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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-mycetin in the treatment of typhoid fever aresufficiently encouraging to suggest that a newmeasure of control may readily be applied to thisdisease which is endemic throughout practicallythe whole world, and which has carried a mortalityrate such as to have played no small part in history.It is worthwhile, therefore, to review at this timesome of the immense literature which has accumu-lated, 'and in particular to note the variousapproaches that have been made, towards thetreatment and control of typhoid and its relatedfevers.

HistoricalTyphoid fever was prevalent during the

Parliamentary Wars (I642-48), and one of theearliest descriptions was that left by ThomasWillis (i684). Huxham (I739) described thePlymouth epidemic of 1737. There was little dis-tinction drawn, however, during the I8th centurybetween typhus and typhoid fevers. Petit andSerres described typhoid fever in I813, andTrousseau (I826) described the intestinal lesions' both for the glory of my Master and for science,'on behalf of his chief, Pierre Bretonneau, whoseems not to have committed himself to printalthough he did make known his findings to theAcademy. Louis (I829), at La Pitie Hospital alsodescribed the disease and the intestinal lesions,and was the first to use the term' fievre typhoide.'To Gerhard of Philadelphia (i837), who had beena pupil of Louis, must be credited the first clearclinical and anatomical descriptions of the twodiseases. Gerhard's work was substantiatedby 'that of Sch6nlein (i839) in Germanyand of Ritchie (i847) and of Jenner (I849)in Britain. Ritchie introduced the term ' entericfever.'An interesting contribution made before the

bacteriological era was that by Budd (I873) whohad also studied at La Pitie Hospital. He insistedthat typhoid fever was spread by contaminatedwater and milk, the likely contaminant being thefaeces of the convalescent patient. Eberth (I88o)discovered the typhoid bacillus although it islikely that Klebs had recognized it earlier, and inI884 Gaffky obtained the first pure culture of the

bacillus which he showed to be the true activatorof the disease.By i896 Widal and Sicard had demonstrated

specific agglutinins in the serum of typhoidpatients, making possible an agglutination re-action in the diagnosis of the disease, and theexperimental work of Chantemesse and Widal(I898) led to the employment of anti-typhoidinoculation by Wright and Leishman (I900).ClinicalThe most comprehensive analysis of the clinical

course and complications of typhoid fever is to befound in the writings of Osler, Thayer, Flexner,Cushing and others in the Johns Hopkins Reportsof the years i894-95, x895 and I900. Thesepapers present a detailed account of typhoidfever as it occurred in Baltimore over a period ofsome eight years, and are well worthy of study. Atthe same time, however, it is to be rememberedthat typhoid fever is a disease of great variabilityin its virulence, its manner of onset and in theseverity and duration of its course, varying greatlyfrom one outbreak to the next. Hence no greatbenefit is derived from a study of the incidence ofsymptoms, the duration of the fever, the incidenceof complications or even of the mortality rate asthese apply in any one epidemic. Moreover, thispeculiar variability of typhoid fever makes it ex-tremely difficult to assess the value of therapeuticprocedures.

For descriptive purposes it is usual to consideran invasive phase or period of onset, then todescribe the features as they present themselvesfrom week to week ; the febrile period may lastone week only or six weeks or even longer.Period of OnsetThe incubation period may be from one to three

weeks but usually is about ten days. Willis (I684)wrote that ' . . . the first assault is for the mostpart accompanied with a shivering or horror .. .'This is not so, for chills are not a pronouncedfeature of the early stage. Headache, often intense,loss of appetite and malaise are most common.Diarrhoea or constipation, usually the former,may be the earliest complaint. Epistaxis, whichmay be copious, is frequent, and occurs more often

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in typhoid fever than in any other infectiousdisease. Bronchitis is usual and dry cough a verycommon feature. More unusual but no less im-portant are the onset with abdominal pain whichso easily simulates acute appendicitis, and thatwith meningism and photophobia, neck retractionand vomiting, even progressing to a purulentmeningitis (Stuart, 1948).First Week

