January, 1947 MOST UNPHYSIOLOGICAL PERIOD OF LIFE

of them. We will do well to scrutinize each detailof early infant care to determine if it fulfills aphysiological optimum or constitutes simply a com-promise of the normal with hospital, obstetric, andpediatric convenience. Such errors as may havecrept into the management of this period are cer-tainly not chargeable directly to the obstetrician,for the time which has wrought these changes hasbeen one in which the pediatrician has assumed,constantly increasing responsibility in the nursery.

From the standpoint of the pediatrician, at leastof this pediatrician, it seems desirable that attemptsbe made to modify the care of the newborn infantin the foll6wing direction:

1. Mothers should receive a minimum of medica-tion as a preliminary to delivery compatible withrelative freedom from severe pain.

2. Chemotherapeutic and anti-biotic substitutesfor Crede prophylaxis should promptly be exploredand introduced.

3. Maternal nursing should be re-accepted as thenormal method of feeding and honest efforts madeto encourage it, not to defeat it.

4. Added opportunity should be provided formother and infant to effect an acquaintance andadaptation during the lying-in period.

5. Circumcision should not be proposed as anedical necessity unless better justification for itcan be advanced.

REFERENCE

1. McCay, C. M., Crowell, Mary F., and Maynard, L.A.: Problems of Ageing. The Effect of Retarded GrowthUpon the Length of Life Span and Upon Ultimate BodySize, J. Nutrition, 10:63, 1935.

Typhus Fever in the Second World War*J. C. SNYDER, M.D.t New York

IN most of the previous conflicts on the Europeancontinent, typhus fever caused enormous suffer-

ing and loss of life among soldiers and civilians.Because it had played a decisive role in many mili-tary campaigns of the past, typhus was regardedat the outbreak of the second World War as oneof the most dangerous of the potential epidemicdiseases which were expected to occur during orafter the war. Although its toll among civilians incertain regions has indeed been considerable in theyears 1939 to 1946, the recent developments inour knowledge of its, prevention and control haveachieved such remarkable results that the discus-sion of these developments at some length nowseems pertinent. In order to provide a backgroundfor an appreciation of the new methods of combat-ing typhus, I shall review the history of typhus andthen describe the events in the second World Waras they bear on our subject.

Hirsch, in his account of historical pathology says:"The history of typhus is written in those dark pages of

the world's story which tell of the grievous visitations ofmankind by war, famine, and misery of every kind. Inevery age, as far back as the historical inquirer can followthe disease at all, typhus is met with in association withthe saddest misfortunes of the populace; and it is, there-fore, a well-grounded surmise that the numerous pestilencesof war and famine in ancient times and in the MiddleAges, which are known to us, not from medical sourcesbut merely from the chronicles, had included typhus feveras a prominent figure among them."'The earliest scientific discussion of typhus probably is

* Presented before the Los Angeles Academy of Medi-cine, April 25, 1946.

t Staff member of the International Health Division ofThe Rockefeller Foundation, New York City, and memberof the United States of America Typhus Commission,War Department, Washington, D. C.

that of Fracastorius in his famous "De Contagione et Con-tagiosis Morbis" publ-shed in 1546.2 The existence of otherepidemic diseases, such as plague, relapsing fever, small-pox, and typhoid, at one and the same time with typhushad made difficult its recognition as a separate entity.Even the description of Fracastorius is confusing in cer-tain respects, and not until 1837, almost 300 years later,were typhus and typhoid clearly differentiated for themedical profession by an American physician, W. W.Gerhard.3

In the h:story of Europe after the fifteenth century,there is no difficulty in finding reports of many outbreakswhich most certaihly were typhus fever. As early as 1489the Spanish soldiers who had fought against the Turks inCvprus brought tvphus to Spain. At the siege of Granada17,000 men in Ferdinand and Isabella's army died oftyphus. almost six times the number killed in combat withthe Moors.4 Soon thereafter typhus appeared in Italy,where Fracastorius had occasion to study its character-istics. In 1528 the French army besieging Naples was atthe point of decisive victory over the forces of Charles V,a victory which would have had enormous effects on thesubsequent developments in. Europe. But then, as Zinsserput it, "typhus made its political debut . . . by one of themost far-reaching and profoundly effective strokes of itsentire career . . ."5 With great rapidity it struck down30,000 soldiers in the camps of the French, and the rem-nants of the army were forced to withdraw.During this period the battles in the Balkans contributed?

greatly to the spread of typhus across the continent ofEurope. Large forces were assembled from various partsof Germany, Italy, and France and were sent against theTurks, but many of the men fell victims to typhus before-they reached the battlefields. The disease became known asthe "Morbus Hungaricus" as it was disseminated through-out Europe by the soldiers returning from Hungary.6During the seventeenth century typhus continued its ex-

ploits in the almost incessant military struggles of that era,affecting civilians and soldiers alike. During the ThirtyYears' War, when the Swedish army under Gustavus Adol-

4 CALIFORNIA MEDICINE Vol. 66, No. 1

phus was about to launch a campaign against Wallensteinat Nuremberg in 1632, typhus, aided by scurvy, killed18,000 soldiers and forced both armies to withdraw.5

