CHAPTER XII
Diagnosis and Treatment of the Venereal Diseases
Paul Padget, M.D.
HISTORICAL NOTE
The history of the treatment of the venereal diseases in World War II may well begin on 7 June 1940.1 The development and application of the methods of treatment used in the U.S. Army prior to this time have been admirably traced and summarized by Siler,2 and need not be recapitulated.
On 7 June 1940, a meeting of the National Research Council was held in Washington, D.C., to form a subcommittee3 on venereal disease control. The Subcommittee on Venereal Diseases by its terms of reference was charged with making general recommendations to The Surgeons General of the Army and the Navy concerning the prevention and treatment of the venereal diseases and with acting in a consultative capacity on questions in its special field that might originate from the armed services.
Following this, meetings were held at frequent intervals (six between 7 June and 19 July 1940), and on the latter date, detailed recommendations were approved concerning the diagnosis and treatment of each of the commonly recognized venereal diseases. These recommendations were submitted to the parent committee and eventually were transmitted to the respective surgeons general as the official recommendations of the National Research Council. They were subsequently incorporated in Circular Letter No. 18, Office of the Surgeon General, 10 March 1941, which became the first official statement of a policy for the treatment of these infections to come from the Office of the Surgeon General during the period of the emergency which culminated in World War II. Much later, Circular Letter No. 195, Office of the Surgeon General, 1 December 1943, ordered that the treatment of all patients
1The author is indebted to Dr. ThomasH. Sternberg and Dr. Ernest B. Howard for material on care and treatment whichhas been incorporated in this chapter. Acknowledgment is also made of theinvaluable assistance gained from the use of the private files of Dr. JosephEarle Moore, formerly Chairman, Subcommittee on Venereal Diseases, NationalResearch Council.
The final editing of this chapter was completed after the death of Dr. Padget.
2Siler, J. F.: The Prevention and Control of VenerealDiseases in the Army of the United States of America. Army M. Bull. No. 67, May1943.
3The subcommittee was composed of Dr.Joseph E. Moore, chairman, and Drs. Edwin P. Alyea, Walter Clarke, Oscar F. Cox,John F. Mahoney, and John H. Stokes, members. With the exception of Dr. Alyea,who withdrew after the 14th meeting on 11 March 1942, the members served throughout the wartime period. Dr. Perrin H. Long (later Colonel, MC, USAR) served fromtime to time ex officio in his capacity as chairman of the Committee onChemotherapeutics and Other Agents, National Research Council, and as problemsdealt with grew in complexity, other specialists were invited to join thesubcommittee either temporarily or as permanent members.
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hospitalized for venereal disease be on the medical serviceor under the direction of the chief of the medical service unless there werecogent local reasons to the contrary. Distinction was thus made early betweenthe prevention and control of venereal diseases and treatment of the infectedsoldier. In the field, it was sometimes the practice to separate these functionsentirely and, as in the European Theater of Operations, U.S. Army, to havecontrol and preventive measures administered by the Preventive MedicineDivision, Office of the Chief Surgeon, while treatment was supervised by theappropriate consultant of the Professional Services Division, Office of theChief Surgeon. In the Office of the Surgeon General, both preventive andtherapeutic measures were eventually supervised from one office under thePreventive Medicine Service, with free exchange of consultation with theProfessional Service and without losing sight of the fact that the individualsin charge of these activities were dealing with separate problems.
It is in keeping with this medical philosophy that a sectionon the treatment of the venereal diseases appears here. It should be noted thatalthough, to a large extent, the venereal diseases may be grouped for preventivemeasures and although the two most important (gonorrhea and syphilis) at theend of the war responded to the same antibiotic (penicillin), nevertheless theseveral venereal diseases are wholly separate and distinct clinical entities.For purposes of diagnosis and treatment, they will be considered individually.
GONORRHEA
At the beginning of World War II, there was probably noprevalent disease comparable to gonorrhea in the wide disparity between thetherapeutic recommendations of the experts and the care usually accorded theaverage patient. Fortunately, the new methods of treatment were so simple thatby the end of the war the management of gonorrhea in the Army followed in largemeasure the directives prepared by the experts and issued by The SurgeonGeneral.
Prior to the publication of Circular Letter No. 18, there waslittle or no uniformity of practice in the diagnosis and treatment of gonorrheaby medical officers. The older officers of the Regular Army Medical Corps, whohad been trained in the disciplines described by Siler, had in general advancedto supervisory or administrative positions; the medical officers who wereactually treating the patients were young physicians from civilian practice.Each of these groups had had different training and experience; most of them hadlittle or no special knowledge of the management of patients with gonorrhea andfew knew little more about the opinions of the experts than a dim awarenessthat the relatively new sulfonamide drugs were useful in treatment.
Circular Letter No. 18 brought a semblance of order out of the chaos whichthese conditions had fostered. The Army was rapidly expanding, but withunimportant exceptions, the troops were stationed in training camps within thecontinental United States. These camps were adequately supplied
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with cantonment-type hospitals, in which it was usualpractice to have venereal disease wards to which an adequate number ofmedical officers were permanently assigned. All patients with gonorrhea werehospitalized, so that they came under the care of a relatively small group ofmedical officers. Accordingly, the information contained in Circular Letter No.18 had to be disseminated to only a relatively small number of medical officers,many of whom had had no previous training in the management of gonorrhea, butall of whom, actually or from necessity, had a special interest in the problem.This point is important because the contrasting situation will be brought outlater in the discussion of the treatment of gonorrhea on a duty status.
It was the consensus of observers during 1941 and 1942 that in general adetermined and satisfactory effort was made to carry out the provisions ofCircular Letter No. 18. The observed deviations were most frequently carelessness in diagnostic technique, for example, preparation and examination ofsmears by a relatively untrained technician using only methylene blue forstaining; a tendency to prescribe larger total doses of the sulfonamides thanrecommended, either by giving greater individual doses or, more commonly, by alonger course of treatment; and the early and often vigorous use of localmethods of treatment, especially urethral irrigation, prostatic massage, and thepassage of sounds.
The provisions of Circular Letter No. 18 with regard to the diagnosis andtreatment of gonorrhea are of more than passing interest. Under the headingentitled "Diagnosis in the Male," the circular says "a diagnosisof gonorrhea must not be made in the absence of laboratory confirmation * **," although it does provide for emergency treatment without diagnosis incase laboratory facilities are not readily available. The section on thediagnosis in the female is much less definitely phrased and contains the clearimplication that the history of exposure to a known case of gonorrhea may beutilized as presumptively supporting the diagnosis.
The regimen recommended for the treatment of acute gonorrhea consisted of19 gm. of sulfathiazole to be given in 10 days (3 gm. the first day, 2 gm.daily thereafter) in cases which responded well; if the clinical response tosulfathiazole was not satisfactory by the fifth day, sulfapyridine, (3 gm. thefirst day, 2 gm. daily thereafter) was substituted. If this exchange provedbeneficial by the 10th day, this drug was continued until a total of 15 days ofchemotherapy (5 days of sulfathiazole, 10 days of sulfapyridine) had beengiven. If the clinical response to this regimen was not good, the patient wasto be transferred (presumably to a general hospital) for special care.
The test of cure advised for the male was based upon theexamination of gram-stained smears of material expressed by prostatic massagedone weekly for 8 weeks. The use of culture was mentioned, but not emphasized.The test of cure advised for the female was based on smear from the urethra,cervix, and Skene's and Bartholin's glands every 2 weeks for 3 months,with cultures from the same areas monthly on the last day of the menstrualperiod.
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The recommended followup for both sexes included one serologic test forsyphilis done 3 to 4 monthsafter the original infection with gonorrhea.
With the deviations noted, theseprocedures were followed for over a year, but in the winter of 1941-42, Dr. P. S. Pelouze, directly representing The SurgeonGeneral, made personal visits to a number of the larger Army camps, and hisreport occasioned The Surgeon General to write to the chairman of the NationalResearch Council, in part, as follows: "Dr. P. S. Pelouze has justpresented to us some evidence that the recommendations of the Council on thetreatment of gonorrhea may need revision in the light of recent advances in thisfield * * *."4
Accordingly, a revision of Circular Letter No. 18 wasconsidered and approved by the Subcommittee on Venereal Diseases in March 1942, and this eventually appeared in Circular Letter No.74, Office of the Surgeon General, 25July 1942. The important changes included alteration ofthe criteria for diagnosis of gonorrhea in the female to bring them into linewith those previously defined for the male; the recommendation of sulfathiazoleor sulfadiazine as the drug of choice to be administered in a dose of 4 gm. daily for 5 days, this course to be repeated no morethan once; the direction that if sulfapyridine must be used it be given in adose of only 3 gm.daily for 5 days; a relaxation of the test of cure; a marked reduction in theperiod of followup (3 weeksadvised, but not insisted upon); and finally the recommendation "* * * that carefullyselected patients with sulfonamide-resistant infections be given ten hours ofsustained fever therapy * * *" without, however, directions or suggestions as to howthe selection should be made. This deficiency was partially rectified byCircular Letter No. 86, Office of the Surgeon General, 18 August 1942, which designated eight named general hospitals as fevertherapy centers and implied that the final decision as to whether the patientshould be treated with fever should be left to the staff of the hospital towhich he was referred for this treatment.