During the first week the fever which is now theleading feature of the illness, gradually rises in a' staircase ' manner, the evening temperaturebeing a degree or so higher than that of the pre-vious evening, to reach its fastigium at Io4° orIo5' F. This is not necessarily so, however, inthe case which begins with a chill as the fever mayreach its fastigium in a matter of hours and oftenhas done so by the time the patient takes to bed.The pulse is increased in rate but not in proportionto the degree of fever and is of characteristicdicrotic type. The eyes are bright and the faceflushed ; often there is at this early stage a flushover the chest-typhoid erythema. The tonguebecomes coated and the abdomen is slightly dis-tended and vaguely tender. Constipation maynow be the rule rather than diarrhoea.The fever becomes steady with only a small

morning remission and is remarkably resistant toattempts to lower it by means of tepid sponging.It persists towards the second week at which stagea few crops of' rose spots ' appear on the chest andabdomen. Each crop lasts a day or two and isusually seen in approximately 8o per cent. of thosewith fair skins but in not more than a quarter ofthe dark-skinned. At the same time the antibodiesof the infecting organism become demonstrable inthe serum of the majority of cases.

Second WeekThe fever is maintained or may fall to a lower

level though usually still of a remittent character;the pulse is still slow but tends to lose its dicroticcharacter, and the clinical picture depends verymuch upon the severity of the illness. In a mildcase the fever will gradually subside, the tongueclean and the appetite return, and one may wellimagine that resolution is taking place in theturgid and infiltrated lymphatic tissue of theintestine. But in the severe cases toxaemia is thedominant feature and a clouding of consciousness,which is so typical of typhoid fever as to be im-plicit in the name itself (Greek xvcpos, a cloud)and makes the victim of the disease so uncom-plaining, deepens to the much more gross dis-turbance of consciousness of the 'typhoid state.'The eyes sunken but bright and roving, staringbut unseeing, delirium only rarely noisy, restless

movements of the arms and picking at the bed-clothes are all features of the typhoid state, andreminiscent of encephalitis. The skin is hot anddry and often loose from loss of weight and de-hydration. The tongue is dry and dirty andsordes collect on the teeth and at the angles of themouth. The toxic state may be so great as tocause death at this stage, not uncommonly in thefirst half of the second week.Between the tenth and fourteenth days the

enlarged Peyer's patches and lymphoid follicles ofthe intestine undergo necrosis and slough to formulcers. The mesenteric nodes are enlarged,sometimes palpable and tender, and may alsoundergo necrosis. The spleen is enlarged and theliver may be palpable and vaguely tender.Haemorrhage may occur with the sloughing andformation of ulcers and is sometimes accompaniedby a sharp drop in temperature to a subnormallevel. Necrosis and sloughing may be extensiveso that the whole of the mucosa of the terminalileum and caecum appears gangrenous and insuch cases there is marked abdominal tenderness;it is often a very difficult matter to decide whetheror not perforation into the peritoneal cavity hasoccurred.

Third WeekTowards the end of the second week the fever

has become intermittent in character and nowgradually settles by lysis; the pulse, no longerdicrotic, is more in keeping with the temperature;loss of weight is by now very apparent and thepatient is weak and exhausted. Though thedisease process will often subside, other complica-tions are wont to appear at this stage. The sorely-tried gut seems paralysed and meteorism may betroublesome and persistent. In a severelycachetic subject femoral and iliac vein thrombosisand parotitis are not unlikely. Neuritis is commonand the 'tender toes of typhoid' seem to be alocalized form of neuritis. Mental depression maylast long into convalescence.