In the century and a half between the Thirty Years'War and the Napoleonic campaigns, typhus contributedalmost continuously to the chronicles of epidemic disease.In the invasion of Russia in 1812, typhus was one of themajor factors in the disaster which befell Napoleon's armyof half a million men. Prinzing gives this account of thecampaign: ". . . When Napoleon's army withdrew fromMoscow it left behind several thousand typhus fever pa-tients, almost all of whom died-only the stronger patientswere taken along on wagons . . . In Vilna, which wasgreatly overcrowded, typhus fever raged furiously. Thelarge number of sick and exhausted soldiers that were leftbehind, owing to the extreme cold . . . sought shelter,partly in private homes, and partly in hospitals., The latterwere in a terrific condition; sick men and dead men werepacked together in the cold unheated rooms, the formerlying on rotten straw, completely deserted, and withoutcare or nourishment. The few unfortunate soldiers whohad survived the awful misery of the march, hungry,clothed in rags, with torn shoes, alive with vermin, withfrozen and gangrenous limbs, scattered in all directions,some going home, and others to strongholds that were inthe hands of the French."7From 1812 we pass over another hundred years to the

first World War and find typhus again striking frightfullyin Serbias89 and later in Russia.10 Estimates place thenumber of cases of typhus fever in Russia as high asthirty million in the years 1918-22 and deaths as manyas three million. Typhus probably has taken as many livesin the past 400 years as have all the weapons of war inthe battles of these blood-drenched centuries.

After surveying this impressive record, it will beof interest to inquire more closely into the charac-teristics of typhus fever. What was known of itsetiology, transmission, prevention, control, andtreatment at the outbreak of the second World War?

STATUS OF KNOWLEDGE OF TYPHUS IN 1939

Etiology. The micro-organism which causesclassical epidemic typhus fever was described in1916 and was given the name of Rickettsiaprowazeki, which honors two of the early inves-tigators who contracted typhus and died. Dr. H. T.Ricketts, an American, and Dr. S. von Prowazek,an Austrian." The term "rickettsial disease" isnow applied not only to typhus fever, but also toseveral other human diseases which are similarclinically to typhus and which are caused by otherrickettsiae. Rickettsiae prowazeki are pleomorphiccocco-bacillary forms which multiply inside certaincells of susceptible hosts. In the classification ofmicro-organisms, rickettsiae occupy a position be-tween bacteria and viruses.

In addition to classical epidemic typhus fever,another form is now recognized-murine typhusfever. The etiologic agent has been named Rick-ettsia mooseri'2 in honor of the Swiss physicianwho observed the micro-organisms in the cells ofinfected guinea pigs. Murine typhus is world widein distribution, occurring sporadically as a rela-tively mild disease with a low mortality. The rela-tionship of murine to classical epidemic typhus is

will be restricted entirely to a consideration ofclassical typhus fever.

Transmission. In 1909, Nicolle, Comte. andConseil discovered that typhus is transmitted bythe body louse, Pediculus humanus corporis.'3Rickettsiae prowazeki are present in the blood ofpatients suffering from typhus during the febrileperiod of the disease. The body louse sucks blood,and the rickettsiae enter the cells lining the intes-tinal tract of the louse. In a few days the rickettsiaehave multiplied so profusely that the cells contain-ing them are swollen and may burst, liberating theorganisms, which may then be passed in the fecesof the louse or may enter still other cells. Even-tually, the typhus-infected lice die of intestinalobstruction caused by the enormous swelling ofthe lining cells. Lice tend to leave febrile patientsin favor of persons with normal temperatures, andlikewise they quickly abandon a corpse and seek a

new host. Each time a louse bites, it makes a smallpuncture in the skin, and it also defecates as itsucks blood. The site of the louse bite is somewhatirritating, and the person tends to scratch, thusrubbing the feces of the louse into the skin, prob-ably over the puncture. This is the usual way inwhich the infection is passed from man to man. Itis also possible to become infected by crushingan infected louse on the skin, by rubbing the in-fected feces into the eyes, or by having dried fecesof the infected louse gain access to the conjunctivaeor the mucous membranes of the respiratory tract,as an airborne infection. It is important to recallthat the typhus infection in lice establishes itselfafter an incubation period, just as it does in man.The period of maximum danger of spread of typhusfrom a louse-infested patient to other persons ex-

tends into the first two weeks of convalescencewhen the victim becomes ambulatory. The hazardin handling corpses within a few hours after deathis obvious. Once deloused and bathed, however,typhus patients are not capable of transmitting theinfection to other persons by contact; Rickettsiaprowazeki does not occur in human saliva, sp,utum,urine, or feces, unless blood is also present (litera-ture reviewed in"4 15).

Louse control. Shortly after the role of the lousein typhus transmission was discovered, demonstra-tions of the efficacy of delousing in controllingepidemics of this disease were made in NorthAfrica in 191214 and in Serbia in 1915.1 It wasestablished that effective delousing of a communitystopped typhus. At that time and until veryrecently, the procedure for delousing required theinfested persons to remove all of their clothes,which were then subjected to heat while the per-sons bathed. When large numbers of persons were

involved, this process was very cumbersome, expen-sive, and time consuming. People objected to thedamage done to their only garments by the heatingprocess, particularly if moist heat was employed.Furthermore, shortages of fuel and apparatus forheating the clothing were the rule under thoge- cir-

most interesting but our attention in this discussion

4

cumstances which'fostered the outbreaks.of typhus.

TYPHUS FEVER

In addition, reinfestation of persons deloused bythis method could, and usually did, occur im-mediately, unless very careful segregation was

achieved. The conditions which predispose tolouse infestation, and consequently to epidemictyphus, are shifting of populations, inadequate andtemporary housing, crowding of people together,lack of facilities for bathing, and weather so coldthat people tend to leave their garments on con-

tinuously day and night, for weeks or months at a

time. It is obvious that under such conditions, a

very efficient organization and an abundance offuel are essential for satisfactory delousing. Thatthis combination has been extremely difficult toobtain is grimly shown by the numerous severe

epidemics of typhus which have occurred in vari-ous countries despite full appreciation of the factthat effective delousing would stop the outbreaks.More practical and rapid methods of delousingwere urgently needed.