These eight hospitals soon proved to be insufficient to carefor the mounting load of patients with sulfonamide-resistant gonorrhea. Theaverage rate of cure with the sulfonamides was falling below 75 percent, owing to the development of sulfonamide-resistantstrains of the gonococcus and to the substantial number of chronic cases thatprobably represented relapse after inadequate self-administered treatment. Everystation and general hospital had a mounting backlog of patients with chronicgonorrhea for whom the only prospect of cure and return to duty at that timelay in treatment with fever. Accordingly, at the request of The Surgeon General,a conference was held on 6 April 1943, under the auspices of the Subcommittee on VenerealDiseases on the use of combined fever and chemotherapy in the treatment ofsulfonamide-resistant gonorrhea. The aim of the conference was to prepare adraft of a circular letter to be sent out by the Surgeon General's Office to
4Minutes, Fourteenth Meeting, Subcommittee on the Venereal Diseases, National Research Council, 11 Mar. 1942.
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appropriate military hospitals. The draft was approved by theSubcommittee on Venereal Diseases on 7 April 1943, forwarded to The SurgeonGeneral, and published as Circular Letter No. 97, Officeof the Surgeon General, 12 May 1943. Thisbroadened the base of the number and type of hospitals authorized to administerfever therapy to patients with sulfonamide-resistant gonorrhea and at the sametime protected the patient by defining with great care the criteria for theselection of patients and details for management of therapy. It had been foundthat one session of 8 hours at approximately 106? F. (rectally)would accomplish cure in about 90 percentof patients with sulfonamide-resistant gonorrhea, that half of the failureswould achieve a satisfactory result from a second similar treatment, but thatfever in excess of two such bouts apparently was valueless. No patient,therefore, was to be subjected to more than two 8-hour sessions of inducedfever, even though manifestations of the disease persisted.
Not long afterward, Circular Letter No. 129, Office of the SurgeonGeneral, 22 July 1943, amended Circular Letter No. 74 intwo important particulars. It pointed out that prostatic massage should not bedone as a test of cure of acute gonorrhea and, thereby, served to prevent asubstantial number of relapses and complications occasioned by this procedure.It advised that for patients with gonorrhea treated in hospital the dose ofsulfathiazole or sulfadiazine should be increased to a total of 33 gm., given as an initial dose of 4gm. followed by 1 gm.every 4 hours night and day of 5 days. This, it was hoped, would somewhat reduce the numberof sulfonamide failures.
Treatment on duty status-Prior to the advent of chemotherapy, it hadbeen the custom in the Army to hospitalize soldiers for the treatment ofgonorrhea,5 in spite of the fact that the vast majority of civilian patientswith gonorrhea were treated on an ambulatory basis. The reasons given for thisare well known: The Army in peacetime felt it impracticable to assign alight-duty status, the philosophy being that the soldier either was able forfull duty or belonged in the hospital. During World War I, however, workingquarantine was extensively employed for the treatment of selected cases ofgonorrhea (especially the chronic and recalcitrant), and this procedure waslater authorized by paragraph 7, AR(Army Regulations) 40-235, 11 October1939. Quoting this regulation as authority, Circular Letter No. 18, 10 March 1941,said in part: "Even under ambulatory conditions,acute gonorrhea may be cured by appropriate measures in a large proportion ofcases. Therefore, when considered desirable and local conditions permit, acutegonorrhea may be treated on an ambulatory basis in working quarantine."However, very little use was made of working quarantine or ambulatory treatment.Accordingly, Circular Letter No. 74, 25July 1942, dealt realistically withthe matter, as follows: "In the Zone of Interior and in the communications zone, venereal disease cases will ordinarily be hospitalizedfor treatment during the infectious stages. In order to maintain effectivestrength of organ-
5See footnote 2, p. 409.
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izations during combat, consideration may be given to thetreatment of venereal disease cases on a duty status with their organization inthe combat zone."
In the meantime, however, dissatisfied both with the large number ofhospital beds occupied by patients with gonorrhea, and with the loss of timefrom training, certain posts in the Fourth Service Command (Camp Forrest,Tenn., was apparently the first) had undertaken the treatment of gonorrhea withthe sulfonamide compounds on a duty status. The method seemed to work and,if it could be shown to be therapeutically efficient, might be used morewidely. Accordingly, in November 1942, a board6 was appointed toevaluate the experiences which had so far been gained.7 The board membersproceeded from the Office of the Surgeon General to posts within the FourthService Command where gonorrhea was being treated on a duty status. Their reportrecommended (1) that the policy of treating uncomplicated gonorrhea on a dutystatus be approved and that the adoption of such a policy wherever feasible beencouraged and (2) that because this method may not be equally practicable underall conditions its adoption not be made mandatory.
The recommendations made by this board were officially authorized in January 1943,8and on 1 February 1943, Circular Letter No. 32, Office ofthe Surgeon General, gave in detail directions for the management of patientswith acute gonorrhea while ambulatory.
Following this, the duty-status treatment of acute gonorrhea was undertakenon a large scale, both in the continental United States and in the overseatheaters, but the sulfonamides were so quickly thereafter replaced by penicillin that there was no opportunity to gain a large-scale evaluation of theusefulness of the method. Even a complete study, however, would have beendifficult to evaluate unless the ambulatory method were a marked improvementover treatment in hospital. This is because of the declining percentage of curesalready being observed among hospitalized patients and the great variation inthe interest, training, and experience of the large number of unit medicalofficers who suddenly became responsible for the diagnosis and treatment ofgonorrhea and for the evaluation of results.
Penicillin-The verbal report, early in 1943 (subsequently published inSeptember 1943), byMahoney and his collaborators,9 on the use of penicillin in the treatment ofsulfonamide-resistant gonorrhea, rapidly removed the
6The board wascomposed of Brig. Gen. Henry C. Coburn, Jr.; Col. (later Brig. Gen.) Hugh J.Morgan, MC; Lt. Col. (later Col.) Thomas B. Turner, MC; Col. Alvin L. Gorby, MC;and Maj. (later Lt. Col.) Robert Dyar, MC.
7(1) Letter, Col. John A. Rogers, MC,Executive Officer, Office of the Surgeon General, to Commanding General,Headquarters, Services of Supply, 19 Nov. 1942, subject: Appointment of Board ofInvestigation of the Treatment of Venereal Disease on a Duty Status. (2) Letter,J. F. McGuire, The Adjutant General's Office, to The Surgeon General, 30 Nov.1942, subject: Board of Officers.
8War Department Memorandum W40-2-43,Treatment of Individuals With Uncomplicated Gonorrhea on Duty Status, 19 Jan.1943.
9Mahoney, J. F., Ferguson, C., Buchholtz. M., and VanSlyke, C. J.: The Use of Penicillin Sodium in the Treatment ofSulfonamide-Resistant Gonorrhea in Man. Am. J. Syph., Gonor. & Ven. Dis. 27:525-528, September 1943.
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practical importance of determining the best way of treatingwith sulfonamide. It appeared that penicillin in almost any dosage effected curein a high percentage of cases and in almost miraculous fashion. This wasconfirmed by Herrell and his coworkers.10
This promise of a solution for all increasingly harrassingproblem of the soldier led, in May 1943, to a clinical investigation in 15 Armyhospitals of the use of penicillin in the treatment of this condition. Within arelatively short time, results of the treatment with penicillin of 1,686patients with sulfonamide-resistant gonorrhea were available. The details ofthis study were later published by Sternberg and Turner.11 All of the 1,686patients were men; their ages reflected the usual distribution in the Army atthe time; they had had on the average 58 gm. of a sulfonamide ending at least 5days before penicillin was administered, and 236 had also had treatment withfever. The patients were divided into groups, each group treated with adifferent dose of penicillin. With a dose of 160,000 units or more, 98 percentof the patients achieved cure; as the dose was reduced below 100,000 units, thecure rate fell off rapidly. There were in all (regardless of dosage) 126failures. Of these, 85 were re-treated, all with 100,000 units and 91.8 percentof them were cured. This raised the overall cure rate for two courses oftreatment to 99 percent.
