History

CHAPTER X

Cutaneous and Other Aspects of Diphtheria

Averill A. Liebow, M.D., and John H. Bumstead, M.D.

Diphtheria was a new and serious problem to the U.S. Armyduring the Second World War. Combat in the tropics again proved to beparticularly favorable for the spread of this disease, especially the cutaneousform. During the First World War, the British recognized the diphtheritic natureof the desert sores that were so prevalent among the troops in Egypt andPalestine. In World War II, lesions of the same nature were common during theNorth African campaign over similar terrain. During 1943 and 1944, cutaneousdiphtheria on a large scale became apparent among troops in the Pacific.Hitherto, it had not been reported from that area, and it was not until Corynebacteriumdiphtheriae was found in such lesions known as tropical ulcer, ecthyma, andjungle rot that their etiology was determined. These lesions were ofepidemiological importance because they were a prolific source of pharyngeal andnasal diphtheria among the soldiers and to those with whom they came in contact.It was found that an enormous reservoir of diphtheria-inthe cutaneous form resembling that seen in soldiers-existedamong natives in the Pacific, particularly among the children. The lesions ofchildhood probably accounted for the immunization of the natives early in life.It seemed that the conditions of combat reduced American soldiers to theepidemiological conditions prevailing among the natives.

Studies of the lesions of soldiers and of natives in thetropics revealed the presence of a hitherto unknown hemolytic corynebacterium,which could easily be confused either with C. diphtheriae on L?ffler'smedium or with the beta hemolytic streptococcus on blood-agar plates.

Several groups of investigators seized the opportunity tostudy the effectiveness of penicillin in the treatment of the numerous carriersand clinical cases of diphtheria that were available in some hospitals.

Part I. General Aspects of the Military Problem

INCIDENCE

Preliminary statistical data on the incidence (total cases) of diphtheria inthe U.S. Army for the years 1942-45 by area, based on sample tabulations ofindividual medical records, are presented in table 40. During 1942 through 1945,619 cases of diphtheria were reported in the Army in the continental UnitedStates and 5,105 additional cases from the Army overseas. Among the overseatheaters in 1945, the year of highest number of cases, the European Theater ofOperations, U.S. Army, had the highest rate, with the

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North African and Mediterranean Theater of Operations, U.S. Army, second, andthe combined Pacific areas, third.

Deaths due to diphtheria, during World War II, totaled 125(table 41). Of the total, 115 occurred in the Army overseas. Mortality wasgreater in 1945 for the Army as a whole, with 67 deaths occurring in theEuropean theater alone.

TABLE 40.-Incidence of diphtheria in the U.S. Army, by area and year, 1942-45

[Preliminary data based on sample tabulationsof individual medical records]
[Rate expressed as number of cases per annumper 1,000 average strength]

Area	1942-45		1942		1943		1944		1945
Area	Number of cases	Rate	Number of cases	Rate	Number of cases	Rate	Number of cases	Rate	Number of cases	Rate
Continental United States	619	0.04	67	0.03	205	0.04	152	0.04	195	0.07
Overseas:
Europe	2,557	0.58	27	0.33	45	0.17	245	0.15	2,240	0.94
Mediterranean¹	1,087	.73	2	.09	197	.43	628	.97	260	.73
Middle East	45	.31	1	.17	23	.43	11	.24	10	.24
China-Burma-India	208	.47	8	.91	15	.38	155	.92	30	.14
Southwest Pacific	615	.33	3	.04	7	.04	100	.19	505	.49
Central and South Pacific	519	.41	4	.03	69	.24	266	.61	180	.48
North America²	19	.04	2	.02	3	.02	14	.11	---	0
Latin America	23	.06	5	.05	2	.02	1	.01	15	.21
Total overseas³	5,105	0.48	55	0.09	364	0.22	1,426	0.37	3,260	0.70
Total Army	5,724	0.22	122	0.04	569	0.08	1,578	0.20	3,455	0.46

¹Includes North Africa.
²Includes Alaska and Iceland.
³Includes admissions on transports.

Evidence is presented (p. 315) that cutaneous diphtheriaprobably played an important role in the dissemination of all forms of thedisease, although relatively few cases were diagnosed and reported officially.For example, the incidence of cutaneous diphtheria in the total Army in 1944 and1945, based on sample tabulations of individual medical records, totaled 485(table 42). The majority of cases occurred in the combined Pacific areas and inthe China-Burma-India theater.

Among the British in the African desert, the rate for allforms of diphtheria was 4 to 5 per 1,000 per annum.^lA comparison of British and American incidence of diphtheria in theMediterranean theater during December 1943 and January and February 1944follows:

	British	American
December 1943	558	64
January 1944	490	42
February 1944	302	33

¹Proceedings of the Conference of Army Physicians, Central Mediterranean Forces, Held at the Institute Superiore di Sanita, Viale Regina Marguerita, Rome, 29 Jan. to 3 Feb. 1945, pp. 101-118.

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TABLE 41.-Deaths due to diphtheriain the U.S. Army, by area of admission and year of death, 1942-45

[Preliminary data based on tabulations ofindividual medical records]
[Rate expressed as number of deaths per annumper 100,000 average strength]

Area	1942-45		1942		1943		1944		1945
Area	Number	Rate	Number	Rate	Number	Rate	Number	Rate	Number	Rate
Continental United States	10	0.07	---	0.00	2	0.04	2	0.05	6	0.20
Overseas:
Europe	72	1.64	---	0	---	0	5	0.30	67	2.82
North Africa	11	.74	---	0	4	.88	3	.46	4	1.13
Middle East	3	2.05	---	0	2	3.77	1	2.16	---	0
China-Burma-India	3	.68	1	11.43	---	0	2	1.19	---	0
Pacific¹	21	.68	---	0	2	.42	8	.82	11	.78
North America	2	.41	---	0	---	0	1	.77	1	1.47
Latin America	---	0	---	0	---	0	---	0	---	0
Total overseas²	115	1.07	1	0.17	8	0.47	20	0.52	86	1.85
Total Army	125	0.49	1	0.03	10	0.15	22	0.28	92	1.21

¹Total Pacific Area (Southwest, Central, and South Pacific).
²Includes 3 deaths on transports in 1945.

TABLE 42.-Incidence of cutaneousdiphtheria in the U.S. Army, by area and year, 1944^-45

[Preliminary data based on sample tabulationsof individual medical records]
[Rate expressed as number of cases per annum per 1,000 average strength]

Area	1944-45		1944		1945
Area	Number of cases	Rate	Number of cases	Rate	Number of cases	Rate
Continental United States	15	0.00	5	0.00	10	0.00
Overseas:
Europe	45	0.01	---	0	45	0.02
Mediterranean¹	6	.01	1	.00	5	.01
Middle East	---	0	---	0	---	0
China-Burma-India	120	.31	110	.65	10	.05
Southwest Pacific	205	.13	30	.06	175	.17
Central and South Pacific	89	.11	54	.12	35	.09
North America²	---	0	---	0	---	0
Latin America	---	0	---	0	---	0
Total overseas³	470	0.06	195	0.05	275	0.06
Total Army	485	0.03	200	0.03	285	0.04

¹Includes North Africa.
²Includes Alaska and Iceland.
³Includes admissions on transports.

NOTE.-Absolute zero is indicated by zero inthe units column; 0.00 indicates a rate of more than zerobut less than 0.005.

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It must be stated, however, that the Americans requiredlaboratory confirmation of diagnosis, whereas the British did not. The rateamong German prisoners of war was far in excess of that of American soldiers.Local epidemics were reported in German prisoner-of-war camps in the UnitedStates.² In some cases, cutaneous diphtheriawas described, and tropical ulcers were reported to be numerous among theprisoners. At the same time, diphtheria increased steadily among Army troops inthe continental United States.

After the occupation of Germany, the incidence ofnasopharyngeal diphtheria increased tremendously, probably through associationof soldiers with the civilian population among whom, during the war years,diphtheria had become a major problem. Circular Letter No. 69, Office of theTheater Chief Surgeon, Headquarters, Theater Service Forces, European Theater,issued on 28 September 1945, summarized for medical officers the generalprinciples to be followed in the diagnosis, treatment, and control ofdiphtheria. In addition, the December 1945 and January 1946 issues of the MedicalBulletin from the Office of the Theater Chief Surgeon contained a series ofarticles on diphtheria written by medical officers in the theater.

During the calendar year 1945, 2,240 cases of diphtheria occurred amongAmerican troops in Europe with 67 deaths (tables 40 and 41). The incidence inDecember 1945 was approximately 2.8 per 1,000. During the early months of 1946,from 30 to 50 cases were being diagnosed each week with 1 or more deaths.

IMMUNIZATION

The policy at first was not to immunize young adultsroutinely against diphtheria because moderate to severe reactions would occur inan appreciable number of cases, although studies were made of the incidence ofSchick-positive reactors among U.S. Army troops and smalldiphtheria-immunization programs were conducted.³Late in 1945, as the incidence of diphtheria increased among U.S. troops in theEuropean theater, only immune personnel were assigned to the army of occupationon the Continent. U.S. Army civilian employees, their dependents, and dependentsof military personnel destined to join the occupation army in the Europeantheater were immunized.

²(1) Fleck, S., Kellam, J. W., and Klippen, A. J.: Diphtheria Among German Prisoners of War. Bull. U.S. Army M. Dept. No. 74, pp. 80-89, March 1944. (2) Monthly Progress Report, Army Service Forces, War Department, 30 Nov. 1943, Section 7: Health, p. 22.
³For a more detailed discussion of the diphtheria-immunization program during World War II, the reader is referred to the following two sources: (1) Long, Arthur P.: The Army Immunization Program. In Medical Department, United States Army. Preventive Medicine in World War II. Volume III. Personal Health Measures and Immunization. Washington: U.S. Government Printing Office, 1955, pp. 271-341. (2) McGuinness, Aims C.: Diphtheria. In Medical Department, United States Army. Preventive Medicine in World War II. Volume IV. Communicable Diseases Transmitted Chiefly Through Respiratory and Alimentary Tracts. Washington: U.S. Government Printing Office, 1958, pp. 167-189.-J. B. C., Jr.

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Accordingly, on 12 January 1946, the Office of the TheaterChief Surgeon, European Theater,⁴ directed allmajor commands to institute an immunization program for (1) all medicaldepartment, hospital, and dispensary personnel, (2) all personnel whose dutiesbrought them into frequent and intimate contact in camps or enclosures withprisoners of war, displaced persons, internees, or German civilians, and (3) allunits of battalion strength or smaller showing two cases in any one week. It wasdecided to dispense with Schick testing at that time.

In May 1946, the rule was changed, and all military personnelgoing overseas who were shown to be susceptible to diphtheria by the Schick testwere ordered to be immunized.

Part II. Tropical Ulcers and Diphtheria

SOURCES AND DISSEMINATION OF INFORMATION

The presence of C. diphtheriae in skin lesions, particularlyulcers, was reported by widely separated groups of observers in the South andSouthwest Pacific Areas and in Burma during World War II. However, in Saffron's1944 review of the literature on cutaneous diphtheria no mention was made of theincidence in these areas.⁵

Cutaneous diphtheria was recognized among American forces inthe Mediterranean theater but was the subject of only one brief general report.⁶More interest was displayed by the British, among whom the incidence ofdiphtheria was generally higher.⁷

South Pacific⁸-Theobservations in the South Pacific Area were made chiefly on members of the25th and 43d Infantry Divisions, as they were evacuated from combat in theSolomon Islands, and on troops of the 27th Infantry Division, following theirevacuation to Esp?ritu Santo in the New Hebrides after the Battle of Saipan.The first of a series of reports from the 39th General Hospital, Auckland, NewZealand, appeared in September 1943. The information was soon disseminatedthroughout the area in Medical Circular Letters Nos. 5 and 14, dated 20 October1943 and 5 January 1944, respectively, Headquarters, U.S. Army Forces, SouthPacific Area.

⁴Medical Bulletin No. 2, Office of the Theater Chief Surgeon, Headquarters, Theater Service Forces, European Theater, January 1946, pp. 1-7.
⁵Saffron, M. H.: Cutaneous Diphtheria as a Military Problem; A Review of the Literature, With Report of a Case. Arch. Dermat. & Syph. 51: 337-340, May 1945.
⁶Medical Bulletin No. 19, Office of the Chief Surgeon, Headquarters, European Theater of Operations, 1 May 1944, pp. 27-29.
⁷(1) See footnote 1, p. 276. (2) Hunt, T. C.: Medical Experiences in North Africa, 1943-44. Brit. M.J. 2: 495-498, 14 Oct. 1944. (3) Diphtheria in Campaigns. British M. Bull. No. 36, pp. 1-2, June 1944. (4) MacGibbon, T. A.: Diphtheria in the Middle East; Some Observations on 71 Cases. Edinburgh M.J. 50: 617-625, October 1943. (5) Williams, H. C. M.: Cutaneous and Conjunctival Diphtheria; Series of Cases. Brit. M.J. 2: 416-417, 2 Oct. 1943.
⁸Unless otherwise indicated, the material presented in this chapter on tropical ulcers and cutaneous diphtheria in the South Pacific is taken from Liebow, A. A., MacLean, P. D., Bumstead, J. H., and Welt, L. G.: Tropical Ulcers and Cutaneous Diphtheria. Arch. Int. Med. 78: 255-295, September 1946.

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Similar material on diphtheria was made available in February1944 by newsletter from U.S. Navy headquarters for malarial and epidemic controlin the South Pacific Area. In addition, there were the evangelical efforts ofthe medical consultant, Col. Benjamin M. Baker, MC, who did much to make thestaffs of the various hospitals conscious of the diphtheria problem. The finalreport totaled 174 cases of cutaneous diphtheria and 94 cases of noncutaneousdiphtheria, in all of which C. diphtheriae had been demonstrated.

The following tabulation is based on a study of patients fromthe Solomon Islands campaign at the 39th General Hospital from 7 February 1943to 1 July 1944, inclusive, and on cases of diphtheria from the 27th InfantryDivision during their stay at the rest area on Esp?ritu Santo:

Type of cases	Number of cases	Proportion of strains toxigenic
Cutaneous diptheria	174	145:173
Throat cases	64	60:62
Nose cases	5	5:5
Nose and throat cases	1	1:1
Carriers	24	12:23

The clinical observations on cases in the Saipan group admitted to the 122d Station Hospital on Esp?ritu Santo were also reported separately from this hospital.⁹ On Fiji, 35 cases of nasopharyngeal diptheria were found in the 164th Infantry of the Americal Division following the Guadalcanal campaign. Diphtheria among marines in process of evacuation from Guadalcanal has been described by Norris and his coworkers.¹⁰ The laboratory work on diphtheria in the various hospitals in the South Pacific has been reviewed by Murray.¹¹

During the early phases of the South Pacific study, fromMarch to September 1943, intensive parasitological and bacteriological studieswere made, including anaerobic cultures, dark-field examinations, potassiumhydroxide smears, cultures for fungi, and Giemsa stains for Leishmania. Cutaneouslesions were searched with care for Leishmania in cases from the SolomonIslands and Saipan, but neither protozoa nor spirochetes were found, and suchfungi as Monilia and Epidermophyton were rarely encountered. Whenthe frequency of C. diphtheriae became apparent, a special procedure wasemployed to investigate the epidemiology and pathogenesis of lesions associatedwith this micro-organism, and bacteriological methods were simplified tofacilitate its detection. A standard clinical record form was designed, whichemphasized such factors as previous diphtheria, immunization, former Schicktests, history of sore throat, and evidences of neurological damage.