In subsequent weeks the temperature may re-main well below normal, the hypothermia of con-valescence common to both typhoid fever andmalaria. Sometimes, however, the fever may re-lapse with a fresh invasion of the blood stream bytyphoid bacilli, but often there are rises of tem-perature not accountable in this way, possibly re-lated to too early physical effort or even to con-stipation.A persistent irregular fever in the fifth and sixth

weeks may be related to localization of the in-fection as in mastoiditis, periostitis, pyelitis,arthritis and liver abscess, to a necrotic mesentericlymph node, to secondary pneumonia or to venousthrombosis.

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September I949 PATERSON : Typhoid and the Paratyphoids : A Review 415

Ambulant CasesIt must be mentioned that occasionally the

sufferer from typhoid fever may never complainor take to bed despite high fever and occasionallypatients may be admitted to hospital because ofintestinal haemorrhage or perforation or some-times because of ruptured recti muscles. The ex-planation may be that the clouding of conscious-ness, already referred to, is enough to prevent thepatient realizing how ill he is and enables him tomake light of his symptoms.Paratyphoid FeversAchard and Bensaude (I896) isolated an

organism which was not the typhoid bacillus froman osteomyelitic lesion of the sternoclavicularjoint in a case of' typhoid fever,' and introducedthe term paratyphoid fever. Two years later ina similar way Gwyn isolated an organism which hecalled a paracolon bacillus. Gwyn's organism wassubsequently isolated by Schottmiiller (I900, I90I)and by Brion and Kayser (1902), and wasdesignated Bacillus paratyphosum A. Schott-miiller also isolated the organism of Achard andBensaude, and it was termed the B. para-typhosum B. In I916 Hirschfeld isolated anorganism from the blood of a Serbian soldier whodied of paratyphoid fever, an organism for whichhe suggested the name B. paratyphosum C.These organisms and the typhoid bacillus differ

in their pathogenicity and in the type of diseasewhich they cause in man. The typhoid bacillusand the paratyphoid A and C bacilli are notnatural pathogens of animals though the para-typhoid A bacillus has been isolated from the pig(Broudin, I927); they commonly cause entericfever but not acute gastro-enteritis in man. Theparatyphoid B bacillus, on the other hand,although mainly a human pathogen has been moreoften recovered from animals and birds (Hor-maeche and Salsamendi, 1936, 1939; Bartel,1938; Edwards and Bruner, I943). In man theorganism causes enteric fever but may also causeacute gastro-enteritis. Topley and Wilson (1946),however, point out that there are differences be-tween the strains causing enteric fever andgastro-enteritis.

In general the dose of paratyphoid organismsrequired to produce infection is greater than thecorresponding dose of typhoid organisms. Henceepidemics of paratyphoid fever are less commonlywater-borne than are epidemics of typhoid fever.Infected food and flies are the means wherebyparatyphoid fevers are spread. Paratyphoid Afever is the commoner- in the Middle and FarEast and paratyphoid B in Western Europe.Paratyphoid C fever is practically confined to theMiddle and Far East.

ClinicalThe paratyphoid fevers may produce a picture

similar in all respects to typhoid fever but thetendency to produce necrosis and ulceration of thelymphoid aggregations in the bowel is much less,and is extremely rare in paratyphoid C fever.Catarrhal inflammation of the small bowel andulceration of the large bowel, especially the caecumand ascending colon, are common in paratyphoidB fever and diarrhoea is in consequence a leadingfeature. The lesser tendency to necrosis andulceration means also a much diminished in-cidence of the compli ations of perforation andhaemorrhage.The fever pattern is less clear-cut as a rule than

that of typhoid fever and is frequently of anirregular and intermittent character. Bradycardiais not typical as in typhoid fever. On the wholethe overwhelming toxaemia of the ' typhoid state 'is absent except in paratyphoid C fever and in somecases of paratyphoid A fever ; rose spots are notso frequent and the illness is generally less severe.There is, however, a greater tendency in the para-typhoid fevers, and especially so in paratyphoid Cfever, to the development of fixation abscessesfrom which a pure growth of the paratyphoidbacillus may often be obtained. The developmentof such an abscess causes a recrudescence of thefever and may by reason of its site determine afatal outcome.

