to ERHLICH, J., BARTZ, Q. R., SMITH, R. M., JOSLYN, D. A., and BURKHOLDER, P. R. (I947), Science, Io6, 417. doubt that it will be at least as effective as the EMWRITHT, J. R. (I941), 3.. Am. Med. Ass., II6, 220. others. FELIX, A. (x935), Lancet, 1, 799. FELIX, A. (I938), Y. Hyg., Camb., 38, 750. Despite the apparent success of inoculation, FELIX, A. (1941), Brit. Med. 3., x, 391. FELIX, A., and PETRIE, G. F. (1938), Ibid., 38, 673. however, there are those who argue that the real FELIX, A., and PITT, R. M. (I934), Lancet, 2, I86. factor to which the of the incidence of FISK, R. T. (1938), Proc. Soc. Exp. Biol. N.Y., 38, 659. lowering FRY, R. M., JONES, R. E., MOORE, B., PARKER, M. T., and typhoid fever is due rests in improved sanitation. THOMSON, S. (1948), Brit. Med. 3., 2, 295. The of GAFFKY, G. (x884), Mitt. a.d.k. Gesundheitsamte, 2, 372. experience Anderson and Richards (1948) GERHARD, W. W. (x837), Amer. Y. med. Sci 20, 289. http://pmj.bmj.com/ might lead to such a conclusion. They en- GORY, M., and GRASSET, E. (1928), C.R. Soc. Biol., 98, 435. GRASSET, E. (1930), Y. med. Ass. S. Afr., 4, 380. countered an outbreak of typhoid fever in a closed GRASSET, E. (I931), C.R. Soc. Biol., xo6, 8Io. of GRASSET, E. (I935), S. Afr. med. 9, 2o8. community inoculated persons and concluded GRASSET, E. (I938), Quart. Bull. Hith. Sect. L.o.N., 7, 700. that the immunity conferred by TAB inoculation GRASSET, E., and GORY, M. (1927a), C.R. Soc. Biol., 96, x8o. GRASSET, E., and GORY, M. (I927b), Ibid., 97, 12II. cannot be of a high order ; that once there is a GREENWOOD, M., and YULE, G. V. (ig95), Proc. Roy. Soc. breakdown of Med., 8, Sect. Epidem., 113. hygiene and the typhoid bacillus is GWYN, N. B. (I898), Johns Hopk. Hosp. Bull., 9, 54. liable to gain access to the body, the magnitude of HARVEY, A. M. (I937), Arch. Intern. Med., 59, 118.

HIRSCHFELD, L. (I919), Lancet, 1, 296. on September 28, 2021 by guest. the infecting dose and the virulence of the strain HODGSON, A. E. (I944), Brit. Med. ., 2, 339. a part in addition to the resistance of the HORMAECHE, E., and SALSAMENDI, R. (1936), Arch. urug. play Mid., 9, 665. individual. Immunization, therefore, cannot re- HORMAECHE, E., and SALSAMENDI, R. (x939), Ibid., 14, 375. HUXHAM, J. (1739) 'Essay on Fevers,' London. Cited by place hygienic measures and however effective it GARRISON, F. H. (1929), 'An Introduction to the History may be in producing immunity, it ought not to be of Medicine,' W. B. Saunders Coy. JENNER, W. (x849), Monthly J. Med. Sci., Lond. F& Ed., 9, 663. allowed to induce a false sense of security. JOHNS HOPKINS REPORTS (I894-5), 4, I-I70. Anderson and Richards also noted that the JOHNS HOPKINS REPORTS (I895), 5, 280-481. JOHNS HOPKINS REPORTS (I900), 8, I55-487. clinical course of the disease was not significantly KERRIN, J. C., ELDER, A. T., and SMITH, J. (I935), Lancet, I, influenced immunization. 1042. by previous Such, too, KELBS, T. A. E. (I88I), Arch. exper. Path. Pharm., x3, 381. was the conclusion of Bulmer (I943) in a report KNOUF E. G., WARD, W. E., REICHLE, P. A., BOWER, A. G., based on the cases to a and HAMILTON, P. M. (1946), J. Am. Mcd. Ass., x13, i34. admitted military LANDOR, J. V. (I94I), Trans. Roy. Soc. Trop. Med. Hyg., 35, I. hospital in the Middle East over a period of I8 LEVI, J. E., and WILLEN, A. (I94I), 3. Am. Med. Ass., xx6, 2258. LOEWENTHAL, H., and CORFIELD, W. F. (1943), Brit. Med. months. Y., 2, Io52. 420 POST GRADUATE MEDICAL JOURNAL Se.temb'err [949 Postgrad Med J: first published as 10.1136/pgmj.25.287.413 on 1 September 1949. Downloaded from LOUIS, P. C. A. (1829), 'Recherches anatomiques, pathologiques SAVINO, E., and MENENDEZ, P. E. (r934), Rev. Inst. Bact., 6, et th6rapeutiques sur la malade connue sous les noms de gastro- 347. enterite, etc.,' Paris, J. B. Bailldre. SCH(ENLEIN, J. L. (x839), 'Allegemeine und specielle Pathologie McSWEENEY, C. J. (I937), Brit. Med.7., 2, 1118. und Therapie,' Freiburg. McSWEENEY, C. J. (I946), Lancet, 2, II114. SCHOTTMULLER, H. (x900), Dtsch. med. Wschr., 26, 5Ix; Med. Research Council (i943), War Memo. Io. SCHOTTMULLER, H. (i90I), Z. Hyg. Infektkr., 36, 368. Monthly Bull. Emerg. Publ. Hlth. Lab. Service (1943), 2, 59. SCHWABACHER, H., TAYLOR, J., and WHITE, M. H. G. MURGATROYD, F. (I949), Brit. Med. Y., x, 851. (1943), Brit. Med. J., 2, 358. ONODERA, N., MURAKANA, G., and LIU, S. (I93i), Dtsch. SMADEL, J. E., LEON, A. P., LEY, H. L., and VARELA, G. Arch. f. Klin. Med., 171, 503. (I948), Proc. Soc. Exper. Biol. N.Y., 68, 12. PARSONS, C. G. (I948), Lancet, I, SIo. SMITH, J. and SCOTT, W. M. (I930), J. Hyg., Camb., 30, 32. PARTINGTON, C. N., and COOPER, T. V. (1948), Brit. Med. ., STUART, V. E. (I948), Brit. Med. Y., 2, 77. 