These dramatic results induced The Surgeon General, on 23September 1943, to address a letter to the service command surgeons authorizingthe use of penicillin in the treatment of sulfonamide-resistant gonorrhea. Thedosage authorized was 50,000 units in doses of 10,000 units at 3-hour intervals,with permission to re-treat with 100,000 units administered in 10,000-unit doseshourly in case of failure of the first course. It must be recalled thatpenicillin was in excessively short supply at the time, a fact that seriouslyinfluenced the size of the dose recommended. As the supply improved, this wasincreased to 100,000 units given in 20,000-unit doses by TB MED (War DepartmentTechnical Bulletin) 9, 12 February 1944. About a month later, 6 March1944, TB MED 16 authorized the use of penicillin for the treatment ofsulfonamide-resistant gonorrhea in station hospitals and directed that it shouldbe administered to patients with gonorrhea immediately after failure to respondto one course of a sulfonamide.
As the supply of penicillin increased, its use was extended.On 21 September 1944, TB MED 96 provided for complete replacement ofsulfonamides by penicillin in the treatment of gonorrhea, except for thoseindividuals who failed to respond to penicillin. This bulletin said further thatthe treatment of uncomplicated gonorrhea with penicillin might be carried out asa hospital or dispensary procedure, but recommended that where satisfactorymedical facilities were available hospitalization be avoided. The recommendeddose
10Herrell, W. E., Cook, E. N., and Thompson, L.:Use of Penicillin inSulfonamide Resistant Gonorrheal Infections. J.A.M.A. 122: 289-292. 29 May1943.
11Sternberg, T. H., and Turner, T. B.: The Treatment of Sulfonamide Resistant GonorrheaWith Penicillin Sodium: Results of 1,686 Cases. J.A.M.A. 126: 157-161, 16Sept. 1944.
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was 100,000 units, given in 20,000-unit injectionsintramuscularly every 3 hours for those in hospital, or five injections spacedover an 8-hour period for outpatients. In the event of failure, re-treatmentwith the same dose was suggested, and if the failure persisted, a third courseof treatment with 300,000 units given in 20,000-unit injections at 3-hourintervals was advised. In the event of failure of these three courses ofpenicillin, the treatment of choice would be sulfathiazole in the 33-gm. doserecommended by Circular Letter No. 129. Finally,TB MED 196, 20 August 1945,redefined the criteria for diagnosis and cure and increased the initial dose ofpenicillin to 200,000 unitsadministered in four injections of 50,000 units every 2 to3 hours, depending on whether the patient was hospitalized or being treated onduty status. Patients failing of cure after the first course were to bere-treated similarly with 200,000 units. Those patients who did not respond tothese two courses were to be hospitalized for more complete urological andbacteriological investigation and, if gonococcul infection were proved, to begiven at least 500,000 units of penicillin in 50,000-unit doses every 2 or 3 hours.
It was at first feared that, with the widespread use of penicillin in thetreatment of gonorrhea, the gonococcus might develop penicillin resistanceanalogous to the sulfonamide resistance already encountered. None of the Armymaterial, however, has proved any evidence to that effect, either clinically orin vitro, although the production of penicillin resistance in vitro has beenreported by Dr. Joseph E. Moore.12 As further experience was gained,it became clear that 10 to 15 percent of patients with gonorrhea failed torespond to 100,000 units of penicillin but that most, if not all, would respondto repeated courses or increased doses. Toward the close of World War II,several cases were reported in which penicillin resistance was suspectedclinically, but it was not determined whether these failures of treatment weredue to true penicillin-resistant strains, to insufficient, deteriorated, orsubstandard penicillin, or to failure to detect the true etiological agent,thereby confusing gonorrhea with nonspecific urethritis.
And so the end of the war saw a therapeutic triumph. Penicillin in adequatedosage had solved the problem of sulfonamide-resistant gonorrhea, had provided asubstitute for dangerous, troublesome, and unpleasant fever therapy, hadrelieved general hospitals of rapidly increasing numbers of patients withgonorrhea, and had made of the disease a relatively minor infection, with fewcomplications and with a small noneffective rate. In 1937, complicationsdeveloped in about one-fourth of all cases of gonorrhea in the U.S. Army; in 1944,complications occurred in approximately 1 percent of all cases.13
Penicillin in oil-beeswax-One remaining difficulty was the fact that theonly effective method for the administration of penicillin then known was by
12Moore, Joseph Earle: Penicillin inSyphilis. Springfield, Ill.: Charles C. Thomas, 1946.
13Monthly Progress Report, Army Service Forces, WarDepartment, 28 Feb. 1945, Section 7: Health.
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injection, preferably intramuscular; yet in the usual aqueousor saline solution, penicillin was so rapidly absorbed and excreted that inorder to maintain therapeutically effective blood levels14 it had tobe given no less frequently than every 3 hours.15 A number of investigators had approached thissubject-onegroup attempting to delay excretion by blocking the kidney;16others, to delay absorption by local vasoconstriction17 or by localapplication of ice packs.18 None of these methods was particularlysuccessful. The first satisfactory method for delaying the absorption ofpenicillin with relative uniformity was devised by Romansky and Rittman at theWalter Reed General Hospital, Army Medical Center, Washington, D.C. Theseinvestigators found the injection of a suspension of 300,000 units ofpenicillin, preferably the calcium salt, in 1 cc. of a vehicle consisting ofpeanut oil containing 4.8 percent by weight of beeswax, was followed byassayable blood levels of penicillin from 24 to 36 hours after injection19and produced excellent therapeutic results in patients with acutegonorrhea.20
The Surgeon General then initiated an investigation of thesubject to be carried out, both clinically and in the laboratory, at theRegional Hospital, Fort Bragg, N.C. Partial confirmation of the results of theoriginal investigators was achieved. Over 90 percent of 88 patients with acutegonorrheal urethritis were cured with a single intramuscular injection of300,000 units of calcium penicillin suspended in the oil-beeswax vehicle.21The substance was not entirely without its objectionable features, however.Uniform blood levels were not always obtained, and after appropriateinvestigation these later investigators concluded that the blood levels produceddepended on both
14In October 1948, the previouslyaccepted concept that assayable levels of penicillin concentration in the bloodmust be maintained in order to gain maximum therapeutic effect was being sharplyquestioned. At the time of the development of POB (penicillin in oil-beeswax),however, there was general acceptance of the concept that maintenance of arelatively uniform concentration of penicillin in the blood was necessary formaximum therapeutic effect.
15Rammelkamp, C. H., and Bradley, S.E.: Excretion of Penicillin in Man. Proc. Soc. Exper. Biol. & Med. 53:30-32, May 1943.
16Beyer, K. H.,Woodward, R., Peters, L., Verwey, W. F., and Mittis, P. A.: Prolongation ofPenicillin Retention in Body by Means of Para-Aminohippuric Acid. Science 100:107-108, 4 Aug. 1944.
17Parkins, W. M., Wiley, M., Chandy, J., and Zintel, H. A.: Maintenance of the Blood Level of Penicillin After Intramuscular Injection. Science 101: 203-205, 23 Feb.1945.
18Trumper, M., and Hutter, A. M.:Prolonging Effective Penicillin Action. Science 100: 432-434, 10 Nov. 1944.
19Romansky, M. J., and Rittman, G. E.: Method of Prolonging Action of Penicillin. Science 100: 196-198, 1 Sept. 1944.
20(1) Romansky, M.J., and Rittman, G.E.: Penicillin: Prolonged Action in Beeswax-Peanut Oil Mixture; SingleInjection Treatment of Gonorrhea. Bull. U.S. Army M. Dept. No. 81:43-49, October 1944. (2) Romansky, M. J., Murphy, R. J., and Rittman, G. E.:Single Injection Treatment of Gonorrhea With Penicillin in Beeswax-Peanut Oil;Results in 175 Cases. J.A.M.A. 128: 404-407, 9 June 1945.
21(1) Kirby, W. M. M.,Leifer, W., Martin, S. P., Rammelkamp, C. H., and Kinsman, J. M.: Intramuscularand Subcutaneous Administration of Penicillin in Beeswax-Peanut Oil. J.A.M.A.129: 940-944, 1 Dec. 1945. (2) Leifer, W., Martin, S. P., and Kirby, W. M. M.:The Treatment of Gonococcal Urethritis With Single Injections ofPenicillin-Beeswax-Peanut Oil Mixtures. New England J. Med. 233: 583-586, 15Nov. 1945. (3) Kirby, W. M. M., Martin, S. P., Leifer, W., and Kinsman, J. M.:Maintenance of Therapeutic Blood Concentrations of Penicillin for Twenty-fourHours Following Single Injections of Penicillin-Beeswax-Peanut Oil Mixtures. J.Lab. & Clin. Med. 31: 313-316, March 1946.
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the concentration of penicillin in the vehicle and the totalamount administered. They also found the mixture so viscid as to requireincubation at 37? C. to go through a 17-gage needle and soimmiscible with water that the slightest amount of moisture in the syringe wouldproduce a completely unmanageable gummy, sticky mass. As the war ended, itseemed that the preparation represented a large step forward but that severalimprovements, even perhaps an entire alteration of its composition, would benecessary before it would be suitable for widespread adoption.