Less Common Varieties of Enteric FeverSeveral of the salmonella organisms which

commonly cause gastro-enteritis in man have, onoccasion, been recovered from the blood stream incases of continued fever.

S. cholerae-suis and its Kunzendorf variantmay give rise to a septicaemia and typhoid-likefever. Boycott and McNee (I936) record a caseof continued fever with a fatal purulent meningitis.S. cholerae-suis was isolated both from the bloodstream and from post-mortem material. Harvey(I937) published 2I cases admitted to the JohnsHopkins Hospital over a period of four yearsand found 50 other cases in the literature.Schwabacher, Taylor and White (I943) mentioneda further I7 cases in the literature followingHarvey's paper and added two fatal cases of theirown. They suggest that the comparative rarity ofthe disease in man is related to the relative in-ability of the organisms to establish themselves inthe small numbers usually ingested. S. bareillywas isolated from cases of enteric fever in Indiaby Bridges and Scott (I93I). S. enteritidis wasisolated from cases of enteric fever during theChaco War by Savino and Menendez (I934) andwas a relatively common cause of enteric feverduring the Japanese Campaign (1942-45). Smith

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and Scott (I93o) described three cases of con-tinued fever in Aberdeen, the infecting organismbeing S. dublin. This organism also causedenteric fever as did S. typhimurium amongsttroops engaged in the recent campaign in Assamand Burma. Kerrin, et al., in 1935, and morerecently Partington and Cooper (1948) have eachreported a case of septicaemia due to S. orianen-burg.

These organisms can give rise to enteric feverof varying degree of severity and in some theremay be intestinal ulceration comparable to typhoidfever. In addition there is a marked tendency tosuch complications as abscess formation, arthritisand purulent meningitis.

DiagnosisThe first' essential towards early diagnosis of

typhoid fever is awareness that the disease isendemic in most countries of the world and hencecases are liable to be met at any time. Further,enteric fever should be suspected in any case ofsustained fever, otherwise inadequately explainedafter three days' duration, and blood culturecarried out. For primary culture a fairly heavyinoculum of blood into a broth medium contain-ing 'liquoide' to eliminate the effect of com-plement is probably the best method. Bloodculture will generally be positive in the first weekof the disease and with decreasing frequencythereafter. At the same time, but with an in-creasing frequency of positive results in thesubsequent weeks, urine and faeces should be cul-tured, ideally using several enrichment media forthe latter. Sometimes in the later stages of theparatyphoid fevers the organism can be isolatedfrom the pus aspirated from an abscess, and veryoften in fatal cases of enteric fever of all types,from the contents of the gall bladder.

Isolation of the causative organism thus re-mains the method of choice not only in establish-ing an early diagnosis but also as the certainmethod of differentiation between the varieties ofenteric fever. In convalescence, culture of thefaeces and urine, and possibly of the duodenalcontents after aspiration through a Miller-Abbotttube, serves to discover which cases becometransient or chronic carriers (about 2 to 3 per cent.cases).The Widal agglutination reaction generally

becomes positive at the end of the first week, butcan only be a contributory diagnostic procedure.In a patient with no history of inoculation or ofprevious infection a titre of I/50 for 'H'agglutinins or of I/Ioo for ' O ' agglutinins in thefirst ten days affords strong presumptive evidenceof infection. In the previously inoculated, 'H'agglutinins may remain in the blood and even a

rise in titre is of no diagnostic significance. Onthe other hand the presence of' 0 ' agglutinins toa titre of I/Ioo six months after inoculation issuggestive particularly when the titre continues torise. In the rare cases in which both 'H' and'0' agglutinins are absent from the bloodthroughout the course of the disease, theVi agglutination reaction may prove helpful(Monthly Bull. Emerg. Publ. Hlth. Lab. Service,I943).Leucopenia is usual in typhoid fever and may be

of additional assistance in the early stages of thedisease, but is by no means the rule in the para-typhoid fevers where even a polymorphonuclearleucocytosis may be found.