2, 298. TOPLEY, W. W. C., and WILSON, G. S. (1946), 'Principles of PETIT, and SERRES (I813), 'Trait6 de la fibvre entero- Bacteriology and Immunity,' 3rd ed. Revised by G. S. Wilson mesent6rique,' Paris. and A. A. Miles, London, Edward Arnold & Co. PETTENKOFER, MAX von (I929), cited by GARRISON, TROUSSEAU, M. (I826), Arch. Gin. de Mid., to 67. Quoted by F. H., 'An introduction to the History of Medicine,' W. B. MAJOR, R. H. (I945), 'Classic Descriptions of Disease,' 3rd Saunders Coy. ed. C. C. PIJPER, A., and CROCKER, C. G.'(x939), S. Afr. Med. 7., 13, 255. Illinois, Thomas. REIMANN, H. A., ELIAS, W. F., and RICE, A. H. (i945), WARD, W. E. (z943), J. Infect. Dis., 72, I72. J. Am. Med. Ass., I28, 175. WIDAL, G. F. I., and SICARD, A. (I896), Bull. Mim. Soc. Mid. RITCHIE, C. (I846-7), Monthly J. Med. Sci. Lond. & Ed., 7, 247. H6p., Paris, 3 ser., 13, 68i. ROBERTSON, R. C., and YU, H. (1936), Brit. Med. 7., 2, II38. WILLIS, THOMAS (I684), ' Practice of Physick,' Basset, London. RUMBALL, C. A., and MOORE, L. G. (I949a), Brit. Med. J., , Quoted by MAJOR, R. H. (I945), 'Classic Descriptions of 615. Disease,' 3rd ed. Illinois, C. C. Thomas. RUMBALL, C. A., and MOORE, L. G. (I949b), bid., ., 943. WOODWARD, T. E., SMADEL, J. E., LEY, H. L., GREEN, RUSSELL, F. F. (I913), Harvey Lecture. R., and MANIKAR, D. S. (1948), Ann. Intern. Med., 29, RUSTEIN, D. D., STEBBINS, R. B., CATHCART, R. T., and 131. HARVEY, R. M. (I945), 7. Clin. Invest., 24, 898. WRIGHT, A. E. (I902), Lancet, 2, 65I. SAPHIR, W., BAER, W. H., and PLOTKE, F. (1942), J. Am. WRIGHT, A. E., and LEISHMAN, W. B. (I9oo), Brit. Med. J. Med. Ass., II8, 964. I, I22. SAPHIR, W., and HOWELL, K. M. (1940), Ibid., 114, 1988. WRIGHT, A. E., and SEMPLE, D. (I897), Brit. Med. J., x, 256 Protected by copyright. A SURVEY OF RECENT DEVELOPMENTS IN BLOOD TRANSFUSION PART I By R. DRUMMOND, M.R.C.S.(Eng.), L.R.C.P.(Lond.) Regional Transfusion Officer, Region VIII (Wales)

At the outbreak of the recent world war, the 4. The diagnosis and treatment of haemolytic study of blood transfusion passed from the transfusion reactions, including incompatible clinician to the laboratory worker. Since that transfusion. time bacteriologists, pathologists, serologists, The studyofdisease withthe aidoftransfusion. http://pmj.bmj.com/ geneticists, physicists, biochemists, statisticians 5. and engineers have all played a part in covering a 1. Collection, Storage, Preservation vast field of study. The developments resulting and Handling of Blood. Study of the from their work have been such that it is no easy Survival of Transfused Red Cells. matter for even the full-time laboratory worker to keep abreast of the times. These two articles can Selection of Donors therefore survey only some of the advances, as The past ten years has seen greatly improved seen by the author, which are of common interest standards with regard to blood donation. The on September 28, 2021 by guest. to the laboratory worker and to the clinician. National Transfusion Service permits only healthy will be considered under the persons who have not suffered from certain Developments diseases to be bled. This is essential since the following headings: assurance must be given that blood donation is I. Collection, storage, preservation and harmless. Such an assurance, presumably, has handling of blood. The in vivo survival of always been given, but cannot always have been transfused red cells. justifiable since, persons suffering from certain 2. Plasma. The recognition of homologous diseases, for instance high blood pressure, were serum jaundice. often used as donors, and such persons may suffer 3. Blood grouping and compatibility tests. serious harm when bled, especially repeatedly, Blood group antigens and their practical im- the standard amount (420 cc.). Rigid precautions portance, especially the Rh factor. must be taken to see that donors are in fact