NONSPECIFIC URETHRITIS
Although not officially classified as one of the venerealdiseases, nonspecific urethritis22 bears consideration here becauseof its close association with gonococcal urethritis, both because of itsetiology and because of the diagnostic confusion which it so often produced. Thecondition was common, amounting in various experiences from 10 to 40 percent of all cases of urethritis, but unfortunately itwas never subjected to careful study. The diagnosis was made entirely by theexclusion of gonorrhea, and treatment usually began with the method thatcurrently was being employed in the management of gonorrhea. This was commonlyunsuccessful, in which case the patient was referred to the urologist andsubsequently treated by various manipulative procedures at the physician'sdirection. These were also frequently unsuccessful, and eventually the processwas allowed to run its natural course, which tended to be one of greatchronicity. There probably was no disease of comparable numerical importanceduring World War II that was so completely neglected both as to definition ofetiology and as to development of satisfactory methods of treatment.
SYPHILIS
Before and during the early stages of mobilization, that is,prior to the publication of Circular Letter No. 18, 10 March 1941, the diagnosis andtreatmentof early syphilis in the Army essentially followed the recommendations of theCooperative Clinical Studies Group23 as elaborated in the standardtextbooks.24 Neoarsphenamine was the arsenical drug most commonlyemployed; many bismuth compounds were used, although a suspension of thesubsalicylate in oil was perhaps the most frequently employed; and rest periodsby either design or accident tended to be more common than the experts wouldadvise. On the whole, however, standards of practice compared favor-
22There is no useful source materialon nonspecific urethritis in the official records. The material on which thissection is based was assembled by Col. Paul Padget, MC, from conversations withmany medical officers from 1942 to 1945 and recorded in his personal diary.
23Cooperative Clinical Studies in the Treatment ofSyphilis; Early Syphilis. Ven. Dis. Inform. 13: 207-231, 20 June 1932; 253-293,20 July 1932.
24(1) Moore, Joseph Earle: The ModernTreatment of Syphilis. Springfield, Ill.: Charles C. Thomas, 1933. (2) Stokes,John H.: Modern Clinical Syphilology. 2d edition. Philadelphia: W. B. SaundersCo., 1934.
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ably with those of the average health department clinic atthe time. As in health department clinics, however, there was much lessuniformity of practice in the management of the various forms of late syphilis,and from a review of old records, one has the impression that many medicalofficers treating patients with late syphilis were actually treating thepositive blood test rather than the patient. For this, of course, the medicalofficers concerned should not be blamed since it was then, and unfortunatelystill is, likewise common in civilian practice.
In supplying the material upon which Circular Letter No. 18 was based (p. 409),the Subcommittee on VenerealDiseases made norecommendations concerning the management of syphilis which were peculiar to theArmy. Instead, this material represented simply a summary of accepted goodpractices in the diagnosis and treatment of syphilis which were then current inbest civilian practice. In this circular letter, accuracy of diagnosis wasemphasized; necessity for clocklike regularity of treatment was reiterated;Mapharsen (oxophenarsine hydrochloride), at that time the only commerciallyavailable arsenoxide, was recommended as the arsenical drug of choice; andtreatment at weekly intervals was to be continued for 15 to 18 months.
The 18-month system of treatment was impracticable even under the relativelystatic conditions of training. In view of the extent to which all practicaladministrative difficulties would be magnified in an oversea theater,particularly after combat was joined, the need for a shorter method for thetreatment of syphilis became obvious. Accordingly, representatives from theOffice of the Surgeon General had informal meetings with members of theSubcommittee on Venereal Diseases, and at a formal meeting on 27 May 1942, thesubcommittee approved recommendations made by this subgroup. These werepublished in Circular Letter No. 74, 25 July 1942.
The principles of accurate diagnosis and the criteria for cure were notsignificantly changed from the form in which they appeared in Circular LetterNo. 18, but the treatment scheme was compressed into 40 doses of Mapharsen and16 doses of bismuth given over a 6-month period. By this system, Mapharsen wasgiven in two courses of 20 injections, each twice weekly for 10 weeks separatedby 6 weeks of therapy with bismuth, the additional bismuth being given in twogroups of five weekly doses concurrently with the beginning of the first and theend of the second courses of Mapharsen.
According to Sternberg and Leifer,25this treatment system was used in the management of approximately 200,000soldiers with syphilis, with a mortality rate ascribable to treatment of about0.003 percent. In a study of the short-term results in 3,000 soldiers with earlysyphilis, 72 percent of whom had been observed for more than 1 year after thecompletion of the 26-week treatment, they say "* * * the results appear excellent withsatisfactory progress in 98.25 percent of seronegative primary, 94.48 percent of seroposi-
25Sternberg, T. H., and Leifer, W.:Treatment of Early Syphilis by Twenty-six-Week Mapharsen-Bismuth Schedule. Am.J. Syph., Gonor. & Ven. Dis. 31: 124-134, March1947.
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tive primary, and 89.34 percent of secondary cases. There were but 18 (0.64percent) abnormal cerebrospinal fluids among the 2,842 examined."
Intensivearsenotherapy.-As the war progressed, this treatment scheme, later shown tobe therapeutically effective by Sternberg and Leifer, became increasinglyimpractical. Six months under the pressure of war was, comparatively speaking,longer and more intolerable than 18 months in peacetime; biweekly injections for20 of the 26 weeks interfered even with military training. Maintenance ofuninterrupted medical control for the time necessary to complete treatmentbecame increasingly difficult. Only 38 percent of the troops with syphilisregisters who came to the European theater during March 1943 had had as much astwo-thirds of the optimal amount of treatment up to the time of theirembarkation.26 None had been treated in transit, which often had imposed anadditional lapse of many weeks. Consequently, there was widespread pressure topersuade the Army to adopt one or another of the rapid treatment systems whichwere in use or could be made available. The 5-day intravenous drip method27was particularly strongly urged because this scheme, unlike other proposedmethods, had had considerable clinical use just prior to this time. TheSubcommittee on Venereal Diseases reviewed the subject in detail on 13 January1942 and 10 June 1943, and it was taken under advisement by the Committee onMedicine, National Research Council, 16 October 1942. This committee concluded:
That the intensive arsenotherapy of early syphilis (including the five-dayintravenous drip method) be considered as still in the experimental stage; thatthe optimum time-dose relationship still requires to be established by furtheranimal and subsequent clinical experimentation; and that at present the methodcannot be recommended for routine use by the Armed Forces.
The need for a rapid treatment method was so great, however, especially inoversea theaters (fig. 56), that at its 19th meeting, 10 June 1943, theSubcommittee on Venereal Diseases bowed to the continuing pressure of theadvocates of the 5-day intravenous drip technique and passed a series ofrecommendations which had been made at a conference on intensive arsenotherapyof early syphilis held on 19 May 1943. These recommendations read in part, asfollows:
1. Owing to the relatively high mortality rate, no system of intensivearsenotherapy compressed into a period of 2 weeks or less is as yet suitable forroutine adoption by the Armed Forces.
2. For the routine treatment of early syphilis in the Armed Forces the26-week system now in use in the U.S. Army should be continued pending furtherinformation concerning intensive treatment systems.
3. It is hoped that the U.S. Public Health Service will amplify a statisticalevaluation of the several methods of intensive arsenotherapy of early syphilis ** *.
26Annual Report, Senior Consultant in Dermatology, Office of the ChiefSurgeon, European Theater of Operations, U.S. Army, 1943.
27Leifer, W., Chargin, L., and Hyman, H. T.: Massive Dose Arsenotherapy of Early Syphilis ByIntravenous Drip Method; Recapitulation of Data (1933 to 1941). J.A.M.A. 117:1154-1160, 4 Oct. 1941.
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4. In oversea areas, whether advanced training or combat zones, twoalternative methods of intensive arsenotherapy of early syphilis, treatmentcompressed within a period of 2 weeks or less, may be utilized provided: (a)That patients be treated under hospitalized conditions rather than on anambulatory basis, and (b) that treatment be administered under the direction ofspecially qualified personnel.
The two treatment systems recommended for early syphilis werethe 5-day intravenous drip and 10-day multiple syringe technique. It was furthersuggested that the same intensive treatment systems might be utilized in thecontinental United States for selected personnel under the same conditions. Analternative 12-week system was advised in the event that hospitalization was notpracticable. Detailed descriptions of the techniques of the three systems wereprovided.
In the Surgeon General's Office, it was decided to give this scheme anexperimental trial in one large hospital before recommending it for general usein the Army, even in oversea theaters. Accordingly, in July 1943,28 aresearch project was set up at Fort Bragg on the use of intensive doses ofMapharsen by intravenous drip.29 The experiment was terminatedinOcto-
28Memorandum, Lt. Col. Thomas B. Turner, Chief, Venereal Disease ControlBranch, Preventive Medicine Division, for General Kirk, 3 July 1943, subject:Short, Intensive Treatment of Syphilis.