⁹Stern, R. L., and Grynkewich, S. E.: Diphtheria Epidemicin Adults in the Tropics. Bull. U.S. Army M.Dept. 5(5): 562-569, May 1946.
¹⁰Norris, R. F., Kern, R. A., Schenck, H. P., and Silcox,L. E.: Diphtheria in the Tropics; A Report of 18 Cases on a United States Naval Hospital Ship.U.S. Nav. M. Bull. 42: 518-524, March1944.
¹¹Murray, R.: Laboratory Service-South Pacific Area. [Official record.]

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Routine nose and throat cultures were taken, and Schick testswere made in all instances where nasal or pharyngeal diphtheria did not makeimmediate treatment imperative. Before a patient was discharged from a hospital,another physical examination with emphasis on the neurological aspects wasperformed.

Burma-In the Burma portion of the India-Burma theater,141 cutaneous lesions were found, chiefly in soldiers from the Myitkyina combatarea. They were reported from the 20th General Hospital, Ledo, Assam, in September 1944, by Livingood and his coworkers, who had given them careful study.¹²In 21 percent of these 141 patients, it was possible to demonstratetoxigenic C. diphtheriae. There was, however, a high incidence ofcomplications among those lesions from which C. diphtheriae was notisolated, but since they were morphologically identical with those harboringthe microorganisms, the diagnosis of cutaneous diphtheria seemed reasonable.Only eight cases of nasopharyngeal diphtheria were diagnosed in the intervalduring which most of these cutaneous cases were observed-September to December1944. Particular attention was paid to the complications of the disease as wellas to morphology of the characteristic lesions and their treatment, and avaluable followup study was made, which furnished an estimate of the cost to theArmy in man-days.¹³

Reports from the 69th General Hospital, Ledo, Assam, inOctober 1944 and January 1945¹⁴referred to 70 patients. All throatcultures in this series were negative, and no clinical cases of nasopharyngealdiphtheria were diagnosed.

It is interesting to note that the British in the India-Burmatheater at the same time were seeing a number of cases of cutaneous diphtheria,some with neurological complications.¹⁵

¹²(1) Cutaneous Diphtheria, 20th General Hospital, 20 April 1945. InBlumgart, Herrman L., and Pike, George M.: History of Internal Medicine inIndia-Burma Theater, inclosure 11 thereto. [Official record.] (2) Letter, Maj.Clarence S. Livingood, MC, Office of Chief of Dermatology and Syphilology, 20thGeneral Hospital, to Commanding Officer, 20th General Hospital, 15 Sept. 1944,subject: Cutaneous Diphtheria. (3) Letter, Maj. Clarence S. Livingood, MC,Office of Chief of Section of Dermatology and Syphilology, 20th GeneralHospital, to Commanding Officer, 20th General Hospital, 9 Oct. 1944, subject:Cutaneous Diphtheria. (4) Letter, Maj. Clarence S. Livingood, MC, Chief, Sectionof Dermatology and Syphilology, 20th General Hospital, India-Burma Theater, toCommanding Officer, 20th General Hospital, 25 Jan. 1945, subject: CutaneousDiphtheria. (5) Letter, Lt. Col. Francis C. Wood, MC, Chief of Medical Service,20th General Hospital, to Commanding Officer, 20th General Hospital, 15 Sept.1944, subject: Cutaneous Diphtheria. (6) Letter, Maj. Herbert S. Gaskill, MC,Chief, Neuropsychiatric Section, 20th General Hospital, India-Burma Theater, toCommanding Officer, 20th General Hospital, 18 Mar. 1945, subject: PreliminaryReport on the Neuritis Complicating Cutaneous Diphtheria.
¹³Letter, Capt. Daniel J. Perry, MC, Assistant Chief,Dermatology and Syphilology Section, 20th General Hospital, to Consultant inDermatology, Office of the Surgeon General, 28 Aug. 1945, subject: Follow-UpStudies of a Group of 140 Cases of Cutaneous Diphtheria.
¹⁴(1) Letter, Capt. Harvey Blank, MC, Chief, Section ofDermatology and Syphilology, 69th General Hospital, India-Burma Theater, toCommanding Officer, 69th General Hospital, 31 Jan. 1945, subject: Analysis of 40Additional Cases of Cutaneous Diphtheria. (2) Letter, Capt. Harvey Blank, MC,Chief, Section of Dermatology and Syphilology, 69th General Hospital, AdvanceSection 3, India-Burma Theater, to Commanding Officer, 69th General Hospital, 1Apr. 1945, subject: Report of Cutaneous Diphtheria Among the Detachment of aGeneral Hospital.
¹⁵Blumgart, Herrman L., and Pike, George M.: History of Internal Medicinein India-Burma Theater. [Official record.]

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Southwest Pacific.-The group at the 9th General Hospital on Biak¹⁶observed a total of 210 cases of diphtheria between 1 November 1944 and 1 March1945. There were 102 cases of dermatitis from which C. diphtheriae wasisolated. Of the 31 recovered strains tested, 19 were virulent. There were also60 other cases with wounds, burns, otitis media, otitis externa, and other suchlesions, and 48 nasopharyngeal infections from which the C. diphtheriae wasisolated. The patients in this group were from nine widely scattered bases inthe Southwest Pacific Area, New Guinea, the Netherlands East Indies, and thePhilippine Islands. On Biak, where the studies were conducted, 112 patients werefrom 22 different organizations.

Quarterly reports from several hospitals in the Southwest Pacific Area, amongthem the 54th General Hospital on Biak and the 105th General Hospital inHollandia, New Guinea, indicated early in 1945 that diphtheria was undersurveillance. During a 3-month period at the 13th General Hospital, Finschhafen,northeast New Guinea, 26 cases of nasopharyngeal diphtheria were seen togetherwith 25 individuals who had cutaneous lesions from which C. diphtheriae wascultured. They were usually virulent microorganisms of the mitis type. TechnicalBulletin No. 17, Office of the Chief Surgeon, Headquarters, U.S. Army Forces inthe Far East, dated 23 October 1944, called to the attention of all medicalofficers the increase in the number of reported cases of clinical diphtheria inthe area and directed that measures be instituted to prevent the spread of thedisease.

Zone of Interior-After prevalence of the condition was recognized, thepatients with cutaneous lesions received thorough study in several large centersin the United States. At the Moore General Hospital, Swannanoa, N.C.,¹⁷askin isolation ward was established to which there were 228 admissions between 1March and 3 October 1945. Cultures of ulcerated lesions in the skin werepositive for corynebacteria in 107, 18 of which proved to be toxigenic. At theHarmon General Hospital, Longview, Tex.,¹⁸ a survey was made of 385admissions; most of the patients in the survey were from the Pacific areas.Seventy persons were proved to have C. diphtheriae either in the noseor throat or in cutaneous lesions. Fifty-eight of these strains of themicro-organism were virulent, but 12 were toxigenic C. diphtheriae. Thisrepresented an incidence of 3.1 percent in the population of the hospital at thetime of admission. Fifty-six of these patients had tropical ulcers or ulcerateddermatitides. In 8 of these, C. diphtheriae was found to be toxigenic andin 30, atoxic. At the Baxter General Hospital, Spokane,

¹⁶Oppel, T. W., Smith, J. J.,Montanaro, A., and Tompsett, R. R.: Clinical Features of Diphtheria in theTropics. [Official record.]
¹⁷Bronson, L. M.: Memorandum on Cutaneous Diphtheria at Moore GeneralHospital. [Official record.]
¹⁸(1) Denhoff, E., and Kolodny, M. H.: Studies on CutaneousDiphtheria and Tropical Ulcers. Arch. Dermat. & Syph. 55: 360-368, March1947. (2) Denhoff, E., Kolodny, M. H., Daniels. W. B., and Mitchell, L. P.: Planto Control Diphtheria in an Army General Hospital. Bull. U.S. Army M. Dept. 6: 59-60, July 1946.

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Wash.,¹⁹ between 1 December 1944and 15 February 1945, there were 62 healed or active cases of cutaneous diphtheria, ofwhich polyneuritis developed in 11. At the Letterman General Hospital, SanFrancisco, Calif.,²⁰ diphtheria in medical personnel attending patients on thedermatology wards again proved a problem, until the diphtheritic nature of manyof the lesions encountered on these wards was recognized. The localized outbreakwas studied in this hospital and will be discussed later.

Diphtheria, particularly of the cutaneous variety, wasdiscussed in detail at the Ninth Service Command Conference on Internal Medicineheld at Letterman General Hospital on 7 and 8 November 1945.

Policies-In recognition of the increasing importance ofthe problem of diphtheria during World War II, information, as it becameavailable, was disseminated by the highest echelon. The diphtheritic nature ofcertain types of tropical ulcers in the Pacific was first given wide publicityin the May 1944 issue of the Bulletin of the U.S. Army MedicalDepartment. Following a tour of inspection of the Pacific area in October 1944by Col. Francis R. Dieuaide, MC, Chief, Tropical Disease Treatment Branch,Medical Consultants Division, Office of the Surgeon General, War DepartmentTechnical Bulletin (TB MED) 143, entitled "CutaneousDiphtheria" was issued in February 1945. This bulletin summarizedthe reports from various tropical areas, gave directions concerning diagnosisand treatment, and emphasized the epidemiological significance of the disease.Similar material on the recognition and treatment of cutaneous diphtheria waspublished in the March 1945 issue of the Bulletin. A specialcircular on management of patients with cutaneous diphtheria was prepared by theMedical Consultants Division, Office of the Surgeon General, and was issued toservice command medical consultants on 3 August 1945.

The many cases of polyneuritis that had been reported fromthe Mediterranean theater,²¹ the South Pacific, Burma,²²andelsewhere, attracted the interest of the Army Epidemiological Board (Board forthe Investigation and Control of Influenza and Other Epidemic Diseases in theArmy), which established an investigative commission composed of Dr. George D.Gammon and Maj. (later Lt. Col.) Emanuel B. Schoenbach, MC. The commissionarrived in Merano, Italy, on 31 May 1945 and devoted its attention tothe many cases among the German prisoners of war, since cases among U.S.soldiers were no longer available in large numbers. A preliminary report of42 cases considered diphtheritic polyneuritis and of 28 others was submittedin August 1945.²³

¹⁹Sampson, J. J.: Late Neuronitis Following Proved and Suspected Cutaneous,Faucial and Wound Diphtheria. Am. J.M. Sc. 212: 432-448, October 1946.
²⁰Letter, Maj. Frank R. Day, PhC, Adjutant, LettermanGeneral Hospital, San Francisco, Calif., to Office of the Surgeon General, 20Oct. 1944, subject: Reported Cases of Diphtheria at Letterman General Hospital.
²¹See footnote 1, p. 276.
²²See footnote 12 (6), p. 281.
²³Gammon, G. D., and Schoenbach, E. B.: Preliminary Report onInvestigation of Polyneuritis in the Mediterranean Theater of Operations, U.S.Army, 20 Aug. 1945. [Official record.]

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MORPHOLOGY

Typical lesions-The characteristic lesion from which C. diphtheriae wasdemonstrated in highest incidence was rounded with angular irregularities, deepand punched out, but did not as a rule extend far into the subcutaneous tissue.In the South Pacific, 84.1 percent of lesions harboring C. diphtheriae hadthis appearance. They were similar to lesions of cutaneous diphtheria seen intemperate zones, to the desert or veldt sores of North Africa and Palestine, tothe "Garigha" of northern India, and to the lesions seen among theMelanesians and Tonkinese in the New Hebrides, and the Chamorros in theMarianas Islands. A typical lesion could develop in as short a time as a month.

The margins of the diphtheritic ulcers were declivitous, indurated, and oftenrolled (figs. 37A and B, and 38). Occasionally, they were slightly underminedbut not to the same extent as the tropical phagedenic ulcers described, forexample, by James in the Melanesians.²⁴ Usually, there was a cone of induration,erythema, and bronze-violet pigmentation about the sharply defined sore (fig.38).

In the India-Burma theater, a dry, black eschar was often noted similar tothat of phenol burns or decubitus ulcers. In other instances, there was afibrinous crust which when removed after the application of soaks revealed thelesion described. The eschar could usually be loosened at the edges but adheredfirmly at the center as if it were a part of the subcutaneous tissue.

Usually, the base was relatively clean, with a moderate serous orserosanguineous discharge, but sometimes there was adherent fibrinopurulentmaterial. The exudate beneath the crust was gray or gray green rather thanyellow. Occasionally, there was a gray-green fibrinous membrane, whichordinarily was difficult to scrape from the surface but could be peeled off insome instances. It was present chiefly in lesions of short duration. Thismembrane was often fitted to the irregularities of the ulcer (fig.39).

Under advantageous conditions, healing occurred bygranulation from below and ingrowth of epithelium from the sides in sucha manner that the scar was on a level with, or slightly below, the surroundingskin and only slightly less in diameter than the original lesion (fig. 37B, C,and D). At the center was a covering of thin white skin surrounded by a borderof persistent bronze-violet pigmentation (fig. 37D). The latter tended topersist for months or years. Persistent hyposthenia or anesthesia in the scarswas emphasized by some observers;²⁵ however, a degree of anesthesiain newlyformed scar tissue is not surprising in any lesion.

²⁴James, C. S.: Tropical Phagaedenic Ulcer in the Pacific.Tr. Roy. Soc. Trop. Med. & Hyg. 31: 647-666, April 1938.
²⁵See footnotes 12 (4), p. 281; and 19, p. 283.

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FIGURE 37.-Multiplediphtheritic ulcers of lower extremity acquired in New Zealand. The patient wasgiven 300,000 units of penicillin in 5 doses per day intramuscularly for 18days. Saline compresses (250 units per cc.) were applied for 4 hours twicedaily. A. Appearance of lesions after 1 months' duration, before treatment, 24May 1944. B. Lesions after 3 days' therapy. C. Appearance of lesions after 17days' therapy. D. Lesions after 33 days of therapy.

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FIGURE 38.-Typical chronic ulcer of 4 weeks' duration. There was bronze-violet pigmentation of the surrounding skin. The patient acquired the lesion in the Solomon Islands.