Vaccination. Following the discoverey of theetiologic agent of typhus fever, many efforts were

made to develop a satisfactory vaccine against thedisease. These attempts were made in the face ofseveral obstacles. First, Rickettsia prowazeki doesnot grow in the absence of living cells; cultivationof the organism was possible only in lice, or vari-ous animal tissues. Second, vaccination with livingrickettsiae of murine typhus, which appeared to bea safe procedure when applied to natives in NorthAfrica, proved to be dangerous for Europeans.'6Third, there was a real hazard in working withtyphus in the laboratory. Several of the early inves-tigators contracted typhus and died.

Contributions toward the solution of the problemof obtaining large quantities of rickettsiae had beenmade prior to 1939. Zinser and Castaneda17 foundthat x-rayed rats could be used to produce murinerickettsiae in abundance. Castaneda 18 introducedthe method, for the preparation of murine vaccinefrom the lungs of rodents. Durand and Giroud"9

made epidemic louse-borne rickettsial vaccine frommouse lungs. Cox 20.21 devised a method even more

practical and satisfactory by utilizing the yolk sac

membrane of developing chick empryos as a growthmedium for rickettsiae of various types. But, in1939, there was no evidence bearing on the efficacyof any of the newly developed vaccines under epi-demic conditions, and it was obvious that Weigl'svaccine, made from the intestines of lice,22 was notsuitable for mass production. Thus, a great deal ofinformation was needed in regard to the recentvaccines.

Treatment. In 1939 no chemotherapeutic agentshad been found for typhus. Immune serum fromhumans and animals had not had an impressiveeffect on the course of the illness. Typhus, beinga disease closely associated with human misery,nearly always occurred under precisely those con-

ditions in which the hospital facilities and medicalstaffs were either sorely taxed or virtually non-

existent. For this reason, relatively few studies hadbeen made of the pathologic physiology of typhus.Indeed, the information in the classic monographof Wolbach, Todd, and Palfrey,23 published in1922, had not been advanced appreciably in regardto the clinical and pathological findings in typhus.

EXTENT OF TYPHUS FEVER OUTBREAKS IN CIVILIAN

POPULATIONS BETWEEN 1939 AND 1945

Having reviewed the record of typhus in orderto call to mind its potentialties as a scourge, andhaving mentioned the principal gaps in our knowl-edge of certain aspects of the disease, we mustagree with those who, in 1939, feared that thesecond World War would provide on an unprece-dented scale the mass misery and famine in whichtyphus has always exacted its heavy toll. The fig-ures which are available for the reported cases oftyphus in certain of the countries in the war area

are presented in Table 1. It may safely be assumsdthat these figures contain numerous inaccuracies.

TABLE 1.-Reported Cases of Typhus Fever For 1940 to 1945 Inclusive For Certainof the Countries in the War Areas.

1940 1941 1942 1943 1944 1945England ............... 1 ... ... 26France ................. 2 230 ? 11? 303Spain .................. 14 9,560 4,144 640 498 27Italy ................... ... ... 699t 1,215t 198Germany ............... 230 2,158 2,043 5,058 2,467 18,000tPoland ................. 12,000* ? ? ? ? 14,000Bulgaria ............... 155 281 709 1,843 702 979Rumania ............... 1,403 1,827 3,992 8,441 6,0004 8,244Hungary ............... 93 652 827 1,012 3,336Greece ................. 43 7 ? 99 388 697Yugoslavia ............. 282 86? ? ? 8,243 2,285Turkey ................ 716 704 427 4,234 3,121 2,700Iran ................... 256 115 907 12,885 6,436 826Egypt .................. 3,636 9,324 32,288 40,084 18,533 15,746Tunisia ................ 651 7,078 16,295 356? 1,007 403Algeria ................. 2.146 12,827 35,205 8,321 1,770 1,024.Morocco ............... 355 1,471 25,846 16,191 2,928 8.243China .................. 2,191 245 369 12? 141 1,874Japan .................. 2 864 ? ? ? ?The figures are compiled from the United States Public Health Reports, vols. 56-61,

except as noted: * League of Nations Bulletin, vol. 10, 1942-43. t U.S.A. Typhus Com-mission files. $ Reports for year incomplete.

January, 1947 5

CALIFORNIA MEDICINE

Observers who were present during some of theoutbreaks are well aware of the inadequacy of thecase reporting facilities and of the unwillingness ofofficials in some places to admit the extent of thetyphus problem in their areas. Despite inaccuracies,however, the table provides us with much informa-tion.

Several points should be emphasized. Some ofthe countries in which typhus had appeared eachwinter in outbreaks of small size before 1939 expe-rienced large increases in the war years, forexample, Morocco, Algeria, Tunisia, Egypt, Iran,Turkey, Yugoslavia, and probably Poland, althoughinformation from the areas occupied by the Ger-mans and the Russians is incomplete.

Typhus appeared in epidemic form in a fewcountries usually free of the disease, notably Spain,Italy, and Germany. The cases reported for Eng-land and France occurred largely in repatriatedpersons who traveled to those countries during theincubation period of the disease.A glance at the figures for the years 1940 and

1941 shows that the areas in which Allied opera-tions occurred in late 1942 were suffering fromsevere outbreaks. Our troops were exposed to therisk of infection by contact with native populations.Furthermore, our forces entered Naples in October,1943, just as that badly overcrowded and heavilybombed city was being thoroughly seeded withepidemic typhus. In the same year our troopsstationed in Iran and in Egypt were exposed to theinfection that was at its height in those countries.