29Fort Bragg was selected not only becauseof its size but because Capt. (later Maj.) Williard Leifer, MC, joint author ofthe original and numerous other papers on the 5-day intravenous-drip techniquewas on duty there.
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ber 1943, when the superiority ofpenicillin became obvious. No new information was obtained from study of thepatients treated up to that time.
In the meantime, in the Office of the Chief Surgeon, European theater (whichwas, because of the disrupted state of communications, virtually isolated fromknowledge of current developments in the Surgeon General's Office), it had beendecided to try an entirely new scheme for the treatment of syphilis withMapharsen. It was undertaken because of the utter impossibility of evenapproximately regular treatment under the existing conditions. Consideration wasgiven to the known facts regarding the toxicity of Mapharsen as determined bythe time-dose relationship. Theoretical considerations and experimental workwith rabbit syphilis, culled from the most recent source material available onmassive arsenotherapy, indicated that the total curative dose of Mapharsen forearly syphilis in the human should be of the order of 20 mg. per kilogram ofbody weight.30 Further, it appeared that the incidence of reactionsis determined almost entirely by the timedose relationship, with a very rapidrise in rate as the total interval for treatment is decreased, becomingintolerable if the treatment interval is reduced significantly below 5 days, butnot decreasing with particular rapidity as the span of treatment is increasedabove 20 days.
With this information, and in consideration of the practical militaryproblems involved, it was decided, for the patient with early syphilis, to giveclinical trial to the following scheme of treatment: One mg. of Mapharsen perkilogram of body weight (but not to exceed a single dose of 75 mg.) was to begiven by syringe daily for 20 days. The choice of a 20-day treatment scheme wasnot only convenient, as it allowed doses of 1 mg. per kilogram per day to total20 mg. per kilogram in 20 days, but was also determined by sound theoreticalconsideration.31 The treatment was carried on in hospital; the patient wascarefully observed both clinically and by laboratory tests. In addition to theMapharsen, he was given at regular intervals 8 doses each of 0.2 gm. of bismuthsubsalicylate suspended in oil; that is, approximately a dose of bismuth everyother day.
Over 4,000 patientswere treated by this method in the European theater, with no deaths. Thetreatment was completed in 96.3 percentof the first 775 patients and in a somewhat higher percentage of the remainder.In one series of 1,343 consecutivecases of early syphilis treated by the 20-day form of intensive arsenotherapy,results of serological tests for syphilis were reported after 6 or more monthsin 982. In 258, followup reports were received more than a year aftercompletion of therapy. Ninety-five percent of both groups had a negativeserological test and a normal cerebrospinal fluid at the time of lastexamination. The time relations of the observed serological relapses were such,however, that approximately twice as many definitely un-
30Moore, Joseph Earle: The Modern Treatment of Syphilis. 2d edition.Springfield, Ill: Charles C. Thomas, 1943.
31See footnote 26, p. 420.
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satisfactory results were noted at the end of 12 months as at the end of 6months after treatment.
The authors who reviewed this material concluded32 that the 20-day scheme for intensive arsenotherapy willyield very satisfactory 1-year results in the treatment of early syphilis butthat when compared to penicillin or penicillin plus chemotherapy given on a lesstoxic schedule it carries an unjustifiable risk. This is illustrated33 byan analysis of 500 consecutive patients who were treated by this method. Fourhundred and seventy-six of these eventually completed the treatment, sometimeswith delays necessitated by minor reactions, but in 24, or 4.8 percent, theprocedure had to be abandoned because of severe reactions. Seven of thesepatients had definite signs of cerebral irritation, and two more presented theclassical picture of hemorrhagic encephalitis. Jaundice occurred in six, toxemia and agranulocytosis in three each, while severe fever occurred in twoand severe albuminuria in one.
Penicillin-In June of 1943, Mahoney and hiscollaborators treated four sailors with early syphilis with penicillin in a doseof 1.2 million units which they had calculated as being the theoretical optimum34 from observations on experimental animals. The resultswere sodramatic that the experiment was immediately extended within the limits imposedby the short supply of penicillin at that time.
This information spread rapidly, largely by word of mouth(all the data concerning penicillin were then classified information). At the20th meeting of the Subcommittee for Venereal Diseases on 29 September 1943,"It was agreed that the clinical and experimental evidence so far availablejustified an extensive trial of penicillin in human beings * * *," and recommendationswere passed for the formation of a penicillin panel, under the National Research Council, to coordinate experimental and clinical trials of penicillinin humans with syphilis which were to be conducted by appropriate facilitiesof the Army, the Navy, the U.S. Public Health Service and eight35 participating civilian clinics. At the first meeting ofthe penicillin panel a month later, six treatment schedules for investigationwere agreed upon. Five of these were to be undertaken immediately, one wasdeferred because of the shortage of penicillin, and the Army agreed tocontribute observations upon
32Pillsbury, D. M., and Loveman, A. B.: Six- toTwelve-Month Follow-Up Results in Early Syphilis Treated by a Twenty-DayIntensive Arsenobismuth System. Am. J. Syph., Gonor. & Ven. Dis. 31: 115-123, March 1947.
33Cormia, F. E., andBlauner, S. G.: Reactions to Twenty-Day Intensive Therapy With Mapharsen andBismuth for Syphilis With a Note on the Use of BAL in Their Management. Am. J.Syph., Gonor. & Ven. Dis. 31: 135-149, March 1947.
34Mahoney, J. F.,Arnold, R. C., and Harris, A.: Penicillin Treatment of Early Syphilis; APreliminary Report. Ven. Dis. Inform. 24: 355-357, Dec. 1943; also Am. J. Pub.Health 33: 1387-1391, December 1943.
35The number was greatly increasedlater, so that at one time there were nearly 40 clinics participating.
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120 patients treated by two of these schedules within the first 3 months of the experiment.36
From this point (October 1943), thedevelopment of the use of penicillin in the treatment of syphilis was,essentially a civilian activity, the history of which has been summarized indetail by Moore. The Army continued to participate in the clinicalinvestigations on a small scale, but it was quite properly much more concernedwith the application of this new, safe, and simple therapeutic method on a masstreatment scale than in attempting clinical investigative work.
On 5 April 1944, Brig. Gen. James S. Simmons, Chief, Preventive MedicineService, Office of the Surgeon General, addressed the following letter to Dr.Moore, Chairman, Subcommittee on Venereal Diseases, National Research Council:
It is desired that the Subcommittee on Venereal Diseases, National ResearchCouncil, consider at its April 20th [1944] meeting the present state ofknowledge of the penicillin treatment of syphilis in relationship to itssuitability for application to Army practice. The present prolonged treatmentschedules place a great chore on the Medical Department and interfere seriouslywith training and combat. Furthermore, in active Theaters of Operation it isimpossible to maintain any degree of regularity in administering treatment.
For these reasons The Surgeon General would appreciate anexpression of opinion of the Subcommittee on Venereal Diseases as to theearliest possible time penicillin treatment of syphilis may be applied to Armypractice.
This was a staggering request. Arsphenamine and its derivatives had beenemployed in the treatment of syphilis for nearly 35 yearswithout reaching satisfactory agreement on the details of its utilization, yethere was a request for advice regarding the large-scale application of anentirely new therapeutic agent which had first been used in the treatment ofsyphilis only 9 months before andwith which experience on any statistically significant scale was only 6 monthsold. Well aware of the magnitude of the responsibility being assumed, butequally aware of the problems confronting the Army, the minutes of the 22dmeeting of the Subcommittee on Venereal Diseases, 20 April 1944, merely say:
The purpose of the request and its relationship to campaignconditions was further amplified in general discussion. This led to thefollowing recommendation: It is recommended that in active theaters of operationthe penicillin treatment of early syphilis (i.e., infections of less than oneyear's duration, whether or not partially treated with arsenical chemotherapy)be adopted immediately. The minimum total dosage of penicillin should be 2.5million units, given over an eight-day period, administered in 64 intramuscularinjections every three hours day and night. It is further desirable that suchpenicillin treated patients be followed without subsequent antisyphilitictreatment (unless in the event of clinical or serologic relapse) as frequentlyas is practicable and that all such cases be thoroughly resurveyed as tosyphilis prior to separation from the service.
36Minutes, Conference on Penicillin inthe Treatment of Syphilis in Human Beings by a Panel Composed of Members of theSubcommittee on Venereal Diseases and the Committee on Chemotherapeutics andOther Agents, National Research Council, 29 Oct. 1943.