These diphtheritic lesions were usually multiple (75 percent in the SouthPacific series), and in almost all patients at least one lesion was situated onan extremity. In some instances, they were found in bizarre locations, as onthe penis (fig. 40) or perianally. A large percentage of lesions were on thefeet and as a result the ulcers were frequently disabling, although in otherlocations they caused little pain or inconvenience to the hardy soldier.

The largest lesion observed in the South Pacific group measured 40 by 45 mm.Occasionally, a very minute, but otherwise typical lesion was found to bediphtheritic. Recurrences were frequent, as the insensitive layer of newlyformed skin was delicate and was subject to such trauma as may have been inpart responsible for the ulcer originally. In recurrent lesions, a wateryblister often formed at the center, but it usually did not contain C.diphtheriae.

In the majority of instances (55 percent in the South Pacificseries, 85.1 percent in the India-Burma series) the onset of the ulcers wasincident to combat or patrol activity and was uncommon in resting troops.Usually, there was a definite history of trauma, insect bite, or leech bite, butsometimes the lesion apparently originated in unbroken skin, in the same manneras impetiginous pustule.²⁶

²⁶See footnote 12 (4), p. 281.

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FIGURE 39.-Diphtheritic skin ulcers. A. Skin ulcer over left clavicle withadherent green diphtheritic membrane. Patient acquired lesion in the SolomonIslands. B. Diphtheritic ulcer in skin over left iliac crest 13 weeks afteronset. The lesion was relatively shallow but punched out with adherentgray-green membrane at the base. The lesion was acquired on the island ofSaipan.

Atypical lesions-Although the diphtheritic lesions usually were of thepunched-out, ulcerated character described, it was not uncommon in the tropicsto culture C. diphtheriae from other varieties of skin lesions. Diphtheritic infection was observed in preexisting epidermophytosis of the feet(fig. 41). Occasionally, the opening of the tract was minute and the patient'sdiscomfort disproportionately great. Five lesions of the interdigital spaces ofthe feet were noted in the India-Burma series. Any unexplained sinus tract ofthe feet in soldiers evacuated from the tropics should be suspected of beingdiphtheritic in origin.

Occasionally in the South Pacific and India-Burma groups and frequently inthe Southwest Pacific,²⁷ C. diphtheriae was cultured from adiffuse, moist, ulcerative, and desquamative dermatitis (figs. 42 and 43).

Diphtheritic paronychias were occasionally observed, two eachin the South Pacific and India-Burma areas. One was associated with a moist,diffuse, desquamative dermatitis of the extremities (fig. 43A); another (fig.43B) was a contact lesion in a wardman at the 39th General Hospital, in theSouth Pacific, who daily dressed such a case for many weeks before thediphtheritic nature of the condition had been proved. There was rapid

²⁷See footnote 12 (3), p. 281.

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destruction of the nail, and in one of the Burma cases this seems to havebeen permanent.

MORPHOLOGY IN RELATION TO THE BACTERIOLOGY OF THE LESIONS

The observers in Burma²⁸ were of the opinion that the appearance of thepunched-out ulcers was sufficiently characteristic to enable the diagnosis ofcutaneous diphtheria to be made or ruled out, purely on clinical grounds, in ahigh percentage of cases. Evidence for this view was that, although toxigenic C.diphtheriae was cultured in only 21 percent of their cases, avery high percentage developed such complications as neuritisand carditis even when the cultures were negative. In the group of cases fromSaipan, an attempt was made to predict from the clinical appearance of thelesions, before the results of culture became available, whether it wouldcontain C. diphtheriae. A correct prediction was made in 69.1 percent ofthe attempts at judging 191 ulcerated lesions. This suggests that, in the agegroup concerned and in the territory under consideration, it was C. diphtheriaethat played the important role in giving the lesions their characteristicmorphological stamp, although no claim is made that the lesion is pathognomonic.The observers in the Southwest Pacific Area did not support this view andstated that there was no characteristic lesion.

FIGURE 40.-Penile ulcers. A. Acute membranous diphtheria of coronal sulcusbeginning 4 days post fellationem. B. Diphtheritic ulcer of penisresembling chancre in its firmness but has adherent green membrane from whichtoxigenic Corynebacterium diphtheriae was cultured. The patient hadjust returned from the Solomon Islands and had not indulged in sexualintercourse for more than 1 year.

Among the factors that may determine whether a culture positive for C.diphtheriae is obtained is the interval between the onset of the lesion and

²⁸See footnote 12 (4), p. 281.

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FIGURE 41.-Epidermophytosis superinfected with Corynebacterium diphtheriae. The indurated, rolled edge and deep cavity was characteristic of diphtheritic ulcers in this region. The lesion was acquired during the Battle of Saipan.

the time of culture. Thus, in the South Pacific series, therewas an incidence of 26.3 and 23.4 percent of toxigenic micro-organisms inulcerative lesions of two groups of soldiers, totaling 556 men, who wereevacuated some 6 to 8 weeks after combat (when most of the ulcers wereacquired), compared to an incidence of 6.2 percent in a group of 224 soldiersevacuated some 20 weeks after combat. In this study, all ulcerative dermatitideswere cultured, although the lesion had the typical punched-out appearance. Theobservers in the India-Burma theater also stated that the chances of a positiveculture decreased with the age of the lesion.

Another factor that may prevent finding C. diphtheriae intypical lesions is the application of various forms of treatment, especiallypenicillin, to which C. diphtheriae is sensitive. The analogy may be thatthe shovel that made the ditch is no longer there. In the Saipan group of theSouth Pacific series, 84.1 percent of lesions containing C. diphtheriae weregrossly typical, but only 98 (53 percent) having ulcers thought clinicallytypical yielded C. diphtheriae on culture some 8 weeks after combat.

The duration of the lesions yielding a positive culture seemsalso to be a determinant of the toxigenicity of the strains recovered. Thus, inthe South Pacific series, 40 of 43 (93 percent) diphtheritic ulcers of less than12 weeks' duration yielded toxigenic micro-organisms, whereas of 25 older ulcersonly 17 (68 percent) contained toxigenic bacilli. In one ulcer, a strainrecovered on 18 November 1943 was toxigenic in contrast with one morphologicallyand biochemically identical obtained on 28 January 1944 from the

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FIGURE 42.-Moist,desquamative, and ulcerative dermatitis. VirulentCorynebacteriumdiphtheriae from scalp and ulcers of leg. Lesion acquired in the SolomonIslands.

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FIGURE 43.-Cutaneous diphtheria as seen in the India-Burma theater. Theresemblance to the lesions shown in figures 37-42 in the South Pacific Area isstriking. A. A recent lesion. The ulcer is still shallow and a thin layer offibrinous material adheres to the base. The surrounding tissue is erythematousand moderately edematous. B. A black adherent eschar forms the center of thewell-defined lesion. C. In another instance the eschar has been elevatedrevealing the punched-out character of the lesion and its relatively clean base.D. A more chronic diphtheritic ulcer retaining the punched-out character withrelatively clean granulations at its base. The margin is indurated. Thesurrounding tissue is slightly edematous and has a bronze-violet color. E. Ahealed lesion. The slightly depressed thin scar has been covered by epithelium.A narrow zone of bronze pigmentation is seen.

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recurrent lesions. Similar observations were made in a caseat the Moore General Hospital,²⁹ and the same general observation was recordedby the Southwest Pacific group, as follows: "In some instances, a cultureearly in the disease shows virulent organisms. Later, organisms with the samemorphology and fermentation reactions were isolated, but were non-virulent byguinea-pig tests.''³⁰ These observations indicate that the longer C. diphtheriaepersist in a cutaneous lesion the less likely is the recovered strain to betoxigenic. This probably accounts for the relatively high incidence of atoxicstrains in cutaneous lesions when seen in the United States.³¹ Neuritis inindividuals carrying avirulent C. diphtheriae suggests that they may atone time have harbored toxigenic micro-organisms. Carriers in general have arelatively high proportion of atoxic strains. The mechanism of this is not clearbut may be based on the formation of atoxic variants.³²

In the Saipan group, to determine whether both toxigenic andatoxic strains might coexist in the same lesion, two or three colonies from theprimary plates were tested in each of five instances, but the various strainswere all toxigenic. Toxigenicity was not lost in vitro when a series ofmicroorganisms, which had been stored on blood-agar slants in frigor for aslong as 14 months with only one intervening transplantation, was retested.

There is a possibility that C. diphtheriae, which isnot toxigenic for the rabbit or guinea pig, may have a destructive activity onthe human skin. This is suggested by the work of Pasricha and Panja,³³who injected microorganisms obtained from the "Garigha" sores ofAssam, intracutaneously into other men. Ulcers resembling those of the donorpatients resulted, while diphtheroids similarly inoculated produced no effect.These experiments require confirmation.

Other bacteria were usually associated with C. diphtheriaein the cutaneous lesions. Considering only the 145 ulcers from whichtoxigenic C. diphtheriae was obtained in the South Pacific group, 6yielded pure cultures of C. diphtheriae on blood-agar plates, and in 84others this was the predominant micro-organism. The associated bacteria in thisgroup were almost invariably staphylococci (65 percent), beta hemolyticstreptococci (47 percent), a new hemolytic corynebacterium (9.6 percent)belonging to the common group that includes the animal pathogens Corynebacteriumpyogenes and Corynebacterium ovis, and other diphtheroids (4percent). The new hemolytic corynebacterium was made the subject of a specialstudy and is discussed on pages 293 and 319. The presence of beta hemolyticstreptococci in such high incidence, both in the soldiers and in the natives,contrary to some opinions concerning the rarity of this micro-organism in trop-

²⁹See footnote 17, p. 282.
³⁰See footnote 12 (1), p. 281.
³¹See footnotes 17, p. 282; and 18 (1), p. 282.
³²Dudley, S. F. : Critical Review. Schick's Test and Its Applications. Quart. J. Med. 22: 321-379, January 1929.
³³Pasricha, C. L., and Panja, G.: Diphtheritic Ulcers of the Skin: The "Garigha"of Chittagong HillTracts. Indian J.M. Research 27: 643-650, January 1940.

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ical environments, is of interest. At Harmon General Hospital³⁴ almost all of the 56 ulcerated dermatitides under study had cultures positivefor hemolytic Staphylococcus aureus, but less than 10 percent werepositive for beta hemolytic streptococci.

METHODS OF DIAGNOSIS

Early difficulties-Until educative efforts emanatingfrom higher medical echelons became effective, or until suspicion was raised bythe development of suggestive complications or nasopharyngeal infection incontacts, there was great delay in accepting any of the cutaneous lesions of thetropics as diphtheritic. In the words of Col. William S. Middleton, MC,³⁵Chief Consultant in Medicine, Office of the Chief Surgeon, European theater,"a new generation in medicine has grown up without clinical awareness ofthe disease [diphtheria]." Part of the difficulty resulted from buryingreason in the shroud of obscurant nomenclature, such as tropical ulcer, ecthyma,or "Garigha," and veldt or "Naga" sores. These exotic localnames for a condition general in the tropics fostered the expectation of anexotic etiology. Part of the difficulty, however, resulted from inadequatebacteriological diagnosis, for few laboratory officers had had extensiveexperience with C. diphtheriae in the United States. In one generalhospital, where an alert clinical staff had correlated expert dermatologicalknowledge with the observation of a large number of cardiac and neurologicalcomplications suggestive of diphtheria, there were no positive reports of skincultures for C. diphtheriae during the first 6 weeks of observation of alarge number of patients. Subsequently, positive bacteriological diagnosis of C.diphtheriae was made in approximately 60 percent of the cases.³⁶

Technique of cultures-In experienced hands, the simplestmethods of culture were effective. It was found best to bring the media to thebedside and to remove a small quantity of material from the base of the ulcerwith a platinum loop filled with saline or broth, if necessary. It was notimportant to get beneath overhanging margins or to scrape deeply. The bacteriawere everywhere over the surface of the granulations at the base. If the ulcerwas relatively clean and not crushed, direct culture of the base was successfulwithout further preparation, and it was not necessary to apply alcohol or otheragents. It was far more satisfactory as a routine procedure in hospital cases toapply a warm saline pack to the lesion from 3 to 24 hours, which helped toremove any excessive exudate, fibrinous crust, or ointment that may previouslyhave been applied. Saprophytic bacteria were relatively abundant in the proteinmaterial of the external parts of the exudate.

Corynebacterium diphtheriae in smears-In smears from the lesions,

³⁴See footnote 18 (1), p. 282.
³⁵Semiannual Report, Chief Consultant in Medicine, Office of the Chief Surgeon, Headquarters, European Theater of Operations,U.S. Army, 1 Jan.-30 June 1945.
³⁶See footnote 12 (1), p. 281.

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C. diphtheriae was often found within polymorphonuclearleukocytes of the exudate (fig. 43C). Sometimes, the micro-organisms werenumerous, and the predominant element of the bacterial population, but usuallythere was an admixture of gram-positive cocci in chains and clumps. In exudates,the micro-organisms were observed frequently to be stouter than in the classicaldescriptions, which are based on the appearance of the bacteria on L?ffler'smedium (fig. 43D). The bacteria from cutaneous lesions assumed the classicalforms when grown on this material. In the tropics, great difficulty wasencountered in distinguishing C. diphtheriae from the new hemolyticcorynebacterium that was so frequently found in these lesions as well as ininfections of the throat. C. diphtheriae could usually be differentiatedfrom ordinary diphtheroids, since the former were longer, more pleomorphic, withslender and club-shaped forms, more granular, and less intensely gram positive.

With the Saipan group, an attempt was made to determine how well purelymorphological criteria would bear the test of subsequent bacteriologicalinvestigation. In smears of exudate from 150 ulcers, the presence or absence of C. diphtheriae was correctly predicted in 83.3 percent. In 10 instances,6.7 percent, the characteristic bacilli were not seen in direct smears but werefound in the cultures. In 15 instances, 10 percent, gram-positive pleomorphicbacilli were incorrectly diagnosed as C. diphtheriae from the smears.This demonstrates that, with experience, a reasonably accurate guess can bemade, which may apply under field conditions where facilities for culture arenot available.

Bacteriological media-With the proper use of blood-agar plates, isolatedcolonies could be studied and picked for subculture, usually within 24 hours. Itwas found important-

1. To adjust the pH of the agar to 7.6 before sterilizing, since C.diphtheriae grows better on slightly alkaline media.

2. To cool the medium to 45^? C. or less before adding freshblood. If the blood is overheated, the narrow ring of hemolytis characteristicof C. diphtheriae type mitis may be obscured and the colonies areless readily distinguished from those of staphylococci and diphtheroids.

3. To employ good streaking technique, so that the colonies on the plate werewell isolated and did not present the cream cheese confluence too oftencharacteristic of routine plates in badly conducted laboratories. On thismedium, the differentiation from the unusual corynebacterium is simple, for thelatter produces intensely hemolytic colonies resembling those of the betahemolytic Streptococcus.