In 1944 the operations of the Yugoslav forceswhich were effectively pinning down several divi-sions of the German army were severely handi-capped by the spread of typhus not only among thecivilian populations but also in the Yugoslav armyitself.

In 1945 as the Allied armies reached and passedthe Siegfried Line, typhus was encountered amongthe "slave laborers" and among the residents ofthe city of Cologne. Many of the German campscontaining prisoners of war were found to have ac-tive typhus cases at the time the inmates wereliberated. But bv far the most serious situationswere found in the notorious concentration campswhere the Germans had assembled political prison-ers as well as ordinary criminals from all parts ofthe continent. The incredibly horrible conditionsexisting in Buchenwald, Belsen, Dachau, Mauthau-sen, Flossenburg, and Vaihingen, to mention a few,have been described in the press and discussed insome of the war crime trials. Typhus contributedto the horrors of these camps. It is probable thatmore than 90 per cent of all the typhus cases inGermany and Austria in 1945 occurred among theinmates of the concentration camps. As the Ger-man armies retreated, they tried at first to take alltheir prisoners to rear areas, and they succeededin transferring 1,000 inmates of the "Death Camp"'near Vaihingen by train to Dachau. These prison-ers were moved despite the fact that the incidenceof typhus was rising sharply in the camp at the

time of the transfer. In early April the militarysituation deteriorated rapidly for the Germans, andtheir attempts to complete the transfer of prisonerswere less successful. A train packed with prisonersfrom Buchenwald took three weeks to reachDachau, a trip of a few hours' duration in ordi-nary times. At Flossenberg the Germans apparentlydid not have any transport available whatever, andthey forced approximately 12,000 of the inmates ofthat concentration camp to march southward; manyfell by the road or were shot if they lagged behind.Discipline finally collapsed when the group wasnear Cham. The fugitives, many of whom weretyphus-infested, scattered into the numerous smalltowns around Cham.

In the fact of the rapid advance of our armies,the Germans then gave up any attempt to moveprisoners. After our armored spearheads liberatedsuch places as Dachau and Mauthausen, a shortinterval elapsed between the removal of the Ger-man guards and the arrival of adequate number ofour infantry to maintain discipline and controlover the camps from the sanitary point of view.In this short interval many louse-infested, typhus-infected inmates "escaped" into the surroundingcountryside. I doubt if there ever has been sucha widespread scattering of typhus in such a shorttime as occurred in April and May, 1945. whenseveral of these concentration camps literally ex-ploded into the adjacent areas. In addition to theconfusion created by the rapid passage of the waracross Germany the situation was further compli-cated by the floods of persons transplanted by theGermans from the occupied countries into Ger-many itself for the purpose of working in the Ger-man war industries. These people were termed"displaced persons" or "D.P.'s" and their exodusfrom Germany created an enormous problem, es-pecially from the point of view of typhus control.Typhus had been seeded among some of the groupsof D.P.'s prior to the arrival of the Allied armieson the scene. They were further exposed to infec-tion by contact with liberated but undelousedconcentration camp inmates who were likewiseseeking the quickest way home and mixing withthe countless streams of displaced persons in theirinformal roadside camps.

In the light of this information, one wonderswhy the figures for the incidence of typhus in 1945were not very much larger than those reported inTable 1, and why typhus has not been a seriousproblem again this winter in the same qreas, oply afew months after the cessation of hostilities. Thosewho participated in the recent developments intyphus control are convinced that the control pro-gram which was worked out by the early part of1944 was highly effective in suppressing the out-breaks of typhus to which it was applied in Italy,24Yugoslavia, Germany and Austria in the zonesoccupied by the Allies. (What has occurred in theRussian areas it not known, since the Russianshave not made available the official figures fortyphus since 1938.) Before describing the new con-trol methods, I wish to emphasize the fact that

Vol. 66, No. I6

TYPHUS FEVER

several groups have participated actively in thisrecent work on typhus: the National ResearchCouncil, the medical departments of the Army andNavy, the United States Public Health Service, theUnited States Department of Agriculture, TheRockefeller Foundation, the United States ofAmerica Typhus Commission, the Connaught Lab-oratory in Canada, the National Institute forMedical Research, members of the Pasteur Insti-tutes in Algeria, Tunisia, Morocco, and Paris,many medical officers in the British and Frencharmies, the officials of the ministries of health inMexico and Egypt.

DEVELOPMENTS IN METHODS OF LOUSE CONTROL

Early in 1942 two groups in America took up anintensive search for more practical methods oflouse control: the entomologists of the Bureau ofEntomology and Plant Quarantine of the UnitedStates Department of Agriculture, and staff mem-bers of the International Health Division of TheRockefeller Foundation. Antilouse powders suit-able for application to the clothing were developedand tested in Florida25 and also in New Hamp-shire.26