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A subsequent letter from The Surgeon General to the commanding generals ofthe oversea theaters for the attention of the chief surgeon summarized currentknowledge of the use of penicillin in the treatment of syphilis and directed(1) that all new cases of primary and secondary syphilis be treated withpenicillin, (2) that the schedule of treatment be 40,000 units intramuscularlyevery 3 hours for a total of 60 doses or 2.4 million units for each case, and(3) that followup examinations should be obtained at monthly intervals for aminimum period of 1 year.37
The receipt of this directive in the European theater coincided almostexactly with the date of the invasion of continental Europe. It was, therefore,particularly welcome in the attempt to provide facilities for proper diagnosisand treatment of the venereal diseases, especially syphilis, within the Armyareas. Evacuation and the loss of a trained soldier to his organization was tobe avoided, but at the same time it was important not to increase the patientload which must be carried by field or evacuation hospitals. Accordingly,venereal disease treatment centers were planned within the Army areas staffed byat least one medical officer with experience and ability in the diagnosis andtreatment of the venereal diseases, and equipped with adequate laboratoryfacilities and technicians detached from the Army medical laboratory. The planproved efficient and was greatly expedited by the availability of penicillin forthe treatment of syphilis. This made is possible to return all patients treatedfor syphilis to their organizations within 10 days or less.
The necessary followup was operated by a central syphilis register set up inthe Office of the Chief Surgeon, European theater, where the soldier's syphilisregister was filed as soon as treatment was completed. The followup wasaccomplished by letters to the commanding officer of the patient's organizationrequesting the desired observations at the appropriate time.
The Subcommittee on Venereal Diseases made further recommendations at its 23dmeeting on 29 June 1944 for the use of penicillin in the treatment of syphilisby the Army. These provided for the treatment of all soldiers with early andlatent syphilis with 2.4 million units of penicillin according to the schemeadvised to the oversea theaters. The necessity for frequent followup of patientswho were treated for early syphilis was emphasized, and it was pointed out thatknowledge concerning the action of penicillin in neurosyphilis was so imperfectas to prevent any advice on its use in such cases. TB MED 106, 11 October 1944,developed in detail the general principles contained in the committee'srecommendations.
As the war ended, TB MED 198, 20 August 1945, defined the criteria for thediagnosis of syphilis, restated the advice to treat early and latent
37Letter,Maj. Gen. Norman T. Kirk, The Surgeon General, to Commanding Generals, allTheaters of Operations, attention of Chief Surgeon, 24 May 1944, subject:Penicillin Treatment of Primary and Secondary Syphilis.
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syphilis with 2.4 million units of penicillin in 7.5 days, defined thedetails of the necessary posttreatment followup, and advised that all patientswith any manifestation of late syphilis, including, of course, neurosyphilis, betransferred to the appropriate neurosyphilis center. Like its companion TB MED196 on gonorrhea, dated 20 August 1945, this bulletin on the management ofsyphilis represented the best information available at the time for the propermanagement of early and latent syphilis among Army personnel, but events whichcould not be foreseen at the time of its preparation necessitated importantchanges in the dosage schedules recommended.
At its 24th meeting on 23 February 1945, the Subcommittee on VenerealDiseases recognized that there were several fractions of the substance known aspenicillin, that none of these fractions was available commercially, and thatthe constitution of commercially available penicillin was not known. It maderecommendations for extending the assay supervision of commercial penicillin andmost importantly made provision for investigation of the chemical and biologicalproperties of the several known fractions. By the following spring, a great dealof information had been assembled and published by Moore, the highlights ofwhich were (1) that the substance known as penicillin was made up of at leastfour chemically individual fractions which in the American nomenclature wereknown as G, F, X, and K, (2) that originally the commercially suppliedpenicillin was largely made up of penicillin G, (3) that with the substitutionof Penicillium chrysogenum Q-176 for Penicillium notatum in themanufacture of penicillin the commercially available preparations contained anunknown, certainly large (the average was estimated at about 50 percent) amountof fraction K, and (4) that fraction K while exceedingly active in vitro wasapparently in some way denatured by the animal or human body to becomecomparatively inert and therapeutically ineffective when injected. As thesefacts were brought out, the manufacturers of penicillin immediately took stepsto convert to the production of a crude penicillin consisting largely offraction G and eventually to the production of crystalline penicillin G on acommercial scale. This took time, however, since so large and complicated anindustry cannot convert itself overnight. For the protection of the soldierpatient, Change 1 to TB MED 198 was published on 21 November 1946. This changedirected (1) that patients with seronegative primary syphilis be given 6 millionunits of penicillin in 60 doses of 100,000 units each at 3-hour intervals for7? days, (2) that those with seropositive primary, secondary, andlatent syphilis be given 8 million units in 80 consecutive intramuscularinjections of 100,000 units at 3-hour intervals for 10 days, and (3) that there-treatment of failures be by the 8-million-unit schedule with the addition of10 doses each of 60 mg. of Mapharsen given twice weekly and five weeklyintramuscular injections each of 0.2 gm. of bismuth subsalicylate suspension inoil. Failures after this combined penicillin, Mapharsen, and bismuth schedulewere to be treated
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by the 26-week Mapharsen and bismuth system outlined in Circular Letter No.74, 25 July 1942.
Comparison between Circular Letter No. 18, 10 March 1941, and TB MED 198, 20August 1945, affords a number of interesting contrasts. To the criteria fordiagnosis has been added the concept of the biological false-positiveserological test for syphilis which was first introduced to the Army in CircularLetter No. 93, Office of the Surgeon General, 30 April 1943; methodsof treatment are totally different, but the most interesting change is in theconcept of proper posttreatment followup. Under the scheme of treatmentrecommended by Circular Letter No. 18, the patient who came under treatment withearly syphilis and pursued the treatment faithfully should have reached andmaintained a negative serological test for some time before the treatment wasended. With rapid treatment with penicillin, this is not the case, and TB MED198 goes to some pains to explain the interpretation of the titered serologicaltest in the posttreatment followup.
Neurosyphilis-Prior to 1944, the Army had made no specialprovision for the care of patients with neurosyphilis and the various forms oflate syphilis. Patients suffering from these maladies, unless by chance theyfell into the hands of someone professionally qualified to individualize theirmanagement, were treated, if at all, by whatever scheme was in vogue at thetime for the treatment of early syphilis. While cardiovascular syphilis and the other forms of late syphilis, other than of the central nervous system,were numerically unimportant, examination, by increasing numbers of medicalofficers, of the cerebrospinal fluid of every patient with syphilis was revealinga substantial number with asymptomatic neurosyphilis. As this situation becamerecognized, a special committee met in Washington at the request of The SurgeonGeneral on 8 March 1944 to consider the problem of theprofessional management of neurosyphilis in the U.S. Army.38In due time, TB MED 48, 31 May 1944, was published creating a number of neurosyphiliscenters in named general hospitals in the continental United States and settingforth standards for diagnosis and treatment. The plan was to staff each of thehospitals with one or more medical officers with special training in themanagement of neurosyphilis and other forms of late syphilis, and although thesehospitals were designated as neurosyphilis centers it was tacitly understood atthe time, and later formally stated in TB MED 198, that all problem cases ofsyphilis would be referred to them.
The provisions of TB MED 198 were largely administrative but the basicprinciples leading to uniformity of diagnosis in the various centers
38Present at themeeting were Drs. Moore and Stokes from the Subcommittee on Venereal Diseases; General Morgan, Lt. Col. ThomasH. Sternberg, MC, Maj. (later Lt. Col.)Charles R. Rein, MC, Maj. (later Lt. Col.) William H. Everts, MC, Major Dyar,and Maj. (later Lt. Col.) Paul G. Reque, MC, from the U.S. Army; Comdr. W. H.Schwartz, MC, and Lt. H. P. Rowe, MC, from the U.S. Navy; Drs. Lewis H. Weed, E.Cowles Andrus, T. R. Forbes, Philip S. Owen, and Maj. Gen. James C. Magee, USA(Ret.), from the National Research Council; Maj. Georges Leclerc, MC, andSurgeon Lieut.-Comdr. R. G. Struthers, MC, Canadian Liaison Officers; and thefollowing invited conferees: Drs. Harry C. Solomon, Paul A. O'Leary, Evan W.Thomas, and Arthur G. Schoch.
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were defined and general recommendations for classificationand treatment were made. These were extended by a series of three articles39which were published in the Bulletin of the U.S.Army Medical Department where they served asauthoritative but unofficial guides.
The specific recommendations of TB MED 48 for treatment were:
1. A trial of routine metal chemotherapy on a duty status for 6 months forall patients with early syphilis or syphilis of unknown duration and Groups I(minimal) and II (intermediate) changes in the cerebrospinal fluid.
2. The same scheme for patients with late syphilisand Group I changes.
3. The immediate induction of fever (preferably by tertianmalaria for whites and Northern Negroes, and by quartan malaria for SouthernNegroes) in those in the first two groups in whom 6 months of metal chemotherapyhad occasioned no improvement in the cerebrospinal fluid, and in all patientswith Group III (maximal) changes in the cerebrospinal fluid, those with lateasymptomatic neurosyphilis and Group II changes, and all patients withsymptomatic neurosyphilis except those with acute syphilitic meningitis orpredominantly vascular lesions.