L?ffler''s serum was found useful when examined 8 to 12 hours afterincubation, for then C. diphtheriae appears in long slender pleomorphicform, permitting a tentative differentiation from the generally much shorter andthicker diphtheroids. It was extremely difficult, however, to distinguish C.diphtheriae from the new hemolytic corynebacterium.

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Tellurite medium, particularly M?ller's modification,³⁷was very successful in some hands. The difficulty with this medium was thatsome batches of crystalline potassium tellurite supplied early in World War IIseemed to have become partly decomposed during the vicissitudes oftransportation through the Tropics and were more toxic for C. diphtheriae. Onthis medium, there was often a delay of up to 48 hours before typical coloniesof C. diphtheriae made their appearance. The advantages under idealcircumstances are the selectivity of tellurite aiding differentiation of thetype of C. diphtheriae. The new hemolytic corynebacterium generally wasmarkedly inhibited on this material.

In the India-Burma theater, contrary to experience elsewherewhere mitis was found, the micro-organisms were described as being of the intermedius variety.³⁸ In the same theater, at the20th General Hospital, 90 percent of micro-organisms described as virulent C. diphtheriaewere said to ferment sucrose but not dextrose or levulose. In the South andSouthwest Pacific³⁹ experiences, all of the virulent C. diphtheriae weresucrose nonfermenters.

ASSOCIATED CLINICAL FINDINGS

It was noted by all observers that, aside from thecomplications of neuritis and myocarditis, there were usually no generalsymptoms of intoxication when the ulcers alone were the seat of C.diphtheriae. The patients usually complained of nothing more than local discomfort, ifthat.

In rare instances in the South Pacific group, there was anunexplained tachycardia. One had a persistent elevation of the pulse rate to ashigh as 120 per minute on complete bed rest, without fever or changes in theelectrocardiogram. The tachycardia disappeared as the ulcers healed.

It was noted by the observers in Burma that the general feeling of well-beingmay have contributed to the psychoneurotic state observed in some patients whosehospitalization was prolonged because the ulcers failed to heal or because therewas a recurrence during attempts at reconditioning.⁴⁰

Suppurativeadenitis or lymphangitis were remarkably rare despite the presence not only ofvirulent C. diphtheriae but frequently of hemolytic Staph. aureus orbeta hemolytic streptococci. Moderate local swelling of the lymph nodes withoutheat, however, was frequent.

In two Schick-positive individuals, a striking erythema andedema occurred about the ulcers following administration of diphtheriaantitoxin. This may be analogous to the Francis reaction as observed inpneumococcal infections.

Hyperhidrosis of the hands and feet in association with cutaneousdiphtheria was noted by the Burma group in 13 percent of the patients.

³⁷Medical Bulletin No. 2, Office of the Theater Chief Surgeon,Headquarters, Theater Service Forces,European Theater, January 1946, pp. 21-24.
³⁸See footnote 12 (1), p. 281.
³⁹See footnote 16, p. 282.
⁴⁰See footnotes 12 (4), p. 281; and 13, p. 281.

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RELATION TO THE SCHICK REACTION

The relation of the incidence of the lesions to the Schickreaction of the individual is of considerable interest, as it has bothetiological and prophylactic connotations. It was found in the South Pacificexperience that individuals with diphtheritic ulcers are much more frequentlySchick positive than the general population of which the patients are a part(table 43). This indicates that the Schick-negative stage is in large measureprotective. At the Moore General Hospital, 13 of the 18 patients with virulent C. diphtheriae in their cutaneous lesions had positive Schick reactions.These lesions had been present for as long as 4 months. All of those at theHarmon General Hospital, however, had negative Schick reactions. In anotherlarge group in the India-Burma theater (69th General Hospital), 40 percent ofinfected individuals were Schick positive, while 20 percent of uninfectedindividuals in a random sampling of admissions were Schick positive. It is notable that the divisions, after combat service in the Tropics, have alower incidence of Schick-positive individuals than the 35 to 45 percent beforegoing overseas. On the dermatology ward at a large hospital in the UnitedStates, 34 percent of patients from the Pacific admitted with this disease wereSchick positive in contrast with the 75 general medical admissions from thePacific areas, of whom only 13.3 percent were Schick positive. Thirty-twopercent of the individuals harboring avirulent C. diphtheriae were Schickpositive. This suggests a general, largely subclinical, diphtherizationanologous to that which Dudley found in his school studies. Bensted,⁴¹during an outbreak of diphtheria among British troops in northwest India,performed Schick tests on his battalion and observed that all of thosesubsequently developing diphtheritic ulcers were Schick positive.

TABLE 43.-Schick reactions of individuals with diphtheritic tropical ulcers in three infantry divisions in the South Pacific Area

Infantry division	Ulcers containing toxigenic C. diphtheriae		Ulcers containing atoxic C. diphteriae		Reactions
Infantry division	Number tested	Percent positive	Number tested	Percent positive	Number tested	Percent positive
25th and 43d combined	57	42.1	14	28.5	---	---
25th	---	---	---	---	9,000	21.0
43d	---	---	---	---	11,968	27.8
27th	74	20.3	12	8.5	12,135	11.0

Source: Liebow, A. A., MacLean, P. D., Bumstead, J. H., and Welt, L. G.: Tropical Ulcers and Cutaneous diphtheria. Arch. Int. Med. 78: 255-295, September 1946.

⁴¹Bensted, H. J.: A Limited Outbreak of Diphtheria Exhibiting BothCutaneous and Faucial Lesions. J. Roy. Army M. Corps 67: 295-307, November1936.

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Several instances, however, have been recorded of the development ofdiphtheritic ulcers in Schick-negative individuals. One patient in the 27thDivision had been found Schick negative 1 month before admission for adiphtheritic ulcer of 2 weeks' duration. In the India-Burma theater, onepatient, a medical officer, who was known to have had a negative Schick testbefore he acquired the infection, later developed postdiphtheritic neuritis andmyocarditis. In the same group, there was another man, previously Schicknegative, from whose ulcers toxigenic C. diphtheriae was cultivated. TwoSchick-negative individuals in whom cutaneous diphtheria appeared are mentionedin the April 1945 report from the 69th General Hospital in the India-Burmatheater. One had been Schick negative 4? months before thecutaneous lesion developed at the site where he had been scratched by apsychotic Chinese soldier patient. The other was a cook who had been foundSchick negative 3 weeks previously; he had suffered a laceration from trippingover a crate. These cases, as well as others in which the Schick reaction wasnegative within 1 to 5 days after apparent onset, indicate that a negativeSchick reaction does not necessarily imply immunity to cutaneous diphtheria andits complications.

The interpretation of a Schick-negative reaction in an individual withestablished ulcers is difficult. The Schick-negative state may either haveexisted at the time the skin became infected or it may have been induced by themicro-organisms resident in the skin.

Certain patients have positive Schick reactions despite thefact that ulcers containing toxigenic C. diphtheriae have existed formany months. This suggests that the skin is not a good absorbing surface for thetoxin. It has long been known that a single attack of pharyngeal diphtheriafails to reverse the Schick reaction in about 60 percent of persons retested 3to 4 months after recovery. Further evidence that the skin does not absorb toxinas efficiently as the pharynx is the long latent period before neuritis developsin the purely cutaneous cases (p. 301) .

CUTANEOUS AND EXTRACUTANEOUS DIPHTHERIA

Incidence-The concomitance of cutaneous andextracutaneous diphtheria has been noted previously, especially by Bensted, andCameron and Muir⁴²in the Middle East. In the South Pacific studies,routine cultures of the nose and throat of 174 patients with diphtheritic ulcersrevealed C. diphtheriae in 19 (11 percent) of them. This is a muchhigher carrier rate than in the general military population of which thesepatients were a part. Ten of the nineteen individuals had clinical pharyngealdiphtheria, and two had fibrinous rhinitis. There were also six pharyngealcarriers and one nasal carrier. In the India-Burma series, only 1 of the 119patients with ulcers had virulent C. diphtheriae in the throat, but 8others had diphtheroids re-

⁴²Cameron, J. D. S., and Muir, E. G.: Cutaneous Diphtheria in NorthernPalestine. Lancet 2: 720-723, 19 Dec. 1942.

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sembling C. diphtheriae. There was another patient with both faucialand cutaneous lesions who was not included in the series.

Autoinfection of nasopharynx from the skin-In theIndia-Burma series, two questionable faucial involvements occurred more than 6weeks after the onset of postdiphtheritic neuritis, which apparently resultedfrom cutaneous diphtheria.

In 3 of the 12 clinical cases of the South Pacific groupmentioned previously, the patients had been sent to the hospital for thetreatment of ulcers and were found to be Schick positive. Acute pharyngitisdeveloped while the patients were in strict isolation for periods varying from2? to 5 weeks. All three had had negative throat cultures and werenot given antitoxin until the pharyngitis became manifest. These casesdemonstrate that in all probability autoinfection of the nasopharynx from theskin can occur. The other clinical cases were admitted primarily for pharyngitisor rhinitis, although in five of them ulcers antedated the diphtheria of thethroat for periods varying from 3 to 7 weeks.

In 27 pharyngeal cases observed at the 122d Station Hospitalin the New Hebrides, 14 (52 percent) had had skin ulcers that antedated thenasopharyngitis from 1 week to 3 months. In the newly described British seriesof 76 cases of cutaneous diphtheria, 12 were coincident infections of the skinand throat. In nine of these, the skin infection definitely preceded that of thethroat or nose.

COMPLICATIONS

Incidence-The incidence may be described as actual andapparent.

1. The actual incidence of complications, as well as theseverity of the disease, is determined by the toxigenicity of themicro-organisms and by the level of susceptibility of the population. Dudley inparticular has pointed out how susceptibility, by a process of latentimmunization, tends to fall in an environment where C. diphtheriae is widelydisseminated. Evidence that this has occurred in the Tropics is the Schickreaction of veterans of the Pacific campaigns as compared with those oftrainees.

2. The apparent incidence, given constant factors oftoxigenicity and susceptibility, is determined by the accuracy with which allcases of diphtheria, complicated and uncomplicated, are diagnosed. This has beenespecially true in the Tropics, where the clinical manifestations frequentlyhave been very mild (as described by Norris and his coauthors) and where, as aconsequence, skillful bacteriological technique is particular necessary. Manycases of diphtheria have been dismissed as ordinary nasopharyngitis when routinecultures are not taken. Brigadier Dorland of the British Army has expressed thispoint in remarking about the apparent high incidence of complications. In 48cases of faucial diphtheria at the 9th General Hospital on Biak, Oppel foundonly 5 with typical membrane. In this hospital, in February 1945, C.diphtheriae were found in the throat of 12 of 24 cases of acute

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pharyngitis or tonsillitis; common colds were not included inthis series. So mild had the diphtheria been that it was actually the presenceof typical complications that first drew attention to the existence of theinfection, which previously had escaped bacteriological detection. This mildnessis probably the result of latent immunization. Obviously, the apparent incidenceof complications will be high if, because of inferior bacteriological technique,few diagnoses of diphtheria are made.

In any particular series, it is difficult to state whether this factor ortoxigenicity and susceptibility have determined the stated incidence ofcomplications, but all of these possibilities should be kept in mind.

Diphtheritic neuritis-Diphtheritic neuritis was reported from many partsof the world, especially from tropical regions, during World War II. Suchfactors as have been mentioned in the preceding section probably account forthe following variations in the stated incidence of the postcutaneous form:South Pacific Area, 3 of 85 patients (4 percent); Southwest Pacific Area, 6 of102 patients (6 percent); India-Burma theater, 61 of 141 patients (43 percent)at the 20th General Hospital and 19 of 40 patients (48 percent) at the 69thGeneral Hospital.

Since the differential diagnosis and detailed clinical description arepresented in another volume in the history of the Medical Department in WorldWar II,⁴³ no more than a few general remarks will be made here.Caution must be exercised in accepting neuritis as a complication of cutaneousdiphtheria. The minimal evidence that neuritis is of cutaneous rather thannasopharyngeal origin is the demonstration of C. diphtheriae in the skinand its absence in the nose and throat. Gathering this evidence has beenneglected in many series of cases, including the earliest ones of Walshe.⁴⁴

Cultures of all known foci of diphtheritic infections are especiallyimportant in view of the mildness of the nose or throat symptoms in some cases,especially of anterior nasal diphtheria, where crusting and nasal discharge maybe minimal. It must be remembered, however, that even if the microorganisms arefound only in the skin they may at one time have been present in the nasopharynxwhere they may no longer be demonstrable. This is emphasized by the fact that insome series it has been specifically stated that the patients spontaneouslymentioned neither the sore throats nor the skin lesions in giving an account ofthe symptoms antecedent to the first neurological illness.⁴⁵ Thus, insome series of cases it is not possible to state to which variety of diphtheriathe neurological complications are related.

In contrast to the nature of the complication followingpharyngeal diphtheria, the cranial nerves, particularly the ninth, were rarelyinvolved in cases proved to be purely cutaneous. It was generally true also inSamp-

⁴³Medical Department, United States Army. Internal Medicine in World War II.Volume III. Infectious Diseases and General Medicine. [In preparation.]
⁴⁴Walshe, F. M. R.: Post-Diphtheritic Paralysis. Note on a Form FollowingCutaneous Diphtheria. Lancet 2: 232-233, 24 Aug. 1918.
⁴⁵Perkins, R. F., and Laufer, M. W.: Clinical Study of PostdiphtheriticPolyneuritis. J. Nerv. & Ment. Dis. 104: 59-65, July 1946.

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son's series of 20 cases, and a similar impression was heldby Quillinan,⁴⁶ although no detailed evidence was presented. This maybe less true of paralysis of accommodation, which is transient, and in whichespecially skillful observation is necessary, than of pharyngeal paralysis.There is no doubt that diphtheritic neuritis can occur in individuals withpositive Schick reactions. Apparently, in some instances, the toxin is absorbedupon the nervous tissues sufficiently to result in neuritis, while not enoughantitoxin is stimulated to reverse the Schick reaction. Generally speaking, asingle clinical attack of nasopharyngeal diphtheria fails to reverse the Schickreaction in approximately 60 percent of cases. Low antibody levels do notpreclude previous, even relatively recent, diphtheritic infections, as Bronson⁴⁷would imply. This is pointed out by the observations of Gammon andSchoenbach. In Bronson's series, it is mentioned that 80 percent of provedcutaneous diphtheria, even of long duration, had positive Schick reactions.Also, Bronson mentioned a patient with nasopharyngeal diphtheria who was Schickpositive 3 months after the infection and who had had antitoxin for treatment inthe meantime. Three in Sampson's series had positive Schick reactions at thetime the neuritis was diagnosed, but in these cases C. diphtheriae was notdemonstrated. In the 20th General Hospital group, all patients with definitecomplications had negative Schick tests.