In December, 1942, the United States of AmericaTyphus Commission was created by executive orderof the President "to formulate and effectuate aprogram for the study of typhus fever and the con-trol thereof, . . ."27 In 1943 both the Typhus Com-mission and The Rockefeller Foundation undertookfield trials of newly devised antilouse powders inEgypt,28'29 Mexico,30 and North Africa.3' By the endof 1943 methods for the application of thesepowers had been worked out29'31 whereby jargenumbers of people could be treated without remov-ing their garments. The powder was shown to beeffective When blow into the hair, up the sleeves,down the neck, around the waist into trousers.The first antilouse powders had pyrethrum as

one of the principal ingredients. Such powdershad certain disadvantages. The supply of pyre-thrum was limited, and the effect of the powdercontaining it was of relatively short duration.There was, therefore, an urgent need for a syn-thetic substance, easy to manufacture, safe to useon human skin, and long lasting in its effect as anantilouse powder. The now famous insect killer,DDT, dichloro-diphenyl-trichloroethane,25 proved tobe nearly the ideal substance. It had been synthe-sized by a German student in 1874, but its use-fulness was not appreciated until a Swiss firm dis-covered its insecticidal properties. Wiesmann ofthe Swiss Agricultural Experiment Station in co-operation with this firm, demonstrated that DDTcould be used for the control of certain agricul-tural pests and houseflies.32 In 1942 the Americanbranch of this company received a sample of DDTas a spray called Gesarol Insecticide. The mate-rial was promptly sent to the United States Depart-ment of Agriculture, whose entomologists eluci-dated the remarkable destructive effect of .the

istration of the National Institute of Health carriedout toxicological tests and gave the verdict that thematerial was safe for use as a powder. Althoughthe manufacture of DDT involved some criticalmaterials and equipment, shortly several plantswere producing large amounts for the use of thearmed forces. The most satisfactory property ofDDT is the persistence of its lethal effect on licefor more than two weeks when dusted into thegarments, or for several weeks when impregnatedfrom an emulsion. Reinfestation of dusted persons

exposed to louse-infested persons was reduced toa negligible degree by this persisting effect ofDDT.The final improvement in delousing technique

was the development by the Army of an air com-pressor which operates ten dust guns simultane-ously. These devices are called power dusters. Theyuse gasoline for fuel and are very simple to oper-ate. By employing power dusters it was possible todelouse more effectively the streams and floods ofdisplaced persons who were pouring out of typhus-infected areas in Germany and Austria as our

armies liberated them. The power dusters wereplaced on the east bank of the Rhine River at thepontoon bridges where the displaced persons werecrossing; they were taken by truck to the concen-tration camps, to the displaced persons centers,to the prisoner of war camps, and to the villages insouthern Germany where secondary cases of typhuswere found.The results of this vigorous delousing campaign

were highly gratifying to those responsible fortyphus control in the European theater. Relativelyfew persons crossed the Rhine barrier into WesternEurope without being deloused with DDT, despitethe suddenness with which many millions of per-sons had to be processed. They many typhus out-breaks all over Germany were promptly handled,and secondary cases in these foci were remarkablyfew. I believe that this reflects great credit on thosewho were responsible for the excellent way inwhich the typhus control program was organized.That the necessary supplies were present on thescene in adequate amounts is likewise a tribute totheir foresight and persistence. They made pos-sible this demonstration that typhus can be con-

trolled quickly under very adverse circumstancesby skillful organization in the application of thenew methods of delousing. However, there mayyet be severe outbreaks of typhus before the war-

torn areas have returned to a more normal stateof affairs if the authorities who are responsible forpublic health in occupied areas do not remain fullyalert to the danger of typhus and do not provideadequate amounts of typhus control supplies wher-ever the need for them may arise.The yolk sac typhus vaccine devised by Cox was

taken to Bolivia and to Spain in 1941 in attemptsto evaluate it under epidemic conditions,33 34 butthese trials were without conclusive results. Sev-eral cases of typhus had occurred among physicians

compound on lice.25 The Food and Drug Admin-

January, 1947 7

n- - . -diseasewho had bee vaec'inated and exposed to, he

CALIFORNIA MEDICINE

in the laboratory. It seemed probable that theirillnesses had been made less severe by the vaccine,but further improvements were sought. To this endit was decided to increase the rickettsial content ofthe vaccine and to introduce certain changes in themethods of preparation intended to improve thepotency and facilitate large scale production.35'36In addition to these changes a much more satisfac-tory method for potency testing of typhus vaccineswas introduced in 1942.36 The very difficult feat ofproducing millions of doses of Cox type vaccinewas accomplished in a relatively short time by sev-eral of the commercial firms under contract withthe government.*

Thus a prodigious amount of typhus vaccine wasmade available for the first time. There wasenough to immunize all of our troops who weresent to areas where they might be exposed toepidemic typhus, and to administer booster doses atproper intervals while the danger of exposure ex-isted. There was enough to permit distribution foruse in the armed forces of our Allies and for usein civilian populations in certain of the dangerzones.The value of Cox type vaccine was demonstrated

in the study undertaken by the United StatesTyphus Commission in cooperation with the Egyp-tian Ministry of Health in Cairo in 1943. There were40,000 cases of epidemic typhus in Egypt in 1943,and several thousand patients were admitted to theCairo Fever Hospital. Many new employees wereadded to the staff to handle this large increase inpatient population. Typhus in previous years hadbeen characteristically severe among the FeverHospital employees, and those who contracted thedisease in 1943 and 1944 without having been vac-cinated were likewise severely stricken. Most of theemployees, however, were vaccinated by the TyphusCommission in that period. It should be stressedthat these employees were exposed to typhus notonly in their hospital duties but also as residentsin the areas of Cairo where the typhus attack ratewas high. There were 61 cases of typhus amongthe vaccinated employees in the two seasons, andof this group only one patient died, a man whosefirst dose of vaccine was given just three daysbefore the onset of illness. Those who had hadtheir vaccine more than 21 days before the onset ofillness had mild, uncomplicated typhus of shortduration.37 From these observations made underactual epidemic conditions, it thus appeared thatCox type vaccine of acceptable potency practicallyeliminated the mortality from typhus fever andrendered the illness,mild and of short duration.