TreatmentThere is considerable controversy in the past

literature on how the victim of typhoid fever oughtto be fed ; severely restricted diets and amplediets have both had their proponents. However,since the disease lasts for two or three weeks oreven longer and there is no means of foretellinghow long it may last in the individual case, andsince exhaustion becomes so marked a feature ofthe later stages there is now some measure ofagreement that it is necessary to persuade thepatient to take a diet of at least 2,500 calories perday. The diet should be easily digestible withroughage reduced to a minimum. Glucose, milk,fruit juice, bread and butter, mashed potatoes,minced meat and milk puddings may all be given.Dehydration tends readily to occur but is obviatedif the fluid intake exceeds the urinary output by alitre and a half per day. Relief of symptoms,especially cough, headache and hyperpyrexia,good nursing and the efficient disposal of excretaare implicit in good management.Of the complications, meteorism is often most

troublesome, but is often relieved by the applica-tion of heat to the abdominal wall (Jenner'sturpentine stupe is surprisingly effective in manycases). In more resistant cases, pituitrin, eserineand duodenal suction through a Miller-Abbotttube may be 'tried. Where haemorrhage occursthe patient should be kept quiet and comfortablewith as little sedation as is necessary. Transfusionshould not be resorted to unless the haemorrhageis gross and continuing. Where perforationis suspected laparotomy should be carriedout although it is not often a life saving pro-cedure.

During the past ten years efforts have beenmade on a world-wide scale to discover some morespecific means of treatment and there has beenconsiderable encouragement in the developmentof serum and bacteriophage therapy, of chemo-therapy and of the use of antibiotics.

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September 949 PATERSON : Typhoid and the Paratyphoids : A Review 4X7Serum Therapy

Grasset and Gory immunized guinea-pigs,rabbits and horses and studied the immune seraat the Pasteur Institute in Paris (Grasset and Gory,1927a, I927b ; Gory and Grasset, 1928). Grasset(1930) then used the immune serum prepared fromthe horse in a therapeutic trial at Johannesburg,where he found it of advantage to use local strainsof the typhoid bacillus in preparing the serum andto concentrate the immune serum. Using thisserum he found that in a series of 35 cases treatedduring the first 12 days of the disease, 32 showedconsiderable remission of fever and decrease oftoxaemic symptoms, and that I9 of 24 cases inwhich the serum treatment was commenced afterthe twelfth day showed similar though less markedimprovement. By 1931 (Grasset, I93i) he wasusing a polyvalent (TABC) serum and hadtreated over 6oo cases, and by 1938 (Grasset,1938) was able to report that he had reduced themortality rate from 20o per cent. to io per cent.,having treated about 3,500 cases. Furthermore,where serum had been administered in the firstthree days of the disease, the mortality rate fell to3 per cent.

Felix and Pitt (i934) conducted experiments onmice and concluded that a serum having a hightitre of ' O0' and ' Vi' antibodies was the mosteffective therapeutic agent. Felix (I935) extendedhis investigation to human cases of typhoid feverin Palestine and found a very striking ameliorationof the toxaemic symptoms following serum in-jection. He attributed this to the ' O' antibodies,but was unable to demonstrate that the 'Vi'antibodies effectively suppressed bacterial in-vasion -6 he had hoped. A therapeutic serumcontaining both antibodies prepared according tothe method of Felix and Petrie (1938) andstandardized by Felix' (1938) technique wasadopted by a League of Nations Commission in1938 as a standard serum.With Felix' serum Robertson and Yu (I936)