In most cases of undoubted diphtheritic neuritis, there is anelevation of spinal fluid protein, sometimes with changes in the colloidal goldcurve, but almost always without pleocytosis.⁴⁸ In Delp, Sutherland,and Hashinger's⁴⁹cases, the spinal fluid protein levels variedbetween 57 and 230 mg. percent. The average in Perkins and Laufer's⁵⁰ seriesof 21 cases was 114 mg. percent, but some were as high as 200 mg. percent. InSampson's group of 20 instances, most of which were postcutaneous, approximatelyone-third were below 40 mg. percent, the others were higher, and the maximum was134 mg. percent. In the India-Burma series, the proteins were described aselevated in nearly every case and in general "proportional to the severityof the neurological disease."⁵¹This so-calledalbuminocytological dissociation has caused a great deal of confusion, and muchneuritis of diphtheritic origin has been classified under the Guillain-Barr?syndrome, rather than under the etiological diagnosis. Often, this has been inflagrant disregard of the principle that eponyms should be applied only to thesyndrome as originally described. A part of the confusion has arisen from lackof knowledge of

⁴⁶Medical Bulletin No. 2, Office of the Theater Chief Surgeon, Headquarters,Theater Service Forces, European Theater, January 1946, pp. 19-20.
⁴⁷Bronson, L. H.: On the Etiology of Neurological Disease FollowingInfections of the Throat and Skin and the Incidence of Diphtheritic Infections. Arch. Neurol.& Psychiat. 56: 558-566, November 1946.
⁴⁸(1) See footnote 8, p. 279. (2) Rankin, J. H.: Diphtheritic Polyneuropathy.ETO M. Bull. 32: 32-35, July-August 1945.
⁴⁹Delp, M. H., Sutherland, G. F., and Hashinger, E. H. : Post-Diphtheritic Polyneuritis: A Report of Five Cases With Albuminocytologic Dissociation SimulatingGuillain-Barr?'s Syndrome. Ann. Int. Med. 24: 618-628, April 1946.
⁵⁰See footnote 45, p. 299.
⁵¹See footnote 12 (4) and (6), p. 281.

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cutaneous diphtheria and its scars. Also, there has beenignorance of the fact that a positive Schick reaction is not incompatible withdiphtheritic neuritis. The greatest cause of the difficulty, however, has beeninadequate bacteriological diagnosis of cutaneous and mild nasopharyngealdiphtheria. These remarks must not be construed to imply that there were noother causes of neuritis among U.S. soldiers; some had all of the features ofthe syndrome as originally described by Guillain, Barr?, and Strohl.⁵²It is desired to emphasize here, however, that the vast majority of cases ofneuritis seen in the tropics were diphtheritic in origin.

In the South Pacific series, it was considered desirable to subdivide thecases of neuritis, as follows:

Group A.-Neuritis complicating proved cutaneous diphtheria without evidenceof C. diphtheriae elsewhere.

Group B.-Neuritis associated with ulcers of the skin unhealed at the time ofadmission but not demonstrated to contain C. diphtheriae.

Group C.-Neuritis in individuals with scars of tropical ulcers.

Group D.-Neuritis in individuals with scars of tropical ulcers and history ofsore throat.

Group E.-Neuritis in individuals proved to have diphtheritic pharyngitis.

Group F.-Other cases of neuritis clinically indistinguishable fromdiphtheritic neuritis.

After the diphtheritic nature of certain tropical ulcersbecame apparent, there was no instance of neuritis of the type discussed that couldnot be related either to the ulcers, sore throat, or to proved diphtheriticpharyngitis or dermatitis.

Notable in cutaneous diphtheria is the long incubation periodof neuritis. In the three cases in group A of the South Pacific series, thesymptoms began between 3 and 7 months after the lesion was first noted bythe patient. In two of the patients, the lesion occurred 2 and 4 months,respectively, from the time that the toxigenic C. diphtheriae was firstcultured from the lesion. In pharyngeal diphtheria, neuritis most commonlybegins within 6 weeks after onset of sore throat. In a series of 21 casesof neuritis observed at a neurological center in the United States, the averagetime of appearance of the neurological symptoms after onset of thenasopharyngeal disease was 26 days, whereas it was 2? months after the onset of the cutaneous lesion.⁵³ There is somevariation in this, since in another group at the Baxter General Hospital⁵⁴ theincubation period of the cutaneous cases varied between 30 and 77 days,and of the pharyngeal cases between 30 and 72 days. The interval betweenthe onset of the ulcers and the onset of the

⁵²Guillain, G., Barr?, J. A., and Strohl, A.: Sur unsyndrome de radiculo-n?vrite avec hyperalbuminose du liquide cephalo-rachidiensans r?action cellulaire. Remarques sur les caract?res cliniques et graphiquesdes r?flexes tendineux. Bull. et m?m. Soc. m?d. d. h?p. de Paris 40: 1462-1470, 13 Oct. 1916.
⁵³See footnote 45, p. 299.
⁵⁴See footnote 19, p. 283.

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neuritis in the India-Burma series was 68 days in the 20thGeneral Hospital group and 73 days in the referred patients. It was of the sameorder of magnitude at the 69th General Hospital in the same theater.⁵⁵ In areported British experience in North Africa,⁵⁶an interval of 6 to10 weeks elapsed in most cases after the skin lesions were noted and before theneurological symptoms appeared.

The duration of the neurological symptoms is considerable. In Sampson'sseries, it varied between 50 and 155 days. In the India-Burma group, the averagecase lasted 100 days.

Among the interesting clinical manifestations is the fact that, contrary toother varieties of neuritis, persistent muscle weakness was rare. One instance,however, is reported by Sampson in which there was residual paralysis of theserratus anterior and deltoid muscles. The group at Baxter General Hospitalobserved a partial electrical reaction of degeneration in all of the severecases. Pain was a most unusual symptom.

Carditis in cutaneous diphtheria-Myocarditis has come to be the mostimportant cause of death in diphtheria. During World War II, tissues from 221cases of diphtheria were sent to the Army Institute of Pathology (now the ArmedForces Institute of Pathology), Washington, D.C., for study.⁵⁷ There wasevidence of myocarditis in 143 or 65 percent of these cases. By 1945,postdiphtheritic myocarditis had become an important cause of death among troopsin the army of occupation in Germany. At the 7th Medical Laboratory,⁵⁸Gr?felfing, Germany, it was the cause of death in 12 of the 285 post mortemexaminations reviewed, and at the 4th Medical Laboratory,⁵⁹ Paris, France,in 15 of 1,021 autopsies. In all but 1 of these 27 fatal cases of myocarditis,antitoxin had been administered 5 or more days after the onset of diphtheria, ifat all. Cutaneous diphtheria also was complicated by myocarditis, as seen ineight of the deaths in the Army Institute of Pathology series with such apathogenesis.

In the India-Burma group of 141⁶⁰ cases ofcutaneous diphtheria, indubitable evidence of carditis existed in fourinstances, one of which came to autopsy, and of probable myocarditis in three, atotal incidence of 5 per cent. In seven others, there were suggestive findingsin the electrocardiographic tracings, but the diagnosis could not be definitelyestablished. All individuals with definite myocarditis had extensive skinlesions. A program of case finding was instituted which included a carefulphysical examina-

⁵⁵See footnote 14 (1), p. 281.
⁵⁶See footnote 7 (2), p. 279.
⁵⁷Gore, I.: Myocardial Changes in Fatal Diphtheria; Summary of Observationsin 221 Cases. Am. J.M. Sc. 215: 257-266, March 1948.
⁵⁸Medical Bulletin No. 2, Office of the Theater Chief Surgeon, Headquarters,Theater Service Forces, European Theater, January 1946, pp. 14-18.
⁵⁹Medical Bulletin No. 1, Office of the Theater Chief Surgeon, Headquarters,Theater Service Forces, European Theater, December 1945, pp. 19-23.
⁶⁰(1) Kay, C. F.: Myocardial Complications of CutaneousDiphtheria. [Official record.] (2) Kay, C. F., and Livingood, C. S.: MyocardialComplications of Cutaneous Diphtheria. Bull. U.S. Army M. Dept. 4: 462-464, October 1945.

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tion, as well as electrocardiographic tracings, as soon as possibleafter the diagnosis of cutaneous diphtheria was made, and at intervals of 15to 30 days thereafter until well after the lesions had become inactive. In thesame group of 141 individuals, the incidence of neurological complications was43.5 percent. All four of those with definite myocarditis had neuritis. Neuritisusually preceded myocarditis except in the one fatal case. The earliestappearance of the electrocardiographic changes was on the 20th day of theexistence of the cutaneous lesion; in the fatal case, the severe symptomsappeared on the 38th day, followed by death 3 days later; and in another case,myocarditis appeared on the 60th day. The duration of electrocardiographicchanges was from 60 to 90 days among those in whom the diagnosis was certain andapproximately 30 days in those in whom the diagnosis was considered probable.The incubation period was shorter in the postpharyngeal cases.⁶¹

The clinical findings were usually minor. Four patients inthe India-Burma group were asymptomatic, two complained of dyspnea and faintnesson slight exertion, and the one who died first suffered abdominal pain withnausea and dyspnea on exertion. Eighteen hours before death, discomfort extendedupward into the chest, then there was vomiting, collapse, fall in bloodpressure, gallop rhythm, and leukocytosis. The electrocardiographic tracingsusually did not show a P-R interval in excess of 0.20 second, nor wereabnormalities in the QRS segment striking. The most consistent abnormalitieswere depression or frank inversion of T-waves in the C-R3 lead. These occurredin all but the fatal case of the India-Burma group. This was also the experienceof Ball who emphasized depression of the S-T interval. Conduction defectsapparent in the two cases of myocarditis that followed nasopharyngeal diphtheriawere not observed among the postcutaneous cases in the India-Burma group, butthey were described in other instances that apparently followed diphtheria ofthe skin.⁶²

Several writers have stressed the importance of serialelectrocardiographic tracings to diagnosis.⁶³Careful observations of pulseand blood pressure must, however, not be forgotten.

Delp and Dimond, who were successful in treating two severecases of myocarditis, emphasized the importance of putting the patients atabsolute rest, elevating the foot of the bed, applying external heat, and slowlyadministering glucose solution by vein.

⁶¹(1) Ball, D.: Diphtheritic Myocarditis; With Report of 2 cases. Am. HeartJ. 29: 704-707, June 1945. (2) Craig, C. McK., and Manch, M. D.: A Study of theAetiology of the "Desert," Septic, or Veldt Sore Amongst EuropeanTroops; And Its Association With Faucial Diphtheria. Lancet 2: 478-479, 13 Sept.1919. (3) Delp, M. H., and Dimond, E. G.: Diphtheria and the Heart. J. Kansas M. Soc. 47: 254-259, June 1946.(4) See footnote 60 (1), p. 302.
⁶²(1) Greene, R. C.: Combined Sulfonamide and Diphtheritic Myocarditis inCutaneous Diphtheria. Am. Heart J. 32: 250-256, August 1946. (2) Solomon, S.,and Irwin, C. W.: Cutaneous Diphtheria With Toxic Myocarditis; Report of FatalCase With Necropsy Findings. Ann. Int. Med. 26: 116-120, January 1947.
⁶³See footnotes 61 (3), above; and 60 (1), p. 302.

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TREATMENT OF CUTANEOUS DIPHTHERIA

Case finding and methods of study-After the high incidence of cutaneousdiphtheria in tropically acquired cutaneous infections was recognized, andparticularly after the dangers of contact cases were realized, relativelyefficient methods of case finding were instituted. These consisted intemporarily isolating all patients with ulcerative dermatitis and makingcultures designed to detect C. diphtheriae. In some institutions, newpatients were held on a special admission ward. Routine cultures were made frommaterial from the cutaneous lesions and from the nose and throat. If the culturewas positive for C. diphtheriae, the patient was treated specifically inisolation until virulent organisms were no longer recovered. The other patientswere released for treatment in a general dermatological ward. Such a method wasfound valuable in the South Pacific study in handling the heavily infected 27thDivision in the New Hebrides rest area. After a series of talks designed toacquaint the battalion surgeons with diphtheria of the skin, a centrally locatedclinic was established to which all patients with tropical ulcers were referredfor culture. Those found positive were hospitalized. In this way, many patientswere put under treatment, and the dissemination of the organisms was checked.This procedure was especially effective in curbing contact cases. Oppel and hiscoworkers reported that a similar method was adopted in the Southwest PacificArea. Individuals who were found to have cutaneous lesions infected with C. diphtheriaeand were Schick positive were treated with antitoxin. The procedure at MooreGeneral Hospital and at Harmon General Hospital was similar. The desirability ofmaking nose and throat cultures in such cases was stressed in theseinstitutions, as was also the use of Schick-negative attendants in caring forthem.

Antitoxin-During the Second World War, serum therapy was not productiveof remarkable results in the local lesions so far as could be determined byobservers of wide experience. Certainly, serum was not lethal to the organisms,which may persist for many days after treatment. At Moore General Hospital, itwas necessary to keep patients isolated for an average of 61 days, whether ornot antitoxin had been administered. Antitoxin, however, may act as aprophylactic in preventing the serious consequences of autoinfection of thenose and throat. Also, experience in the India-Burma theater indicated thatantitoxin, even when given late in the course of a cutaneous infection, seemedto be valuable in preventing complications (table 44). On the other hand, thehealing time in the India-Burma group was not reduced; in 69 individuals givenantitoxin, the average was 48 days in contrast with 41 days among 28 individualswho did not receive antitoxin. It was also the impression in the India-Burmatheater that better scars resulted in those treated with antitoxin, provided itwas administered within 30, or better, within 12 days of onset. It issignificant to note that of the 14 patients in the India-Burma group who werereclas-

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sified or transferred to the Zone of Interior, none had haddiphtheria antitoxin within 32 days after onset of the lesions. These statementsare to be regarded as suggestive, rather than final, statistically provedconclusions. According to Livingood,⁶⁴ the most importantfactors in preventing complications, loss of man-days, and loss of life fromcutaneous diphtheria are early diagnosis of the disease, prompt hospitalization,and administration of diphtheria antitoxin as soon as possible.

TABLE 44.-Study of influence of antitoxin on incidence of complications in 103 patients with diphtheria, 20th General Hospital, India-Burma theater

Complication	Antitoxin given within 32 days after onset (36 patients)	Antitoxin given 32 days after onset (36 patients)	No antitoxin given (31 patients)
Neuritis	6	10	17
Neuritis and probable myocarditis	---	1	---
Neuritis and myocarditis	---	---	2
Myocarditis, probable	1	---	---
Myocarditis, acute, severe	---	---	1
Percent patients with complications	19.4	30.6	64.5

NOTE.-Most of the men who received no antitoxin, or who received it late in the course of the disease, had the more severe lesions. Therefore, the results recorded in the table must be viewed with caution.