Great stress was laid upon the necessity for both frequent and long continuedfollowup examinations of all patients treated for neurosyphilis, and detaileddirections for accomplishing this were laid down regardless of whether the manstayed in the Army or was separated.
On 13 November 1945, Change 3 toTB MED 48 advised that allpatients with neurosyphilis should be treated with penicillin. The recommendeddose was 3.6 million unitsgiven in 120 injections of 30,000 units each in the usual manner.
The patients who qualified for a trial of metal chemotherapy alone under theprevious regimen were to be returned to duty after completion of the treatmentwith penicillin, followed with clinical examination and retest of thecerebrospinal fluid at 3 and6 months after treatment, and returned for reevaluation if either examinationgave abnormal results 6 months after treatment was completed.
The same group of patients as previously were considered candidates for fevertherapy, and the suggestion was made that the first doses of the prescribed 3.6 million units of penicillin be given at the time ofthe first febrile paroxysm.
Records-The old practice of recording treatment ofsyphilis, as outlined in Circulars Nos. 2 and 3, 13 December1910 and 3 June 1911, respectively, Office of the Surgeon General, wascontinued in more or less its orig-
39(1) O'Leary, P. A., Moore, J. E.,Solomon, H. C., Stokes, J. H., and Thomas, E.: Asymptomatic Neurosyphilis. Bull. U.S. Army M. Dept. 80: 46-51, September1944. (2) Solomon, H. C., Moore, J. E., O'Leary, P. A., Stokes, J. H., andThomas, E.: Symptomatic Neurosyphilis; A Clinical Survey. Bull. U.S. Army M. Dept. 81: 55-64, October 1944.(3) Solomon, H. C., Moore, J. E., O'Leary, P. A., Stokes, J. H., and Thomas, E. W.: The Treatment of Neurosyphilis. Bull. U.S. Army M. Dept. 82: 66-76, November 1944.
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inal form until after World War I, during which it had provedto be unnecessarily laborious and to serve no useful purpose. By this timenumerous individual medical officers had created their own record systems andtheir ideas were consolidated, eventually to produce WD MD Form 78, The SyphilisRegister. This was authorized by War Department General Orders No. 6, 13February 1923, and incorporated in AR 40-235 on 30 December 1924.
This form with relatively minor changes (the last wasnecessitated by the introduction of penicillin) has been employed since itsfirst introduction. The form is opened at the time of the original diagnosis ofsyphilis, contains all of the relevant information concerning both the infectionand the general physical condition of the patient, provides space for recordingtreatment, reactions, the results of laboratory tests, and progress notes and isclosed at the completion of treatment and a specified period of observation.Upon completion, the record was transmitted to the Venereal Disease ControlDivision, Preventive Medicine Service, Office of the Surgeon General, where itwas reviewed and, if found acceptable, filed for future record.40
During the period in which the treatment for syphilis wasprolonged, this record facilitated continuity of treatment of the patient whichmight all be carried out in the same place or by the same medical officers.During the first part of World War II, however, because of the rapid and secrettroop movements, it frequently became impossible for the syphilis register tokeep up with the patient. Several different methods of accomplishing this wereexplored, including a brief trial of having the syphilis register transmittedwith the service record of the soldier concerned, but none proved to be entirelysatisfactory.
In an effort to obviate this difficulty, there wasinaugurated at Fort Bragg, in 1941,41an individual record of treatment patterned after the similar form supplied toseamen under the auspices of the then functioning Health Organization of theLeague of Nations. This served to give the patient a pocket record of treatmentwhich provided adequate information for any medical officer into whose hands hemight fall. The proper functioning of this accessory form, of course, dependedon the willingness of the patient to report for treatment before his syphilisregister caught up with him, but experience showed that on the average the formsubstantially reduced the number and duration of lapses from treatment. Similarforms were introduced in the European theater in 1942 and in the MediterraneanTheater of Operations, U.S. Army, in 1943. Still another but again similar form(WD MD Form 78a) which had been authorized by The Surgeon General in October1943 was made available by TB MED 3, 11 January 1944.
40By an agreement betweenThe Surgeons General of the Army and the Public Health Service and the ChiefMedical Officer of the Veterans' Administration, the syphilis registers fromWorld War II were filed with the Veterans' Administration to arrange for men incertain categories, especially those treated for neurosyphilis, to be followedthrough the Public Health Service.
There were also other exceptions to this standard procedure; for example, theCentral Syphilis Registry used in the European theater.
41Annual Report, Office of the Surgeon, Fort Bragg,N.C., 1941.
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After the introduction of rapid treatment methods, all doneunder the continuing control of one small group, a form of this type was nolonger required for assisting in continuity of treatment, but it may continue toserve a useful purpose in facilitating posttreatment followup.
THE MINOR VENEREAL DISEASES
Aside from chancroid, which became troublesome in certainareas, the lesser venereal diseases (lymphogranuloma venereum and granulomainguinale) were of little numerical importance during World War II. Althoughthese three types of venereal diseases were less common than gonorrhea orsyphilis, the period of disability often produced by each of them waspotentially great enough to vest them with a certain degree of militaryimportance. The earlier deliberations of the Subcommittee on Venereal Diseaseswhich had led to the suggestions upon which Circular Letters Nos. 18 and 74 were based, included considerations of the lesservenereal diseases, and these circulars laid down methods of diagnosis andtreatment of these conditions. Later, TB MED 157, dated April 1945, with Change 1, dated 17 December1946, brought up to date the accepted practices in thediagnosis and treatment of the minor venereal diseases.42
Chancroid-Up to the end of WorldWar II, the diagnosis of chancroid was one of exclusion and thereforeessentially unsatisfactory. Circular Letters Nos. 18 and 74 and TB MED 157 emphasizedthe necessity of excluding syphilis, both by dark-field examination and byserological followup, and that this must be done even if the diagnosis ofchancroid can be proved bacteriologically in order to exclude a mixed infection.At the time of the first directive, the bacteriology of Hemophilus ducreyi was sounsatisfactory that Circular Letter No.18 reads, as follows: "Laboratory tests for the absolute diagnosis ofchancroid (Ito-Reenstierna skin test or the staining or cultural isolation ofthe Ducrey bacillus) are not recommended." In TB MED 157, considerableadvance in the bacteriology of the causative organism is illustrated in thefollowing statement: "The diagnosis of chancroid may be aided by thelaboratory examination of stained smears from the lesion, or by culture of pusfrom the lesion or the bubo." This reflects a growing interest in thebacteriology of chancroid and the fact that the experts have developed methodsfor more accurately staining and for culturing the Ducrey bacillus which aresatisfactory in their hands. The complete omission of the
42TB MED 157 was based on the recommendations of a specialcommittee which convened on 25 January 1945 at the request of The SurgeonGeneral. Present at the meeting were Dr. Moore, Subcommittee on VenerealDiseases; Lt. Col. (later Col.) Harrison J. Shull, MC, Colonel Sternberg, andMajor Rein, representatives of The Surgeon General; Dr. Paul D. Rosahn,Technical Aide to the Committee on Medical Research, Office of ScientificResearch and Development; and the following conferees: Dr. Arthur W. Grace, LongIsland College of Medicine, Brooklyn, N.Y.; Dr. Geoffrey W. Rake, Squibb Institute for MedicalResearch, New Brunswick, N.J.; Dr. Katherine H. Anderson, Vanderbilt UniversitySchool of Medicine, Nashville, Tenn.; Dr. Franco Mortara, New York UniversityCollege of Medicine, New York, N.Y.; and Dr. Robert B. Greenblatt, U.S. PublicHealth Service.
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Ito-Reenstierna or other similar skin test from this latestdirective is apparently a reflection of the growing doubt of the value of skintests of this type in general.
In contrast to the unsatisfactory state surrounding the diagnosis ofchancroid, treatment with the sulfonamide drugs was eminently satisfactory.Circular Letter No. 18 recommended sulfanilamide in the dose of 33 gm. givenover a period of 14 days and local treatment with powdered sulfanilamide afterprimary syphilis had been excluded by a series of at least three darkfieldexaminations of material from the lesions. Surgical procedures, such ascircumcision or dorsal slit, "* * * should be resorted to only on the basisof sound clinical judgment." Incision of the fluctuant bubo was allowed butnot advised.
The changes between the recommendations just cited and those contained in TBMED 157 are worthcomment. The more recent recommendations were to treat systemically withsulfadiazine in a dose of 1 gm., four times daily, for 5 to 7 days; no local treatment except soap and water; aspirationof the fluctuant bubo with a 16-gage needle if necessary but, "the buboshould never be incised," and regarding other surgical procedures"circumcision or dorsal slit is undesirable and is rarely necessary."