treated 52 patients in Shanghai. Twenty showeda decrease in toxaemic symptoms and decrease ofpyrexia, and seven a decrease in toxaemic symp-toms only. Cookson and Facey (I937) treated73 cases at Poole, McSweeney (I937) 6i cases atDublin, Hodgson (I944) 57 cases of whom 25cases had serum, at Liverpool, Pijper and Crocker(I939) 36 cases at Pretoria and Landor (194I)used serum at Singapore in a number of cases,though he was unable to supervise personally allthe cases being treated. All of these observersconfirmed Felix's view as to the value of serumtherapy and Pijper and Crocker considered thatthere is a definite relation between the course ofthe disease and the titre of' Vi' antibodies in thepatient's serum. The serum was prepared by the

Lister Institute and dispensed in 33 cc. and 66 cc.quantities. Administration was by intramuscularinjection or intravenously in the more toxic cases.

Bacteriophage TherapyIn I926 D'Herelle suggested the use of bacterio-

phage in the treatment of typhoid fever, butthough some excellent results were obtained theywere, on the whole, variable (Bower, I938).Craigie and Brandon (I936a, I936b) then demon-strated not only specific Vi-anti-typhoid bacterio-phage but that there were several such bacterio-phages, and later Craigie and Yen (1938) showedthat serologically identical strains of S. typhi couldbe differentiated by the use of specific phages.Fisk (I938) and Ward (I943) showed that miceexperimentally infected with S. typhi could betreated successfully by means of parenteral in-jection of type-specific phage. Knouf and hiscolleagues (I946) continued Bower's work at LosAngeles using type-specific bacteriophage in thetreatment of 56 patients ; I mi. of the Craigie andYen type II phage diluted to 500 ml. with 5 percent. glucose was given by slow intravenous drip.Since not all strains are sensitive to this phage andseveral days are occupied in testing them, Desran-leau (I948) used a polyphage (types I to IV) in20 cases.The results were very promising, particularly

where treatment was given in the early stages.There is a rigor with a fall in blood pressure andrise in temperature for a few hours after injection.The temperature falls to normal within 24 to 48hours and the 'typhoid state' disappears. Bloodcultures became negative but three of Desran-leau's cases given phage late in the disease becamecarriers.

Chemotherapy and AntibioticsButtle, et al. (I937) demonstrated that sul-

phanilamide inhibited the growth of S. typhi innormal blood in vitro though not in broth, andthat mice could be protected from multiple lethaldoses of S. typhi and S. paratyphi B by its use.However the sulphonamide drugs alone have notproved to be of value in the treatment of typhoidand paratyphoid fevers in man (Medical ResearchCouncil Report, I943).

Bigger (1946) found that the combination ofpenicillin and sulphathiazole had a pronouncedbactericidal effect on S. typhi and suggestedmaking use of this synergistic action in treatment.McSweeney (I946) tried this method in six casesof typhoid fever in Dublin and reported dramaticimprovement. He gave ten.million units of peni-cillin and about 34 gm. sulphathiazole in four daysand a second similar course after an interval of twodays. Pyrexia subsided, toxic symptoms dis-

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appeared and the organisms were cleared from theblood, faeces and urine. Parsons (I948) reportedon a trial of this method on cases of typhoid feverin British Military Hospitals in the Middle East,but was unable to confirm McSweeney's results.Reimann and his colleagues (1945) reported the

trial of streptomycin in five cases of typhoid feverand considered that it had exerted some bacteri-cidal effect. They recommended its administra-tion by both parenteral and oral routes.