There is another important aspect of typhus vac-cine from the point of view of the possibility ofspread of the disease in a louse-infested commu-nity. The lice which feed on patients who contracttyphus after a course of typhus vaccine developvery few rickettsiae in comparison with lice fromunvaccinated patients. Persons who have had

* Cox himself played an Important role in this respect.

booster doses infect their lice only rarely or notat all.3'839'43 Thus vaccination of a community un-doubtedly will reduce the potentiality for spread ofthe disease by lice.

In addition to the studies in the Cairo FeverHospital the experience of our armed forces con-tributes some evidence for the effectiveness of Coxvaccine. I have already called attention to the highincidence of typhus in the regions into which ourarmies were sent between 1942 and 1945. Officialfigures have not been released by the War Depart-ment, but I am permitted to say that there havebeen fewer than 100 proven cases of classical epi-demic typhus fever in our armed forces during thesecond World War. There have been no deathsfrom typhus among our forces, and indeed noauthentic record has come to our attention of adeath from typhus after Cox vaccine, administeredmore than 21 days before the onset of illness. Incontrast, we may point out that 200 cases of proventyphus in the British forces were mentioned byvan Rooyen,4' and 21 cases with seven deaths weredescribed by Stevens.42** These reports refer to theperiod before general antityphus vaccination wasadopted by the British forces.

It seems safe to assert on the basis of the in-formation now available that Cox type vaccinewhen properly prepared and administered willreduce the mortality from typhus to a negligiblepoint, will lessen the severity of the illness greatly.and should decrease enormously the possibilitv oftyphus attaining epidemic proportions in a thor-oughly vaccinated community.

DEVELOPMENTS IN THE THERAPY OF

TYPHUS FEVER

Developments in the therapy of typhus have beenmade in two directions: first, as regards a betterunderstanding of the pathologic physiology of thedisease, and second as regards specific sero- orchemotherapeutic agents. In the first category be-long the observations on the presence and impor-tance of azotemia in typhus fever.43 It was notedas long ago as 1862 that the blood urea nitrogenwas increased in typhus fever, and several reportsare in the literature confirming this finding. Bycareful observation of the patients on the TyphusCommission ward in the Cairo Fever Hospital dur-ing three seasons it has been possible to advanceour understanding of this phenomenon.43'45 It wasapparent that the development of renal insufficiencywas one of the earliest indications that the courseof the illness would be very severe or even fatal.

** When this article was in preparation, the followingstatement appeared: "In the winter and spring of 1942-43typhus was epidemic in North Africa and there werehundreds of thousands of instances of the disease In thecivilian population. Among American Army personnel whohad been Immunized and reimmunized with the Cox typeof typhus vaccine only two mild cases of the diseasewere recorded in the first four months of 1943, while dur-ing the same period in a comparable group of Alliedtroops among whom vaccination was not initiated untilthe end of February or the first of March, 1943, a totalof 43 cases were recorded, with a case fatality rate ofroughly 30 per cent." Long, P. H., J.A.M.A., 130:985, 1946.

8 Vol. 66, No. I

TYPHUS FEVER

Several factors may participate in the developmentof renal insufficiency in typhus. There may bedamage to the kidneys produced by growth ofrickettsiae in those sites. A rapid drop in systolicblood pressure of a few hours' duration or longermay initiate serious changes in the kidney as a con-sequence of reduced renal blood flow in the periodof hypotension. Severe dehydration may exagger-ate the situation. It is difficult to evaluate thesefactors individually. They are not all uniformlypresent in the patients who develop renal insuffi-ciency, but by directing supportive measures toreduce their influence as much as possible, the pa-tients may be appreciably benefited. For example,careful attention to the fluid intake and outputmakes it possible to reduce the extent of dehydra-tion and to assure an adequate urine volume. Thedrop in systolic blood pressure which is of suchserious prognostic import may be attacked byprompt administration of plasma intravenously.

In the other category, that of specific therapeuticagents, a considerable list of substances receivedattention in the war years. I shall mention just afew of these, and then discuss in some detail theone which seems to me to offer the most promiseat present in the treatment of typhus-the chemical,para-aminobenzoic acid.

Hyperimmune refined and concentrated anti-typhus rabbit serum, prepared in the same waythat the antipneumoccocus rabbit serum was pro-duced,46 was administered to typhus patients inEgypt42 47 and in Germany.48 In the first few daysof illness large amounts of serum seemed to modifythe course of the infection, but the effect was lessstriking in patients who had been sick nearly aweek.An antimalarial drug called sontoquine was used

in typhus by French physicians who felt that itexercised a beneficial influence on the clinical pic-ture.49 The Germans were impressed by the drugcalled rutenol, which is a combination of a nitro-acridin derivative and arsinic acid.50 The Englishworkers found a drug, para-sulphonamidobenza-midine, which had strongly antirickettsial effects inexperimental typhus, but the clinical trial was dis-appointing.51 52 Penicillin was found to have someantirickettsial activity in experiments with eggs andmice,53 but a thorough clinical trial was not carriedout on typhus patients. Toluidine blue and a drugcalled forbisen were shown to be of some valueagainst experimental typhus,54 but these substanceswere not given clinical trial. The common dyemethylene blue was found by three groups of work-ers to possess activity against rickettsiae of tsutsu-gamushi disease,55568 57 and when given in largeamounts, against typhus also.55 Clinical trial inBurma by a United States Navy group indicatedthat methylene blue was difficult to give in adequateamounts by the oral route. Despite its toxicity itseenied to be of benefit by the intravenous route.58The substance which seems to offer promise in