As indicated earlier, chancroid became exceedingly prevalent and consequentlytroublesome in certain areas. This was especially true in the Philippines,43at the end of the war, and earlier in North Africa44 and theChina-Burma-India theater.45 Recommendation by special investigatorsof the problem in the Philippines, however, dealt largely with control andpreventive measures. In no theaters in which chancroid was troublesome was thereadvance in therapy greater than that reported in TB MED 157.
Lymphogranuloma venereum-Fortunately, this diseasewas of low incidence both in the continental United States and in the theatersof operations. In the latter, the disease occurred almost entirely in smallsporadic outbreaks clearly suggesting a single focus of infection. The samethree directives (p. 430) deal with diagnosis and treatment.
Between the first and the last, there was essentially nochange in the diagnostic criteria laid down. TB MED 157 explains that the diagnosis is based upon collateralconsideration of the results of the Frei test, the clinical picture,epidemiological information, and the exclusion of other causes of inguinaladenopathy. It is emphasized that a positive Frei test is not in itself adequatereason for making the diagnosis of lymphogranuloma vener-
43Letter, Dr. Joseph Earle Moore,Consultant to The Surgeon General, U.S. Army, and Lt. Col. Thomas H. Sternberg,MC, Director, Venereal Disease Control Division, Office of the Surgeon General,U.S. Army, to The Adjutant General, U.S. Army, 6 June 1945, subject: VenerealDisease in the U.S. Army in the Philippine Islands, and Recommendations forTheir Control.
44Annual Report, Preventive Medicine Division, Officeof the Surgeon, North African Theater of Operations, 1943.
45Letter, 1st Lt. M. A. Bouton, MC, VDControl Officer, Office of the Theater Surgeon, Rear Echelon, Headquarters, U.S.Army Forces, China, Burma, and India, to Commanding General, Rear Echelon,Headquarters, U.S. Army Forces, China, Burma, and India, 8 Apr. 1943, subject:Venereal Disease Situation in the C.B.I. Theater.
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eum in the absence of the typical clinical picture, but it issuggested that a negative Frei test in the presence of a suggestive clinicalpicture is of some value in excluding the diagnosis.
In the treatment of lymphogranuloma venereum, conservatism is advised. TB MED157 recommends aspiration of fluctuant nodes where necessary but avoidance ofradical surgical procedures; chemotherapy with sulfadiazine in doses of 3 gm.daily for 21 days; and the utmost conservatism in management of rectal stricturewhen it occurs. Perirectal abscess and fistulo-in-ano may be dealt withradically in the hope of gaining surgical cure. The use of Frei antigenintravenously, which was previously touched upon lightly in Circular Letter No.18, was not even mentioned.
Granuloma inguinale-This disease was completely unimportant from themilitary standpoint but was included in the various directives (p. 430) for thesake of completeness. TB MED 157 suggests that the diagnosis of the conditioncan be made by a competent observer on the basis of morphology alone but pointsout the obvious desirability of demonstrating Donovan's bodies in smears fromthe lesions.
Fuadin (stibophen) was recommended as the drug of choice. This is givenintramuscularly by a rather complicated dosage schedule, is commonly welltolerated, and is therapeutically effective in the majority of instances. Wherethere was no response to Fuadin, tartar emetic was recommended. This is givenintravenously also on a rather complicated dosage schedule. It was furtherrecommended that if secondary infection was present, penicillin be used in dosesof 10,000 units intramuscularly every 3 hours for a total of 400,000 units. Withthe exception of this addition of penicillin for secondary infection, there wereno other advances in the treatment of this condition during World War II.
Miscellaneous-The more strictly urologic conditionswhich are sometimes grouped with the venereal diseases (venereal warts,gangrenous balanitis, and so on) need not be considered here, but the role ofscabies as a venereal disease must be mentioned.
In the early winter of 1942, the Senior Consultant in Dermatology, Office ofthe Chief Surgeon, European theater, had noted that the incidence of scabiessevere enough to require hospitalization in the European theater was greatly inexcess of the frequency of the disease among troops in the United States. Adetermined campaign was instituted to educate unit medical officers in the earlydiagnosis and proper treatment of the disease and to provide them with benzylbenzoate for its treatment.
The incidence of the disease continued to increase and thefollowing simple facts led to an inference that the disease was venereal inorigin. Troops arriving from the Zone of Interior were free from the disease;the disease was exceedingly common among the British, especially the civilians;and the pattern of distribution of the individual cases made soldier-to-soldierspread most unlikely. From this obvious inference, a comprehensive study
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of the matter was initiated based on the same type ofinterview by the same interviewers used in the contact investigation ofgonorrhea and syphilis, and the study resulted in the conclusion that at least 90percent of scabies among U.S. soldiers in the Europeantheater was venereal in origin.46 This thesis, incidentally, was amply verified inthe experiences of our troops in Germany after V-E Day. There the incidence ofscabies made a meteoric rise, exactly paralleling the increase in the incidenceof the venereal diseases.47
INDUCTION OF INDIVIDUALS WITH VENEREAL DISEASE
In the early period of mobilization, persons known to havevenereal disease were rejected for military service. This policy resulted in theaccumulation of a large backlog consisting mainly of men rejected because theyhad syphilis. It was the practice, at the time, to defer men with gonorrhea andchancroid only until they became asymptomatic and then to refer them forinduction. By 1942, this reservoirof manpower had grown to tremendous proportions, the manpower shortage wasbecoming acute, and the Army felt that its medical facilities and trainingprogram were sufficiently advanced to undertake the additional burden ofinducting men with syphilis. In the fall of that year, plans were initiated toprovide in certain selected posts, camps, and stations additional treatmentfacilities with a total capacity of 6,510 bedsfor the management of inductees with syphilis and to a much lesser extent theother venereal diseases. The plan was placed in operation in December 1942 by directives from The Adjutant General48 and was functioning smoothly by March 1943.
The inductees with syphilis were hospitalized in speciallyprovided barrack-type hospitals which were staffed by officers especiallytrained in the diagnosis and treatment of the venereal diseases. Some of thesemedical officers had been recruited from civilian life but most had been given ashort intensive course at the Institute for the Control of Syphilis at theUniversity of Pennsylvania, Philadelphia, Pa., under the auspices of the U.S.Army.
As a result of this program, 200,000 individualswith venereal disease were inducted into the Army through December 1945. Of these, nearly 170,000 were syphilitics.49The treatment which they received followed the current directives for themanagement of the venereal diseases occurring after induction and require nospecial comment.
One administrative problem was greatly expedited by adirective, in June 1943,50 authorizingpreinduction hospitalization for the examination of the cerebrospinal fluid ofall those found to have a positive serological test for
46See footnotes 26, p. 420.
47Quarterly Report, Preventive Medicine Division, Office of the Chief Surgeon, U.S. Forces intheEuropean Theater, 1 Apr. to 30 June 1946.
48Radiograms, The Adjutant General, to all Service Commands, 7 and 10 Dec. 1942.
49Karpinos, B. D.: Venereal Disease Among Inductees. Bull. U.S. ArmyM. Dept. 8: 806-820, October 1948.
50Letter, The Adjutant General, to all ServiceCommands, 9 June 1943, subject: Induction of Individuals With Positive Serology for Syphilis.
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syphilis. This made possible the preinduction rejection ofregistrants with neurosyphilis, thereby avoiding the laborious process ofboarding for a certificate of disability for discharge of the 15 to 20 percentof the men with syphilis who would be found to have an abnormal cerebrospinalfluid at the first examination.
THE RESULTS
The extremely energetic venereal disease control program which was sponsoredby the Army throughout the war was effective in minimizing the number ofvenereal infections. In spite of these preventive activities, however,gonorrhea and syphilis continued to be among the important disease
problems.51 The yeoman's task of reducing to theminimum the number of days lost from duty because of these infections remainedfor the therapist who may well be proud of the accomplishment which he canreport.
The reduction in the noneffective rate and changes in therapy, incidence, andduration of treatment of venereal disease in the U.S. Army in the con-
51Medical Department, United StatesArmy. Preventive Medicine in World War II. Volume V. Communicable DiseasesTransmitted Through Contact or By Unknown Means. Washington: U.S. GovernmentPrinting Office, 1960.
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CHART 23.-Changes in therapy,incidence, and duration of treatment of venereal disease, Army in the UnitedStates, June 1942 to August 1945
tinental United States are shown in charts 22 and 23. Ifthe length of treatment required in June 1942 hadbeen maintained without change, the venereal disease noneffective rate for thecontinental United States would have been 2.0 per1,000 per day in December 1944 and 2.5 per1,000 per day by August 1945. Asit was, in spite of the mounting venereal disease rate which skyrocketed afterV-E Day, in December 1944 thenoneffective rate was less than 1 per 1,000 per day and was only 0.66 per 1,000per day in August 1945.