Local treatment-The most important principles in healingthe ulcers seen in the South and Southwest Pacific and in Burma seem to havebeen bed rest and the application of moist dressings. Outpatient treatmentresults in the lesions remaining unhealed for many weeks and continuing as aprolific source of diphtheria bacilli. Although C. diphtheriae is sensitivein vitro to sulfonamides, in ulcers it seemed to be almost unaffected by thesedrugs. In many instances in the South Pacific, the organisms were cultureddirectly from lesions packed with crystals or covered with sulfonamide ointment.Application of sulfonamides, however, gave the lesions a cleaner appearance.

Penicillin, locally applied in concentration of 250 units percubic centimeter in physiological saline, has certain very definite indicationsthat became evident during the course of a series of controlled observations inthe South Pacific Area on Schick-negative individuals whose lesions containedtoxigenic bacilli. The actual healing time of the ulcers was not significantlyreduced. Results of treatment of lesions containing toxigenic C. diphtheriaeinSchick-negative individuals are shown, as follows:

Type of treatment	Number of patients	Mean healing time (days)
Local, exclusive of penicillin	27	18.6
Penicillin soaks	43	16.5

⁶⁴See footnote 12 (4), p. 281.

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In the India-Burma experience, penicillin seemed to give moreinitial improvement and afforded more relief from pain, but after 2 weeks itseffect was not superior to those of other measures. Nevertheless, in the SouthPacific, in each of six instances where an ulcer treated locally with penicillinwas compared bacteriologically with a saline-treated control in the sameindividual, it was found that the toxigenic bacilli invariably disappeared fromthe former within 48 hours after the application of penicillin, whereas, in thelatter, they persisted until the lesion was almost healed. The observations atHarmon General Hospital were similar, pathogenic organisms being eliminated incases treated parenterally with penicillin in an average of 4 days; in thosetreated with saline alone, only 25 percent were cleared of the organisms in anaverage period of 8 days. Penicillin reduced not only the hazard of long contactwith C. diphtheriae to the patient himself but to the community at large.

There seems to be some variation in resistance of diphtheriabacilli to penicillin, as emphasized by McDaniels.⁶⁵ His results indicatingpenicillin resistance of a majority of strains, however, are not in harmony withthose of other observers, nor with the general clinical experience as summarizedin the preceding section. McDaniels did not state the number of bacilli employedin his test, an important factor in determining resistance to inhibitory agents.

Surgical measures-The experience of the India-Burmagroup indicated that operation should be considered if the ulcer fails to healin 60 to 70 days. In diphtheritic ulcers a contracting scar was not formed;also, the thin new skin broke down once in every three patients. The mostsuccessful methods in a small group treated by Royster⁶⁶ seemed to beexcision of the ulcer and a small margin of normal skin, followed by applicationof a split-thickness skin graft, rather than of the sliding flap, or extensiveundermining and simple closure. The skin adjacent to the graft became morepliable. Skin grafts simply applied to large ulcers, even after they had begunto granulate cleanly, failed to take.

Factors in healing time-If an atoxic organism waspresent, the healing time seemed to be significantly reduced. The followingtabulation shows the relation of toxigenicity of C. diphtheriae tohealing time in hospital:

C. diphtheriae	Patients (number)	Mean healing time (days)
Organisms toxigenic	107	19.2
Organisms atoxic	21	11.4

⁶⁵McDaniels, H. E.: Penicillin Resistance of Diphtheria Bacilli. Mil. Surgeon 96: 95-96, January 1945.
⁶⁶Royster, H. P.: Surgical Management of Cutaneous PostdiphtheriticUlcers. Plast. & Reconstruc. Surg. 3: 294-302, May 1948.

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Conclusions-These observations suggest that the most efficient way ofhandling the patients is to put them at rest in bed and to apply penicillinlocally in continuous soaks of 250 units per cubic centimeter. Most cliniciansrecommend the administration of antitoxin, at least if the individual is Schickpositive. In retrospect, it would probably have been best to send onlySchick-negative individuals into combat in the Tropics.

COST OF CUTANEOUS DIPHTHERIA TO THE ARMY

A substantial amount of disability was caused by cutaneous diphtheria duringWorld War II. The lesions were present in all tropical areas, but the exactincidence is difficult to estimate. In the 35th Infantry, 25th Division, 6weeks after evacuation from the New Georgia campaign, 19.4 percent of 200 menwho were carefully questioned and examined had either active lesions or scarssuggestive of previous infection with C. diphtheriae. Two of these wereactually proved to have the organisms in their lesions. At the 54th GeneralHospital on Biak, 29 percent of admissions to the medical service were becauseof skin disease. It can be assumed that a considerable proportion of this was ofdiphtheritic etiology. In the South Pacific Base Command between 1 January and30 June 1944, skin disease was the primary diagnosis of 9 percent of all medicalevacuations to the United States. Many of these skin cases that had been studiedat the 39th General Hospital were proved to be diphtheritic.

Much of the disability was the result of the location of the lesions on thefeet and other places likely to be injured, an obvious consequence of the factthat trauma was a factor in their causation.

In a followup study of 140 patients in the India-Burma series, a total of18,783 man-days were lost, an average of 4? months per man, notincluding the days lost by 30 patients after their return to the Zone ofInterior.⁶⁷ The total duration of skin lesions from appearance to healingaveraged 91 days in another series in the India-Burma theater.⁶⁸

The chief causes of prolonged hospitalization were breakdown of the thinscars when activity was resumed, or the neuritic or cardiac complications of thedisease. In 53 of the 140 cases in the India-Burma group, the scars broke downupon resumption of activity and 13 of these showed no tendency to heal. This wasthe final result reported in August 1945. At the end of January 1945, in thatgroup,⁶⁹the causes of hospitalization in excess of 70 days in atotal of 96 patients (69 percent of the total) were summarized, as follows:

⁶⁷See footnote 13, p. 281.
⁶⁸See footnote 14, p. 281.
⁶⁹See footnote 12 (4), p. 281.

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	Number
Neuritis	40
Indolent lesions	24
Recurrent lesions	23
Cardiac complications	4
Neuritis and definite cardiac complications in the same patient	3
Impetiginous eczema	2
Total	96

The total number of man-days lost in the 106 individuals on whom data are available in the South Pacific series was 2,077, an average of 19.6 days per man. The difference probably lies in the selection of cases. Probably only the more typical and severe cases were studied in Burma. This perhaps also accounts for the high incidence of neuritis in the India-Burma theater as compared with the South Pacific Area.

The followup study of the experience in the India-Burmatheater showed that 60 percent of the men had returned to full duty; 18 percenthad been reassigned, 12 of 25 because of cutaneous diphtheriaalone; 22 percent had been returned to the Zone of Interior, 13 of 30because of cutaneous diphtheria alone. It seemed, however, that prolongedinactivity occasioned by the cutaneous diphtheria had predisposed to thedevelopment of psychoneurosis which was listed as the primary diagnosis in somecases. When this is added to the followup study, the results are that 20 of 25 were reassigned and22 of the 30 were returned to the Zone ofInterior for causes ascribable to cutaneous diphtheria.

ROLE OF CUTANEOUS LESIONS IN THE SPREAD OF DIPHTHERIA

Evidence that Schick-positive individuals may infect the nasopharynx fromtheir own cutaneous lesions has already been presented. Much evidence hasaccrued that ulcers can be a prolific source of diphtheria in others.

Evidence from contacts in hospitals-Inthe late springand summer of 1943 at the 39th General Hospital, in the South Pacific group,there were six instances of apparent contact infections among members of thestaff or patients before tropical ulcers were recognized to be diphtheritic. Anurse attending an officer with widespread desquamative and ulcerative lesionshad paronychia and an abscess in her arm from which C. diphtheriae andbeta hemolytic streptococci were isolated. Another nurse attending the samepatient contracted a sore throat which was not of membranous type. This nursewas known to have been Schick negative previously. Another officer, who had beenadmitted for jaundice 2 weeks before and who did not have a sore throatat the time of admission, was placed in the cubicle next to the first case anddeveloped an extensive membranous nasopharyngeal diphtheria. A wardman onanother ward, where many patients with tropical ulcers were kept, developed aparonychial granulomatous and ulcerative lesion from which the toxigeniccorynebacteria were cultured (fig. 44), and shortly

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thereafter another attendant on the same ward developeddiphtheritic pharyngitis. Pharyngeal diphtheria developed in a wardman onanother dermatology ward where there were many ulcer cases. All of thesemembers of the hospital staff had been on wards caring for patients withcutaneous lesions. After isolation procedure was instituted for diphtheritictropical ulcers, no other contact cases appeared except one in a nurse,attending an isolated patient with diphtheritic pharyngitis, who acquired asevere membranous nasal diphtheria. From all seven of these contact cases,virulent corynebacteria were isolated.

This experience in the South Pacific Area was not unique. In the India-Burmagroup,⁷⁰ 11 patients acquired cutaneous diphtheria after a period ofhospitalization for another disease or injury. Faucial diphtheria developed in another patient in the 20th General Hospital 4weeks after admission to the dermatology ward. Two of the patients withcutaneous diphtheria acquired pharyngitis and tonsillitis. In one patient,virulent organisms were isolated 3 weeks after admission, and in the othernontoxigenic bacilli were found 6 weeks after admission. Similarly, in aBritish experience in North Africa,⁷¹ one nursing sister and one orderly in thedermatology ward contracted faucial diphtheria, and the medical officer incharge developed cutaneous diphtheria.

At the 13th General Hospital,⁷² Finschhafen, two cases ofdiphtheria were recognized in the dermatology ward. Within the next 8 days, 7clinical cases and 33 carriers were found by culture and were isolated, and inthe following 7 days, 3 cases and 2 carriers were discovered. Seven patients inthe dermatology section were found to be harboring the organism in skin lesions.The experiences at Lae, New Guinea, and at Hollandia were similar. In summary,then, beginning in the latter part of September 1944, cases of pharyngealdiphtheria appeared in wards devoted exclusively to dermatological cases andsimilar outbreaks centered around these wards.

At Harmon General Hospital,⁷³ a case of faucial diphtheriadeveloped on a dermatology ward. The procedure described in the section ontreatment and case findings was then instituted (p. 304). The results ofculturing 42 patients and 11 attendants on the ward at the time the first casewas discovered were that 10 were found to have C. diphtheriae, 2 of whichwere proved to be toxigenic. One of the patients with toxigenic organisms was anurse.

At Letterman General Hospital,⁷⁴ eight cases of diphtheria originated in thedermatology section between 21 and 29 September 1944. The first four occurred inwardmen; the next two were in personnel of the physiotherapy section. All wereof the pharyngeal type and were moderately

⁷⁰See footnote 12 (4), p. 281.
⁷¹See footnote 7 (2), p. 279.
⁷²Essential Technical Medical Data, U.S. Army Forces in the Far East, for October 1944.
⁷³See footnote 18 (2), p.282.
⁷⁴See footnote 20, p. 283.

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severe except the first, which was fulminating, withhemorrhagic membrane. All organisms isolated were of the toxigenic mitis variety.Cultures of dust from the dermatology ward were found to contain C. diphtheriae,which was virulent for a guinea pig. The noses and throats of the patientsand personnel of the dermatology and physiotherapy sections and in the castroomwere also cultured and 14 were found to harbor toxigenic C. diphtheriae. Sixof the fourteen were Schick positive. These observations emphasize the menace ofunrecognized cutaneous diphtheria.

GENERAL CONSIDERATIONS OF DIPHTHERIA IN THE TROPICS

Diphtheria among the natives-In the course ofinvestigating the cutaneous diphtheria among the soldiers in the New Hebridesand later on Saipan, it was noted that the natives, particularly young children,had cutaneous lesions resembling those of the soldiers. Many of these were foundto contain C. diphtheriae. Two of four Melanesian natives (figs. 43E and45), one with apparently superinfected yaws, yielded atoxic C. diphtheriae. Six of fifty-three Tonkinese children had multiple punched-out lesionsgenerally more superficial but like those observed in the soldiers (fig. 44).Four of these yielded organisms that had the morphological and biochemicalcharacteristics of C. diphtheriae type mitis but were nottoxigenic. Lesions of identical appearance were found in large numbers amongChamorro children on Saipan. Fifteen strains of C. diphtheriae type mitisderived from these were tested for toxigenicity and one was found to betoxigenic. It is of some interest to note, and not easy to explain, that some ofthese ulcers occurred in older children who were Schick negative. The lesionswere most numerous where trauma was likely to occur, as about the knees, butthey also were found elsewhere. Scars of such lesions were abundant in childrenmore than 7 months of age, and they were almost universal above the age of 3years.

Many studies have been made of Schick reactions of thenatives in the Tropics. All have shown a high level of immunity. This has beenfound to be true among Filipinos, Malayans, Javanese, Hondurans, Brazilians, andthe Bantu of Africa.⁷⁵During World War II, in the British Army, theincidence of Schick-positive individuals among 900 sepoys was 1.1 percent,whereas among the British troops it was 27 percent.⁷⁶ In the SouthPacific Area, the Schick reactions of natives more than 5 years of age werealmost invariably negative in the Solomons (Melanesians), New Hebrides(Melanesians and Tonkinese indentured laborers and their families), and Saipan (Chamorros).Only between the ages of 7 months and 3 years was there a high incidence ofSchick positives, in excess of 50 percent, among

⁷⁵(1) Grasset, E.: Studies on Nature of Antidiphtheritic Immunity AmongSouth African Bantu by Means of Schick Test and Antitoxin Titrations. SouthAfrican M.J. 7: 779-785, 8 Dec. 1933. (2) Murray, J. F.: Diphtheria Amongst theBantu. J. Hyg. 43: 159-169, September 1943.
⁷⁶See footnote 1, p. 276.

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FIGURE 44.-Diphtheriticparonychiae. The patient was a wardman and, forseveral weeks, had attended an officer with lesions resembling those shown infigure 42. This was a contact case that occurred at the 39th General Hospital inNew Zealand, 1943.

FIGURE 45.-Toxigenic Corynebacterium diphtheriae in skin of palms andmultiple paronychiae of 6 weeks' duration, acquired in the Solomon Islands.There was moist, desquamative dermatitis of the extremities with ulcer of leg.

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the natives of the various races investigated. The theory wasadvanced for the first time, that the rapid reversal of Schick reaction was theresult of immunization by the cutaneous route. It appears that the antitoxinlevel falls sufficiently to give a positive Schick reaction for only a shorttime, after loss of the transplacentally acquired immunity. This probablyaccounts for the rarity of severe nasopharyngeal diphtheria among natives of theTropics.