the treatment not only of typhus but also of tsu-tsugamushi disease and perhaps Rocky Mountain

spotted fever as well, is para-aminobenzoic acid,which is referred to as PABA. The effect of thissubstance in experimental murine typhus was firstnoted in 1942 in The Rockefeller Foundation lab-oratory in New York City.59 Its activity was inde-pendently discovered in 1944 by Greiff, Pinkerton,and Moragues.60 PABA was given to patients inEgypt6" in 1943, 1944, and 1945. In Germany itwas used in an attempt to alleviate the severity ofthe typhus outbreak at the concentration camp atDachau in 1945.48 PABA was shown to be effectiveagainst experimental tsutsugamushi disease62 63 andin a clinical study in Burma.64 In 1945 workers inTexas65 and in the Army Medical School66 foundthat PABA has activity against spotted fever. Onehuman case of proven Rocky Mountain spottedfever has been treated with therapeutic amounts ofPABA with apparent benefit.67 Thus this agent seemsto have possibilities for the treatment of at leastfour different rickettsial infections of man. It nowhas been given in large amounts to more than 100patients and appears to be entirely safe for humanuse.68 Precautions are taken to follow the whiteblood cell count, which tends to be depressed by thedrug, and to measure the pH of the urine at fre-quent intervals. It is important to adjust the intakeof bicarbonate to keep the urine neutral or alkalinein reaction to prevent formation of crystals ofPABA in the kidneys. Experimental evidence sug-gests that larger concentrations of PABA are re-quired for an effect against tsutsugamushi diseasethan for typhus.69 Rocky Mountain spotted fevermay be found to respond to smaller concentrationsthan typhus,66 although that should be labeled asspeculation at this time.PABA seems to arrest the progress of typhus and

to permit the immunity mechanisms of the host todeal with the rickettsiae. Direct contact of the or-ganisms with the same concentrations of PABAwhich are attained in the blood of patients has noapparent effect on either the viability of the rickett-siae or on their toxic properties.69 It seems probablethat PABA acts by inhibiting the multiplication ofrickettsiae inside the cells. Whether it affects pri-marily the chemical processes in the cytoplasm ofthe host cells or whether it interferes with theprocesses which take place inside the rickettsiaethemselves is not known.

There is no evidence that PABA will benefit pa-tients who have been ill longer than seven days atthe time treatment is first started. When treatmentis started before the end of the first week of illnessthere seems to be a significant correlation betweenthe duration of fever and the incidence of com-plications on the one hand, and the length of timebetween onset of illness and beginning of treat-ment. It is very difficult to make a diagnosis oftyphus definitely before the appearance of thecharacteristic rash on the fourth or fifth day. Inusing PABA the effort must be made to start ad-ministration of the drug as soon as the diagnosis oftyphus is suspected or established. A more thor-ough appreciation of the value and limitations of

January, 1947 9

10 CALIFORNIA MEDICINE Vol. 66, No. 1

PABA as a therapeutic agent must be derived frommore extensive clinical experience.

SUMMARY

In the past typhus fever has been one of the mostfeared of the epidemic diseases associated withwars and human misfortunes. In the second WorldWar several new methods of controlling the diseasewere applied successfully to the outbreaks in Italy,Yugoslavia, Germany, and Austria. In the tech-nique of delousing, a method has been developedfor application of antilouse powder directly to theclothes of louse-infested persons, without requiringthem to remove their garments. The chemical DDThas been applied on a large scale and has beenfound to be safe and effective as a delousing, agent.Power dusters using DDT powder have greatly in-creased the efficiency and the scope of the delous-ing process. Vaccine of the Cox type has been pro-duced in huge quantities and has been used success-fully by our armed forces. Our information bearingon clinical aspects of the disease has been advanced,and a new drug, para-aminobenzoic acid, has beenfound to offer promise in the treatment not onlyof typhus fever but of other rickettsial infections aswell.The conclusion may be drawn that our knowledge

of typhus has been extended in several fields andthat, if our information is properly applied in thefuture, classical epidemic typhus fever will notcause the suffering and loss of life which it didin the past.

REFERENCES

1. Hirsch, August: Handbook of Geographical andHistorical Pathology, transl,ated by Creighton, London,1:545-546, 1883.

2. Hieronymi Fracastorii, de Contagione et Conta-giosis Morbis et Eorum Curatione, Libri III, translatedby W. C. Wright, New York, pp. 101-102, 1930.

3. Gerhard, W. W.: On the Typhus Fever WhichOccurred at Philadelphia in the Spring and Summer of1836, Am. J. Med. Sc., 20:289, 1837.

4. Villalba, Joaquim: Epidemiologia Espanola, etc.,quoted from Zinsser, H.: Rats, Lice and History, LittleBrown and Co. New York, pp. 242-243.

5. Zinsser, H.: Rats, Lice and History, Little Brownand Co., New York, p. 248, 1934.

6. P?rinzing, Friedrich: Epidemics Resulting fromWars, Oxford, p. 22, 1916.

7. Prinzing, Friedrich: Epidemics Resulting fromWars, Oxford, pp. 115-120, 1916.

8. Strong, R P., Shattuck, G. C., Sellards, A. W.,Zinsser, H., and Hopkins, J. G.: Typhus Fever withParticular Reference to the Serbian Epidemic, HarvardUniversity Press, Cambridge, 1920.

