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Chapter X

Contents

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. Army during the Second World War. Combat in the tropics again proved to be particularly favorable for the spread of this disease, especially the cutaneous form. During the First World War, the British recognized the diphtheritic nature of the desert sores that were so prevalent among the troops in Egypt and Palestine. In World War II, lesions of the same nature were common during the North African campaign over similar terrain. During 1943 and 1944, cutaneous diphtheria 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 Corynebacterium diphtheriae was found in such lesions known as tropical ulcer, ecthyma, and jungle rot that their etiology was determined. These lesions were of epidemiological importance because they were a prolific source of pharyngeal and nasal diphtheria among the soldiers and to those with whom they came in contact. It was found that an enormous reservoir of diphtheria-in the cutaneous form resembling that seen in soldiers-existed among natives in the Pacific, particularly among the children. The lesions of childhood probably accounted for the immunization of the natives early in life. It seemed that the conditions of combat reduced American soldiers to the epidemiological conditions prevailing among the natives.

Studies of the lesions of soldiers and of natives in the tropics revealed the presence of a hitherto unknown hemolytic corynebacterium, which could easily be confused either with C. diphtheriae on Löffler's medium or with the beta hemolytic streptococcus on blood-agar plates.

Several groups of investigators seized the opportunity to study the effectiveness of penicillin in the treatment of the numerous carriers and 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 in the U.S. Army for the years 1942-45 by area, based on sample tabulations of individual medical records, are presented in table 40. During 1942 through 1945, 619 cases of diphtheria were reported in the Army in the continental United States and 5,105 additional cases from the Army overseas. Among the oversea theaters in 1945, the year of highest number of cases, the European Theater of Operations, U.S. Army, had the highest rate, with the


276

North African and Mediterranean Theater of Operations, U.S. Army, second, and the 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 was greater in 1945 for the Army as a whole, with 67 deaths occurring in the European theater alone.

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

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

Area


1942-45

1942

1943

1944

1945


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


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

Evidence is presented (p. 315) that cutaneous diphtheria probably played an important role in the dissemination of all forms of the disease, although relatively few cases were diagnosed and reported officially. For example, the incidence of cutaneous diphtheria in the total Army in 1944 and 1945, based on sample tabulations of individual medical records, totaled 485 (table 42). The majority of cases occurred in the combined Pacific areas and in the China-Burma-India theater.

Among the British in the African desert, the rate for all forms of diphtheria was 4 to 5 per 1,000 per annum.l A comparison of British and American incidence of diphtheria in the Mediterranean theater during December 1943 and January and February 1944 follows:

 


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.


277

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

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

Area

1942-45


1942

1943

1944

1945

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 cutaneous diphtheria in the U.S. Army, by area and year, 1944-45

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

Area


1944-45

1944

1945


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 in the units column; 0.00 indicates a rate of more than zero but less than 0.005.


278

It must be stated, however, that the Americans required laboratory confirmation of diagnosis, whereas the British did not. The rate among 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 United States.2 In some cases, cutaneous diphtheria was described, and tropical ulcers were reported to be numerous among the prisoners. At the same time, diphtheria increased steadily among Army troops in the continental United States.

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

During the calendar year 1945, 2,240 cases of diphtheria occurred among American troops in Europe with 67 deaths (tables 40 and 41). The incidence in December 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 adults routinely against diphtheria because moderate to severe reactions would occur in an appreciable number of cases, although studies were made of the incidence of Schick-positive reactors among U.S. Army troops and small diphtheria-immunization programs were conducted.3 Late in 1945, as the incidence of diphtheria increased among U.S. troops in the European theater, only immune personnel were assigned to the army of occupation on the Continent. U.S. Army civilian employees, their dependents, and dependents of military personnel destined to join the occupation army in the European theater 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.


279

Accordingly, on 12 January 1946, the Office of the Theater Chief Surgeon, European Theater,4 directed all major commands to institute an immunization program for (1) all medical department, hospital, and dispensary personnel, (2) all personnel whose duties brought them into frequent and intimate contact in camps or enclosures with prisoners of war, displaced persons, internees, or German civilians, and (3) all units of battalion strength or smaller showing two cases in any one week. It was decided to dispense with Schick testing at that time.