Chloromycetin, originally isolated from Strepto-myces venezuelae by Erhlich et al. (I947), wasfound to be active against rickettsiae, and usedtherapeutically in typhus fever due to R. prowa-zeki by Smadel and his colleagues (1948).Smadel's group then proceeded to try its effect onscrub typhus fever in Malaya and in so doingaccidentally treated and observed its effect ontyphoid fever. Woodward, Smadel and others(1948) reported the first ten cases of typhoid fevertreated with chloromycetin. There is an im-mediate improvement in the patient's generalcondition, a lessening of toxicity and a rapid fallof temperature. Given orally there is a rapid dis-appearance of bacilli from the faeces. Murgatroyd(I949) reports a case of typhoid fever in which thefavourable outcome may well have been due tochloromycetin therapy, and Bradley (I949) in apreliminary communication on the use of chloro-mycetin in a recent outbreak of typhoid fevercomments on the dramatic relief of symptoms andpyrexia. Chloromycetin has recently been syn-thesized and named cbloramphenicol (Brit. Med.J. 1949). The synthetic product is effective intyphus, in lymphogranuloma venereum andin psittacosis, and reports of its use in typhoidfever are awaited.

Treatment of CarriersThe control of the chronic carrier is a trouble-

some problem and where the occupation of theindividual has involved the handling of food,subsidies and even threats have been amongst themany measures to which resort has been made.It is of small wonder that numerous medical andsurgical procedures have been advocated in orderto rid the unfortunate carrier of his organism.Laxatives, biliary disinfectants, vaccines andphages have generally proved unsatisfactory.

Cholecystectomy, originally suggested by Dehler(1907), is in some cases effective (Bigelow andAnderson, 1933 ; Coller and Forsbeck, I937).Appendicectomy and nephrectomy have also beencarried out.

Iodophthalein, a biliary antiseptic, was suggestedby Onodera et al. (193I), and several successeshave been reported (Saphir and Howell,' 1940;Enwright, I941 ; Saphir et al., I942).

Levi and Willen (I941) reported the cure of achronic typhoid carrier with sulphaguanidine, andLoewenthal and Corfield (I943) found this drugeffective in a chronic carrier of B. paratyphosum.Cutting and Robson (1942), however, failed toproduce any effect in six chronic carriers aftertreatment with iodophthalein, sulphonamides andphenothiazine.

Bigger's method of employing the synergisticaction of penicillin and sulphathiazole was appliedto two carriers by Comerford, Richmond andKay (1946, I947) with success. Fry and hiscolleagues (1948) tried the method on a largerseries of cases but did not have encouraging re-sults though they considered that penicillin wasexcreted in the bile in adequate amount. Rumballand Moore (I949a) cleared a chronic carrier using acombination of penicillin and sulphamerazine andsuggest that it is necessary to maintain the ' bloodsulpha' level at over io mgm. per Ioo ml. inorder to obtain the full synergistic effect ofpenicillin.

Rustein et al. (I945) studied the effect ofstreptomycin. Parenterally administered strepto-mycin had little or no bacteriostatic effect ontyphoid bacilli in the faeces, and given orally incapsules the effect was only transitory.

Chloromycetin has been used recently in achronic typhoid carrier by Rumball and Moore(I949b), but although the organism was sensitive tochloromycetin in vitro, it was not cleared from thefaeces after chloromycetin had been given in dosesof 30 mgm./Kg. body weight for seven days. Theauthors state that this dose was about three timesgreater than the calculated therapeutic dose for theacute disease and suggest that even heavier dosagemay'be required for the chronic carrier.

PreventionHygiene. The decline in the incidence of

enteric fever in this country dates from the passageof the Public Health Act of I875, together withthe abatement of the grosser nuisances. At aboutthe same time Max von Pettenkofer had all butrid the city of Munich from typhoid by the pro-vision of a' proper drainage system. Pure watersupplies, efficient sewage and garbage disposal,and the maintenance of standards of cleanlinessfor food production and distribution still providethe best means of limiting the disease. Notificationof the disease when it occurs and the search forand control and treatment of carriers are otherindispensable measures.