Conditions among soldiers analogous to those of the natives-It hasbeensuggested that the same conditions which favor the establishment of the enormousreservoir of cutaneous diphtheria that has been demonstrated among the nativesprevail also among soldiers in combat. These conditions are:

1. The warm, moist condition of the skin, which comes to resemble thepharynx.

2. The lack of facilities for washing.

3. The intimate crowding of the population.

4. The numerous opportunities for minor trauma produced mechanically or byinsects.

5. The abundance of flies.

All of these conditions are extremely favorable for thespread of cutaneous diphtheria. Among the soldiers, where there are manyindividuals with low antitoxin titers, in contrast with the natives, there was ahigh incidence of nasopharyngeal as well as cutaneous infection. The barrier ofcleanliness accounts for the fact that colonizers living in the Tropics underpeacetime conditions are generally more susceptible than the natives, asindicated by the results of Schick tests, and that the former sometimes havenasopharyngeal diphtheria in epidemic form. One such epidemic is recorded by Foxand MacDonald (quoted by Forbes),⁷⁷ in a school at Shillong, Assam, the veryregion where tropical ulcers have been so common in natives as well as in U.S.soldiers.

The tropical environment in association with the dirt and crowding is thedetermining factor in the spread of the cutaneous varieties of diphtheria. Theoriginal source of C. diphtheriae is difficult to determine. Carriers arealways present in our own population, and the native reservoir may at times beimportant.

ASSOCIATION OF CUTANEOUS AND NASOPHARYNGEAL DIPHTHERIA IN MILITARY UNITS IN THE TROPICS

As in the desert campaigns described so well by Bensted,⁷⁸ andCameron and Muir,⁷⁹ nasopharyngeal diphtheria has been coexistentwith, but usually

⁷⁷Forbes, J. G.: The Prevention of Diphtheria. Special Report Series No.115. London: His Majesty's Stationery Office, 1927.
⁷⁸See footnote 41, p. 296.
⁷⁹See footnote 42, p. 297.

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has been exceeded in incidence by, cutaneous diphtheria. Thiswas true again in British experience in the Mediterranean, in the South Pacific,and in the Southwest Pacific, although at the 20th and 69th General Hospitals inthe India-Burma theater⁸⁰relatively few nasopharyngeal cases werediagnosed. The course of the epidemic in the 27th Division while at the restarea in the New Hebrides is shown in table 45. The peak occurred on 23

CHART 14.-Number of cases of skin diseases and diphtheria and tonsillitis in the Afrika Korps, 1942

September 1944. In this same group, 17 nasopharyngeal caseshad previously been diagnosed on Saipan, shortly after the campaign on thatisland. In a more general way, the incidence of skin disease and diphtheria andtonsillitis was closely parallel also in the Afrika Korps (chart 14).

It will be noted in table 45 that, as the patients with ulcers were removedfrom the division by use of the outpatient clinic described previously, theincidence of nasopharyngeal diphtheria decreased rapidly. The course of theoutbreaks was almost identical in the 25th and 43d Divisions previously studiedin New Zealand.

Skin-to-skin contact seems the most usual method of thespread of the bacilli among the crowded combat troops in the Tropics. This issupported by the fact that in general the nasopharyngeal carrier rate among U.S.troops in the Tropics has been low. It was less than 1 percent among 800 menfrom two divisions tested in the South Pacific Area. In a series of 174 patientswith ulcers, the incidence of asymptomatic carriers was 4 percent.

⁸⁰See footnote 15, p. 281.

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TABLE 45.-Cases of diphtheria in the27th Division in restarea in the New Hebrides, 16 September-28 October 1944

Date of admission	Skin cases			Throat carrier	Throat case	Total
Date of admission	Throat negative	Throat carrier	Throat case	Throat carrier	Throat case	Total
1944
September 16	1	1	0	0	4	6
17	2	0	1	0	1	4
18	5	0	1	0	1	7
19	1	0	0	0	2	3
20	0	0	0	0	1	1
21	3	0	1	0	4	8
22	3	0	0	0	1	4
23	11	0	0	1	2	14
24	7	1	0	0	1	9
25	7	0	1	0	0	8
26	5	0	0	0	0	5
27	0	0	0	0	1	1
28	1	0	0	0	0	1
29	2	1	0	0	0	3
30	0	0	0	0	0	0
October 1	0	0	0	0	0	0
2	2	0	0	2	1	5
3	1	1	2	0	1	5
4	2	0	0	0	0	2
5	2	0	0	0	1	3
6	1	1	0	0	0	2
7	1	0	0	0	0	1
8	0	0	0	0	0	0
9	1	0	0	0	2	3
10	0	0	0	0	0	0
11	3	0	0	0	0	3
12	1	0	0	0	0	1
13	1	1	0	0	1	3
14	0	0	0	0	1	1
15	0	0	0	0	0	0
16	1	0	0	0	1	2
17	1	0	0	0	1	2
18	1	0	0	0	1	2
19	3	0	0	0	0	3
20	0	0	0	0	0	0
21	0	0	0	0	0	0
22	0	0	0	0	0	0
23	2	0	0	0	0	2
24	1	0	0	0	0	1
25	0	0	0	0	0	0
26	1	0	0	0	0	1
27	1	0	0	0	0	1
28	3	0	0	0	0	3
Total	77	6	6	3	28	120

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The one group in which the carrier rate has been extremelyhigh in the absence of clinical diphtheria was among German prisoners ofwar⁸¹ at the camp in Merano. Here, it was 17 percent in apparently healthyindividuals in a camp where there were many cases of neuritis. This carrier ratewas exceeded only in convalescents from clinical diphtheria at the same camp.Evidence has been presented that diphtheria can be spread not only from skin toskin but also from skin to pharynx and from pharynx to skin. The same or otherindividuals can be involved in this process.

Other factors were considered in Burma. Investigators cultured rice paddiesas possible sources of C. diphtheriae among soldiers in the Myitkyinaarea but found them to be negative.⁸²Flies, in places wherecutaneous diphtheria was prevalent, were cultured in the Southwest Pacific Area.⁸³They were found to harbor C. diphtheriae on several occasions,but all strains were atoxic. The role of flies certainly deserves further study,since their known persistence and the attraction which the ulcers seem to havefor them possibly may make them important in spreading the organism in theTropics.

DIPHTHERIA TRANSMITTED FROM MILITARY TO CIVILIANPOPULATIONS

There is some evidence suggesting that tropically acquired cutaneousdiphtheria in soldiers may ultimately be the source of infection to much largersusceptible civilian populations in temperate climates where it takes thenasopharyngeal form. The evidence may be summarized, as follows:

1. Cutaneous diphtheria is frequently ignored by the soldier and oftenescapes undiagnosed by his physician. Consequently, when the soldier returnsfrom tropical combat to contact with civilians, his movements are unrestricted,and there is excellent opportunity for the dissemination of bacilli in theoften rich secretions of the diphtheritic lesions of the skin.

A specificexample is cited in a case investigated by the New York State Department ofHealth. The following is quoted from a letter from Dr. Hollis S. Ingraham,Chief, Division of Communicable Diseases:

An Army captain had been hospitalized in New Britain [Bismarck Archipelago]in February 1944, for cutaneous ulcers of the legs, buttocks, and hand. He wasreturned to this country and was again hospitalized at Fort Dix, [N.J.] in June1945. He visited at his home in Hornell, N.Y., from July 27 to August 10, 1945.At the time, there was still a deep ulceration on his left hand and arm. A sonborn in the household on July 26 was circumcised on July 31. Thischild was noted to be ill on August 18 and on inspection, the circumcision woundwas found to be unhealed and covered with a diphtheritic membrane. Virulentdiphtheria bacilli were recovered from the wound, and the child responded tospecific therapy.

An adult female, the captain's wife, developed sore throat on 24 August.Virulent diphtheria organisms were found in her throat and she respondedpromptly to antitoxin.

⁸¹See footnote 23, p. 283.
⁸²Letter, Maj. J. L. Arbogast, MC, 9th Medical Service Detachment(Laboratory), to Commanding Officer, 9th Medical Service Detachment(Laboratory), 16 Nov. 1944, subject: Diphtheria Survey.
⁸³See footnote 16, p. 282.

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A 7-year-old boy, another son, developed mild diphtheria onAugust 30 and responded promptly to treatment. Virulent diphtheria organismswere recovered from his throat. The captain developed no sore throat and therewas no mention of any change in the ulcers on the left hand and arm. It wasreported that a culture taken from his hand on August 23, 1945 at Fort Dix wasnegative. These lesions were cultured in Hornell on September 6, and pureculture of diphtheria organisms were recovered. On the whole, it appears highlyprobable that the infection was introduced by the captain but, as you will notefrom the dates, the case was not proved beyond doubt.

2. The return of infected soldiers has in some countries beenassociated with a striking increase in diphtheria among the civilian population.This occurred in Germany and certain occupied countries, and also in NewZealand.

Diphtheria had a high incidence in the summer months of 1941and 1942 in the Afrika Korps, and in each year it waned during the falland winter months. This information is derived from captured German documentsin the European Order-of-Battle Section, G-2, Headquarters, Army Ground Forces.The epidemic began late in July 1941. In September, there were 416 diagnosedcases, largely in the 21st Panzer Division, but there were some also inthe 15th Panzer Division.⁸⁴ In the report of thechief surgeon of the Panzer Army in 1941, the following statement appears(translated):⁸⁵ "There were four outstanding diseases, which in increasingmeasure had an uncommonly high incidence: Dysentery, jaundice (infectiousicterus), diphtheria, and ulcers of the skin, especially of the lowerextremities." In the next year, the table of incidence taken from thecorresponding report, is very similar (chart 14). Diphtheria of the skin amongGerman soldiers was reported in several papers in Der deutsche Milit?rarzt.⁸⁶

One such outbreak in the United States was carefully studied by Fleck, Kellam,and Klippen.

The high carrier rate in the prisoner-of-war camp at Meranoand the associated diphtheria there have been discussed previously. Theevacuation of Germans from the North African campaign was progressingcontinuously in 1941 by hospital ship to Naples, Italy, thence by train toGermany, where Munich was the usual debarkation point. From April to December1941, 8,400 were sent from Italy to Germany by train.

Diphtheria underwent a sudden and simultaneous increase among the civilianpopulations in Germany, Norway, and the Netherlands in Septem-

⁸⁴Deutsches Afrika Korps. T?tigkeitsbericht der Abt. IVb, 30 Sept. 1941.[Captured German document.]
⁸⁵Armeearzt, Hauptquartier Panzerarmee Afrika. Erfahrungsbericht, 28 Feb.1942. [Captured German document.]
⁸⁶(1) Binhold, (NFI): ?ber Wundiphtherie. Deut. Milit?rarzt8: 521-527, September 1943. (2) Funk, C. F.: Die chr?nisch-ulcerosen fl?chenhaften Pyodermien: Ecthyma simplex, Pyodermia papillaris vegetans et exulcerans, sowie das Ulcus cruris ohne Ulcus varicosum. Deut. Milit?rarzt 9:401-404, September 1944. (3) Quartiermeister (Rom) IVb, Zurzer T?tigkeitsundErfahrungsbericht f?r die Zeit von 6.2.1941 bis 31.12.1941 des Danit?tssoffz.bei QM. Rom (Heer). Sect. VI. Abtransport Verwundeter und Kranker derPanzergruppe Afrika, 28 Jan. 1942. [Captured German document.]

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ber 1941 (chart 15), at the same time the diphtheria epidemicwas at its height among the German soldiers in North Africa and while troopswere being continually evacuated from that theater. In France, the increaseoccurred largely in the northern, occupied parts of the country.⁸⁷ Itwas not until after a considerable interval of time that the disease becameprevalent in neutral countries, such as Sweden and Switzerland, to which travelfrom Germany was relatively slight (chart 16).

CHART 15.-Diphtheria in Germany, Norway,and the Netherlands, 1939-44

It may be objected that dietary conditions in these countrieswere poor. However, a similar increase in incidence of diphtheria occurred inNew Zealand where the diet was more than adequate. Here, it was associated, atleast in time, with the return of U.S. Marines and later U.S. Army troops fromcampaigns in the Solomon Islands. Diphtheria among the Marines has beendescribed by Norris and others. The influx into the country began after themiddle of 1942. The 25th Division appeared en masse in New Zealand in 1943; the43d Division arrived later. Diphtheria among these soldiers is described indetail in this chapter. Thus, the stream of individuals infected with C. diphtheriaehad been uninterrupted until the middle of

⁸⁷Stowman, K.: Diphtheria Rebounds. Epidemiol. Inform. Bull. 1: 157-168, 28 Feb. 1945.

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1944. Therefore, the morbidity from diphtheria in the New Zealand civilianpopulation as of 1940-41, with the rise which began in 1942 is as follows:

	Number
1940	368
1941	383
1942	643
1943	830

CHART 16.-Diphtheria in France, Denmark, Sweden, and Switzerland, 1939-45

The previous peak in New Zealand was in 1917-18 and may havebeen associated with the return of soldiers at that time from Gallipoli and theDesert.

It is of interest that the great pandemics of previouscenturies appear to have come from the South.⁸⁸ According toFriederich L?ffler, quoted by Nuttall,⁸⁹ "The disease appearsto have been perfectly well known in Egypt, Syria, and Palestine even in ancienttimes. This is proved by repeated references to it in the BabylonianTalmud." Also, according to Rolleston,⁹⁰ in the first centuryA.D., "an unmistakable description of diphtheria is given by Aretaeus ofCappadocia under the name of Syriac or Egyptian ulcers owing to its havingoriginated in Syria and Egypt whence it spread to all European countries."The "ulcers" refer to the appearance of the throat and not to the skinin this instance.

These correlations are not held up as final proof of the importance ofcutaneous diphtheria among the military as the ultimate source of the epidemicin Europe. However, as Rolleston says: "Subjects of clandestine diphtheria,like clandestine prostitutes, are of considerable epidemiological

⁸⁸Russell, W. T.: The Epidemiology of Diphtheria During the Last 40 Years.Special Report Series No. 247. London: His Majesty's Stationery Office, 1943.
⁸⁹Nuttall, G. H. F., and Graham-Smith, G. S.: The Bacteriology ofDiphtheria. Oxford: Cambridge University Press, 1908.
⁹⁰Rolleston, J. D.: Acute Infectious Diseases. London: William Heinemann, Ltd., 1925.

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importance as both, owing to their innocent appearance, maywidely spread disease before their true nature is recognized." Streptococcimay be similarly introduced since they abound in cutaneous lesions in theTropics.

Part III. A New Hemolytic Corynebacterium in Man

A hemolytic corynebacterium was frequently cultivated from nasopharyngealand cutaneous infections in soldiers evacuated from tropical islands of thePacific and from natives of the New Hebrides and the Marianas. This organismwhich was given the tentative designation "Corynebacterium hemolyticum" is similar to a large group⁹¹of hemolytic corynebacteria, suchas C. ovis and C. pyogenes, known to be pathogenic for animals. Thisorganism is important because:

1. It may readily be confused with C. diphtheriae in direct smears ofexudates and on L?ffler's slants, and with beta hemolytic streptococci onblood-agar plates.