9. Hunter, William: The Serbian Epidemics of Typhusand Relapsing Fever in 1915, Proc. Royal Soc. Med.,13:29-158, 1919.

10. Beeuwkes, H.: American Relief AdministrationBulletin, Series 2, No. 45 (April), 1926.

11. da Rocha Lima, H.: Zur Aetiologie des Fleck-fiebers, Befl. Klin. Wochenschrfs., 1:567, 1916.

12. Monteiro, J. L.: Estudios Sobre o Typho Exanthe-matico de S. Paulo, Memorias do Instituto Butantan,6:131, 1931.

13. Nicolle, C., Comte, C., and Conseil, E.: Transmis-sion Experimentale du Typhus Exanthematique Par lePou du Corps, Compt. Rend. Acad. des Sc. De Paris,149:486, 1909.

14. Otto, R., and Munter H.: Fleckfieber, Handbuchd. Pathog. Mikro-org., 3rd edition, vol. 8, 1107-1262.

15. Buxton. P. A.: The Louse, E:dward Arnold Co.,London, 1939.

16. Palacios, R., Chavez, F., and Avendano, O.: Aisla-miento de Virus Murino de Individuos Inoculados conVacuna Blanc, Rev. del Instituto Bact. de Chile, 4:49.1935.

17. Zinsser, H., and Castaneda, M. R.: A Method ofobtaining Large Amounts of Rickettsia Prowazeki byX-ray Radiation of Rats, Proc. Soc. Exper. Biol. andMed., 29:840-844, 1932.

18. Castaneda, M. R.: Experimental Pneumonia Pro-duced by Typhus Rickettsiae, Am. J. Pathol., 15:467-476, 1939.

19. Durand, P., and Giroud P.: Essais de VaccinationContre le Typhus Historique au Moyen de RickettsiaeTuees Par le Formol, Compt. Rend des l'Acad. des Sc.,210:493-496, 1940.

20. Cox, H. R.: Use of Yolk Sac For DevelopingChick Embryo As Medi=m For Growing Rickettsiae ofRocky Mountain Spotted Fever and Typhus Groups,U.S.P.H. Reports, 53:2241-2247, 1938.

20b. Cox, H. R., and Bell, E. J.: Epidemic and En-demic Typhus: Protective Value For Guinea Pigs ofVaccines Prepared from Infected Tissues of the De-veloping Chick Embryo, U.S.P.H. Reports. 55:110-115.1940.

21. Cox, H. R.: Cultivation of Rickettsiae of theRocky Mountain Spotted Fever, Typhus. and Q FeverGroups in the Embryonic Tissues of Developing Chicks,Science, 94:399-403, 1941.

22. Weigl, R.: Untersuchungen und Experimente anFleckfieberlausen, Die Technik der Rickettsia-Forschung,Beitr. z. Klin. der Infektionskr., 8:353-376. 1920.

23. Wolbach. S. B.. Todd. J. L.. and Palfrey, F. W.:The Etiology and Pathology of Typhus, Harvard Uni-versity Press, Cambridge. 1922.

24. Wheeler, C. M.: Control of Typhus in Italy, 1943-1944, by Use of DDT, Am. J. Pub. Health, 36:119-129,1946.

25. Bishopp. F. C.: The Medical and Public HealthImportance of the Insecticide DDT, Bull. of N. Y. Acad.Med., 21 :561-80. 1945.

26. Davis, W. A., and Wheeler. C. M.: The Use ofInsecticides on Men Artificially Infested with BodyLice, Am. J. Hyg., 39:163-76, 1944.

27. Bayne-Jones. S.: The United States of AmericaTyphus Commission, Army Medical Bulletin, No. 68.4-15, 1943.

28. Soper, F. L., Wheeler, C. M., and Snyder, J. C.:Report to the Director of the U.S.A. Typhus Commis-sion (June), 1943.

29. Report to Typhus Conference, London, November-11, 1943, on Experiments in Egypt by C. M. Wheeler.

30. Davis, W. A., Juvera, F. M., Lira, P. H.: Studieson Louse Control in a Civilian Population, Am. J. Hyg.,39:177-88, 1944.

31. Soper, F. L., Davis, W. A., Markham. F. E.. Riehl,L. A., and Buck. P.: Louse Powder Studies in NorthAfrica (1943), Arch. de l'Inst. Past. d'Algerie, 23:183-223, 1945.

32. Wiesmann, R.: Quoted from 25.33. Rockefeller Foundation, Annual Report, 1941, New

York, N. Y.34. Dyer, R. E., and Topping, N. H.: Personal com-

munication to the author.35. Craigie, J.: Application and Control of Ethyl-

Ether-Water Interface Effects to the Separation ofRickettsial from Yolk Sac Suspensions, Canad. J. Res.,E, 23:104-14, 1945.

36. Topping, N. H.. Bengtson, I. A., Henderson R. G.,Shephard. C. C., Shear, M. J.: Studies of TyphusFever, National Inst. Health Bull., No. 183, U. S. Govt.Printing Office, Washington, D. C., 1945.

37. Ecke, R. S., Gilliam, A. G., Snyder, J. C.. Yeo-mans, A.. Zarafonetis. C. J., and Murray. E. S.: TheEffect of Cox Type Vaccine on Louse-Borne Typhus-Fever, Am. J. Trop. Med.. 25:447-62, 1945.

38. Smorodintseff, A.: Personal communication to the-author.

39. Wohlrab, R.. and Patzer, G.: Die InfektiositatGeimpfter und Ungeimpfter Flecktyphuskranker, Munch.Med. Wochenschrt., 91:57-59, 1944.

40. Snyder, J. C.. Wheeler. C. M., Yeomans, A., andMurray, E. S.: Paper in preparation.