Immunization. The practicability of inoculationwas demonstrated by Wright (Wright and Semple,I897; Wright, 1902), and he inoculated over3,000 troops inIndia and the British Forces in theSouth African War. Russell (I9I3) continued and

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extended this work in America. Greenwood andYule (19I5) demonstrated the markedly lower in-cidence of typhoid fever in a statistical analysis ofthe data of the Antityphoid Committee (I913).Boyd (1943a), in an account of the experiencesgained in P.O.W. Camps near Benghazi wheresanitary conditions were of a very low order,provides strong evidence of the effectiveness of theTAB vaccine used by the British Army anddemonstrates its superiority to that used by theItalians. In one camp where there were about24,000 British troops there was an absence ofenteric fever although it was present among theirItalian captors. In the other camp with Italianprisoners, enteric fever was not controlled by theirown vaccine but diminished strikingly after theprisoners had been inoculated with the BritishArmy vaccine.An efficient vaccine must be prepared from

virulent strains under standard and controlledconditions. The British Army TAB was a heat-killed, phenol-preserved vaccine. Grasset (x935)in South Africa prepared an endotoxoid vaccinewhich was used in South African troops in theNorth African Campaign with a protective effectequal to that used by the British Army (Boyd,I943b). Felix (1941) prepared an alcoholizedvaccine in which the Vi antigen is destroyed to alesser extent than in a heat-killed vaccine.Although this vaccine has not been used in a fieldtrial on a wide scale, there is no reason todoubt that it will be at least as effective as theothers.

Despite the apparent success of inoculation,however, there are those who argue that the realfactor to which the lowering of the incidence oftyphoid fever is due rests in improved sanitation.The experience of Anderson and Richards (1948)might lead to such a conclusion. They en-countered an outbreak of typhoid fever in a closedcommunity of inoculated persons and concludedthat the immunity conferred by TAB inoculationcannot be of a high order ; that once there is abreakdown of hygiene and the typhoid bacillus isliable to gain access to the body, the magnitude ofthe infecting dose and the virulence of the strainplay a part in addition to the resistance of theindividual. Immunization, therefore, cannot re-place hygienic measures and however effective itmay be in producing immunity, it ought not to beallowed to induce a false sense of security.Anderson and Richards also noted that the

clinical course of the disease was not significantlyinfluenced by previous immunization. Such, too,was the conclusion of Bulmer (I943) in a reportbased on the cases admitted to a militaryhospital in the Middle East over a period of I8months.

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A SURVEY OF RECENT DEVELOPMENTS INBLOOD 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, thestudy of blood transfusion passed from theclinician to the laboratory worker. Since thattime bacteriologists, pathologists, serologists,geneticists, physicists, biochemists, statisticiansand engineers have all played a part in covering avast field of study. The developments resultingfrom their work have been such that it is no easymatter for even the full-time laboratory worker tokeep abreast of the times. These two articles cantherefore survey only some of the advances, asseen by the author, which are of common interestto the laboratory worker and to the clinician.

Developments will be considered under thefollowing headings:

I. Collection, storage, preservation andhandling of blood. The in vivo survival oftransfused red cells.

2. Plasma. The recognition of homologousserum jaundice.

3. Blood grouping and compatibility tests.Blood group antigens and their practical im-portance, especially the Rh factor.

4. The diagnosis and treatment of haemolytictransfusion reactions, including incompatibletransfusion.

5. The study ofdisease with the aid oftransfusion.1. Collection, Storage, Preservation

and Handling of Blood. Study of theSurvival of Transfused Red Cells.Selection of DonorsThe past ten years has seen greatly improved

standards with regard to blood donation. TheNational Transfusion Service permits only healthypersons who have not suffered from certaindiseases to be bled. This is essential since theassurance must be given that blood donation isharmless. Such an assurance, presumably, hasalways been given, but cannot always have beenjustifiable since, persons suffering from certaindiseases, for instance high blood pressure, wereoften used as donors, and such persons may sufferserious harm when bled, especially repeatedly,the standard amount (420 cc.). Rigid precautionsmust be taken to see that donors are in fact

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