2. There is suggestive evidence of its pathogenicity for man.In smears of exudates and L?ffler's slants, the new organism closely resembles C. diphtheriae, although it tends to be more slender. It ispleomorphicand granular, but the granules are not metachromatic. On filtered sugar mediaenriched with human serum (serum or blood is necessary for abundant growth),sucrose is fermented without the production of gas, as are also dextrose,maltose, lactose, galactose, and dextrin, but not xylose or mannitose. C.hemolyticum also differs from C. diphtheriae in coagulating milk, inslowly liquefying gelatin, and in not reducing nitrates. When inoculatedintracutaneously into guinea pigs or rabbits, C. hemolyticum produceslesions resembling those caused by C. diphtheriae, but these are notprevented by diphtheria antitoxin, in the standard virulence test of Fraser andWeld. C. hemolyticum produces hemolytic and skin necrotizing toxins inbroth that will not pass the Seitz filter.

On 24-hour blood-agar plates (pH 7.4), the organism is morehemolytic than C. diphtheriae type mitis, and its coloniesresemble those of the beta hemolytic streptococcus. When the plates are allowedto incubate for 48 to 72 hours the colonies of C. hemolyticum continue togrow and become discoid, contrary to those of the Streptococcus, and thezone of hemolysis becomes enormous, usually after passing through a doublephase. Other colonial characteristics are a lenticular dark spot visible bytransillumination and etching of the surface of the blood-agar plates. Both ofthese phenomena are manifest in colonies more than 24 hours old and are not seenwith the beta hemolytic streptococcus (fig. 46-55).

⁹¹Brooks, R. F., and Hucker, G. J.: A Study of CertainMembers of theGenus Corynebacterium. J. Bact. 48: 295-312, September 1944.

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The pathogenicity of C. hemolyticum for man is indicated by itscapacity for producing lesions when inoculated into the skin. Its lowinvasiveness, however, is inferred by the absence of complications afterintracutaneous injections in man and by the failure of development ofsignificant symptoms when sprayed on the normal throat. It readily becomesparasitic in the nasopharynx, where it may persist for many weeks. Inconjunction with another infectious agent or a lowering of resistance of thehost, however, it is possible that C. hemolyticum may become an"opportunist pathogen" for man. This is supported by the evidence ofclinical cases in which C. hemolyticum was the dominant organism duringthe course of an acute respiratory illness, was unassociated with a knownpathogen, and disappeared with the subsidence of the disease.

FIGURE 46.-Exudate from diphtheritic ulcer.Corynebacterium diphtheriaewithin the leukocytes. Irregular granular bacilli. Gram stain. (X 500)

FIGURE 47.-Exudate from ulcer in one of the lesions depicted in figure 37A.Note double suppository forms of Corynebacterium diphtheriae sometimesobserved in direct smears of exudate. (X 1,100)

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FIGURE 48.-Chronic ulcer of ankle containing Corynebacterium diphtheriae. This condition was nontoxigenic in Melanesian native of Esp?ritu Santo, New Hebrides Islands.

Part IV. Use of Penicillin in Treatment of Diphtheria

Interest in penicillin as a possible therapeutic agentagainst diphtheria was high since it was known from earlier observations of theBritish that C. diphtheriae was sensitive to penicillin in vitro. Someevidence of variation in the susceptibility of various strains has been pointedout by McDaniels. In the European theater, investigation of the subject wasstimulated by Administrative Memorandum No. 151, Office of the Chief Surgeon,dated 27 November 1944, outlining a tentative program for the observation of theefficacy of penicillin in the treatment of diphtheria.

All observers were agreed that following use of the drug inthe active nasopharyngeal form of diphtheria there was often evidence ofclinical improvement,⁹² but some ascribed this to the effect on the frequentlyconcomitant streptococcal infection. It soon became obvious by the review offatalities and serious complications that penicillin, even when given early andabundantly, did not prevent myocarditis.⁹³ In the words of ColonelMiddleton, Chief Consultant in Medicine, European theater:⁹⁴ "There is nosubstitute for antitoxin administration on suspicion without undue reliance

⁹²Karelitz, S., Moloshok, R. E., and Wasserman, L. R.: Penicillin in theTreatment of Diphtheria and the Diphtheria Carrier State. ETO Med. Bull. 32:67-72, July-August 1945.
⁹³(1) See footnote 59, p. 302. (2) Berman, B. B., and Spitz, S. H.:Penicillin in Clinical Diphtheria. [Official record.]
⁹⁴See footnote 35, p. 293.

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FIGURE 49.-Diphtheritic ulcers in children. A. Melanesianchild in New Hebrides Islands with typical punched-out ulcers of the skin andyaws of the right foot. Ulcerative lesions in both instances containednontoxigenic Corynebacterium diphtheriae. B. Tonkinese child, about 2years old, with multiple ulcers. Some appear punched out; others are partly orcompletely scarred with bronze-violet pigmentation of surrounding skin. Atoxic C. diphtheriae was cultured from one of the lesions.

on the laboratory on the part of the clinician."Otherwise, by delaying specific treatment until laboratory identification iscomplete, the clinician may himself perpetrate a virulence test on Homo sapienswith irreversible effect.⁹⁵

Penicillin seemed particularly promising for use in thetreatment of carriers, and was given study in various quarters with somewhatdiverse results. There was variation in the definition of carrier and in themethods of application and dosage of penicillin. Among the criteria for checkingthe results of these experiments should be consideration of (1) whether anadequate number of cases was used, (2) whether a check was made on the naturaldecline of the carrier state, and (3) whether the recurrence of organisms wastested.

For these reasons, the work of Karelitz and his coworkers must be consideredinconclusive. Berman and Spitz⁹⁶ in each of 10 cases instilled 1 cc.

⁹⁵See footnote 7 (3), p. 279.
⁹⁶Berman, B. B., and Spitz, S. H. Treatment of Diphtheria Carriers With Penicillin. Bull. U.S. Army M. Dept. 4: 87-91, July 1945.

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FIGURE 50.-Corynebacterium hemolyticum colonies on blood agar from18 to 24 hours. Hemolysis is beginning.(X 4) Inset shows actual size of colonies.

FIGURE 51.-Cornyebacterium diphtheriae 24 hours on5 percenthuman blood agar, for contrast with C. hemolyticum. (X 4) Inset showsactual size.

FIGURE 52.-Corynebacterium hemolyticum 48 hours on 5percenthuman blood agar contrasted with beta hemolytic streptococcus. Note greatertranslucency and less sharply defined border of Streptococcus colony. Inthe original, the latter has a silvery rather than pink color. Zone of hemolysis is now relatively smaller in contrast with appearance at24 hours.Note minute pit at apex of C. hemolyticum colony. (X 4) Insetshows actual size of colony.

FIGURE 53.-Corynebacterium hemolyticum colony 96-120 hours asseen under low-power, split lens of microscope. Note pebbled-leather appearanceof surface of colony and lenticular opaque central mass. Light is partlytransmitted and partly reflected from surface.

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into each naris and the posterior pharynx four times each day for 5 days-atotal of 20,000 units per patient for the 5-day period. Twelve controls had onlyhot gargles. All 10 penicillin-treated cases were negative within the treatmentperiod or on the first day thereafter, and were still negative 4 weeks later. Inthe untested group, 7 of the 12 cases reverted spontaneously to negative withinthe fifth week. Berman and Spitz concluded that penicillin seemed useful, butthe number of cases is small and the incidence of spontaneous reversals tonegative was not checked 2 weeks after the treatment period when this might beat its height.

FIGURE 54.-Corynebacteriumhemolyticum, 48 hours on L?ffler's serum at 37? C.Gram stain. (X 1,100)

FIGURE 55.-Corynebacterium diphtheriae, 48 hours onL?ffler's serum at37? C. Gram stain. (X 1,100) (Compare with fig. 54.)

Bagnall and Bain⁹⁷ of the No. 14 Canadian General Hospital, in theMediterranean, performed careful experiments using 175 patients and givingpenicillin intramuscularly. Two groups were used: Group A received a total of600,000 units in 5 days on a dosage schedule of 15,000 units every 3 hours;group B received a total of 1,200,000 units in 6 days on a schedule of 25,000units every 3 hours. The percentage of success was higher in group B than ingroup A, which was no better than the control group. Bagnall and Bain pointedout that, in seven instances, positive cultures recurred after three consecutivenegative cultures and in four instances, after four consecutive negativecultures. The writers' conclusions were that the results were disappointing.

Even less satisfactory were the results of intramuscular treatment ofindividuals who were still carriers 2 to 7 weeks after the clinical disease.Kocher and Siemsen⁹⁸ gave 25,000 units every 2 hours for 7 days, a total of2,100,000 units. The cultures remained positive in their subjects.

⁹⁷See footnote 1, p. 276.
⁹⁸Kocher, R. A., and Siemsen, W. J.: Diphtheria Carriers TreatedWith Penicillin. Ann. Int. Med. 24: 883-886, May 1946.

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These observers concluded, however, on the basis of another experiment, thatlocal therapy is effective. Their method was to useglycerine-gelatine lozenges, which required 20 to 30 minutes for solution, oneeach hour for 12 doses. The early patients in the series received lozengescontaining 500 units, but their content was later raised to 1,000 units. Also,penicillin sprays to the nose were given. Twenty-three of thirty-one individualscleared promptly in 1 to 10 days after treatment was started, and eight casesthat were persistently positive had large tonsils. After tonsillectomy, however,these became consistently negative. Scrutiny of the table presented by theseworkers, however, shows that 10, rather than 8, cases must be consideredfailures. Furthermore, in seven others, the cultures were already negativebefore local treatment was started and are therefore "no test."

It still remains to be proved that penicillin is effective interminating the carrier state. Certainly, it is much less effective inpersistent carriers than tonsillectomy.

Part V. Problems Remaining for Investigation

Numerous problems have presented themselves during the course of thesewartime investigations. They are, as follows:

1. Cutaneous diphtheria should be investigated among the natives of the NewWorld Tropics. If the epidemiological factors are indeed the tropicalenvironment in association with dirt and crowding, cutaneous diphtheria shouldbe just as common in Haiti or Uganda as in Saipan. A study in relation to therapid development of the immunity by performing antitoxin levels in natives invarious age groups might be most revealing.

2. Of special interest would be an investigation of whether cutaneousdiphtheria has a significant incidence in the poorer parts of the SouthernUnited States where it may account for the high levels of Schick immunityobserved there.

3. Further information should be gathered concerning the occurrence ofcutaneous diphtheria in individuals previously Schick negative.

4. The suggestion from the observations of Pasricha and Panja that C.diphtheriae, which is not toxigenic for the guinea pig, may yet be capableof producing lesions in the human skin requires careful investigation. Thefactor of hypersensitivity may have significance in this connection.

5. Further study should be made of the newly described hemolyticcorynebacterium of the C. pyogenes group in regard to its distributionamong the peoples of the Tropics and its pathogenicity and origin, which may bein some species of animal.

6. Sufficient evidence in controlled experiments has not asyet been gathered concerning the efficiency of penicillin in treating thecarrier state. Further investigation is highly indicated.

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7. It was found that beta hemolytic streptococci were extremely common incutaneous lesions of the natives. These should be investigated by typing andalso in relation to the Dick reaction. A good deal may be learned concerning theactual prevalence of streptococci in the Tropics, contrary to previous opinionsof their rarity in these regions.

Part VI. Summary

Diphtheria was a problem of increasing importance to the Army during WorldWar II, particularly after the occupation of Germany. Many cases originated inthe Tropics where the disease largely took the cutaneous form, as it has inprevious tropical campaigns.

The lesions, which usually were preceded by trauma or insect bites, mostcommonly assumed the form of punched-out ulcers with declivitous margins andrelatively clean bases, to which occasionally a grey-green membrane or fibrinouscrust was adherent. The borders were usually indurated and blue or bronze violetin appearance. Exanthematous or moist desquamative lesions of entirely differentappearance could, however, harbor large numbers of C. diphtheriae.

The complication of neuritis or myocarditis occurred occasionally, or insome groups of cases frequently, but usuallythere were no general symptoms of intoxication.

Aside from these complications, the lesions were important for:

l. The ulcers were usually on the extremities where they reduced the militaryefficiency of the soldier.

2. It is possible for a susceptible individual to infect his own nasopharynx.

3. The lesions, when unrecognized, can be a prolific source of both cutaneousand nasopharyngeal diphtheria for others. This is demonstrated by evidence ofspread of diphtheria from patients on dermatology wards to other patients and toward personnel; concomitance of nasopharyngeal and cutaneous diphtheria inmilitary populations in the Tropics; and suggestive evidence that unrecognizedcutaneous diphtheria in Rommel's soldiers was responsible for the epidemic inEurope where, on account of climatic conditions, the diphtheria took therespiratory form. The epidemic in Europe began in September 1941, when bothcutaneous and nasopharyngeal diphtheria was at its height in the AfrikaKorps and while large numbers of German soldiers were being returned toGermany as patients. It involved first those countries under direct occupationby the Germans and the neutral countries not until much later.

The conditions favoring the cutaneous localization of C. diphtheriae underconditions of combat in the Tropics are:

1. The warmth and moistness of the skin which comes to resemble the lining ofthe pharynx.

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2. During combat, there is little opportunity for cleanliness.

3. Many minor infections occur and are neglected.

4. Flies are extremely numerous and travel from skin to skin.

5. There is frequent and extreme crowding of the troops.

These same conditions prevail among the natives in theTropics, who constitute a tremendous reservoir of C. diphtheriae. Amongthem, cutaneous diphtheria is universal by the fourth year of age. Only betweenthe ages of 9 and 24 months is there a high incidence of Schick-positivereactions among these people. Immunization by the cutaneous route probablyaccounts for the rapid conversion to the Schick-negative state. The level ofimmunity is probably only slightly depressed during this brief interval of time,and this probably accounts for the low incidence of nasopharyngeal diphtheria.

When the susceptible soldiers are forced by the vicissitudesof combat in the Tropics into the same epidemiological conditions as thenatives, then severe faucial as well as the more common cutaneous forms ofdiphtheria become widespread.

The best treatment for cutaneous diphtheria appears to be to put the patientat rest in bed and to apply penicillin locally in continuous, moist salinecompresses. Diphtheria antitoxin intramuscularly may prevent the consequences ofautoinfection of the pharynx and possibly may diminish the incidence ofcomplications.

The best measure of prevention of a cutaneous diphtheria is to send onlySchick-negative troops into combat in the Tropics. The fact that moreindividuals who have diphtheritic ulcers are Schick positive than the generalpopulation, suggests that the Schick-negative state is, at least to some extent,protection against the development of the tropical ulcers.

In both cutaneous and nasopharyngeal infections in theTropics, hemolytic corynebacteria are common which may resemble C. diphtheriaein direct smears and on L?ffler's media. These require further investigation.

More study is necessary concerning the use of penicillin interminating the carrier state and in the therapy of clinical nasopharyngealdiphtheria. Penicillin alone, even when given early and abundantly, does notprevent the complications of the disease.

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