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

Part II. Tropical Ulcers and Diphtheria

SOURCES AND DISSEMINATION OF INFORMATION

The presence of C. diphtheriae in skin lesions, particularly ulcers, was reported by widely separated groups of observers in the South and Southwest Pacific Areas and in Burma during World War II. However, in Saffron's 1944 review of the literature on cutaneous diphtheria no mention was made of the incidence in these areas.5

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

South Pacific8-The observations in the South Pacific Area were made chiefly on members of the 25th and 43d Infantry Divisions, as they were evacuated from combat in the Solomon Islands, and on troops of the 27th Infantry Division, following their evacuation to Espíritu Santo in the New Hebrides after the Battle of Saipan. The first of a series of reports from the 39th General Hospital, Auckland, New Zealand, appeared in September 1943. The information was soon disseminated throughout the area in Medical Circular Letters Nos. 5 and 14, dated 20 October 1943 and 5 January 1944, respectively, Headquarters, U.S. Army Forces, South Pacific 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.


280

Similar material on diphtheria was made available in February 1944 by newsletter from U.S. Navy headquarters for malarial and epidemic control in the South Pacific Area. In addition, there were the evangelical efforts of the medical consultant, Col. Benjamin M. Baker, MC, who did much to make the staffs of the various hospitals conscious of the diphtheria problem. The final report totaled 174 cases of cutaneous diphtheria and 94 cases of noncutaneous diphtheria, in all of which C. diphtheriae had been demonstrated.

The following tabulation is based on a study of patients from the Solomon Islands campaign at the 39th General Hospital from 7 February 1943 to 1 July 1944, inclusive, and on cases of diphtheria from the 27th Infantry Division during their stay at the rest area on Espíritu 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 Espíritu 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, from March to September 1943, intensive parasitological and bacteriological studies were made, including anaerobic cultures, dark-field examinations, potassium hydroxide smears, cultures for fungi, and Giemsa stains for Leishmania. Cutaneous lesions were searched with care for Leishmania in cases from the Solomon Islands and Saipan, but neither protozoa nor spirochetes were found, and such fungi as Monilia and Epidermophyton were rarely encountered. When the frequency of C. diphtheriae became apparent, a special procedure was employed to investigate the epidemiology and pathogenesis of lesions associated with this micro-organism, and bacteriological methods were simplified to facilitate its detection. A standard clinical record form was designed, which emphasized such factors as previous diphtheria, immunization, former Schick tests, history of sore throat, and evidences of neurological damage.

9Stern, R. L., and Grynkewich, S. E.: Diphtheria Epidemic in 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, March 1944.
11Murray, R.: Laboratory Service-South Pacific Area. [Official record.]


281

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

Burma-In the Burma portion of the India-Burma theater, 141 cutaneous lesions were found, chiefly in soldiers from the Myitkyina combat area. They were reported from the 20th General Hospital, Ledo, Assam, in September 1944, by Livingood and his coworkers, who had given them careful study.12 In 21 percent of these 141 patients, it was possible to demonstrate toxigenic C. diphtheriae. There was, however, a high incidence of complications among those lesions from which C. diphtheriae was not isolated, but since they were morphologically identical with those harboring the microorganisms, the diagnosis of cutaneous diphtheria seemed reasonable. Only eight cases of nasopharyngeal diphtheria were diagnosed in the interval during which most of these cutaneous cases were observed-September to December 1944. Particular attention was paid to the complications of the disease as well as to morphology of the characteristic lesions and their treatment, and a valuable followup study was made, which furnished an estimate of the cost to the Army in man-days.13

Reports from the 69th General Hospital, Ledo, Assam, in October 1944 and January 194514 referred to 70 patients. All throat cultures in this series were negative, and no clinical cases of nasopharyngeal diphtheria were diagnosed.

It is interesting to note that the British in the India-Burma theater 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. In Blumgart, Herrman L., and Pike, George M.: History of Internal Medicine in India-Burma Theater, inclosure 11 thereto. [Official record.] (2) Letter, Maj. Clarence S. Livingood, MC, Office of Chief of Dermatology and Syphilology, 20th General 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 General Hospital, to Commanding Officer, 20th General Hospital, 9 Oct. 1944, subject: Cutaneous Diphtheria. (4) Letter, Maj. Clarence S. Livingood, MC, Chief, Section of Dermatology and Syphilology, 20th General Hospital, India-Burma Theater, to Commanding Officer, 20th General Hospital, 25 Jan. 1945, subject: Cutaneous Diphtheria. (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, to Commanding Officer, 20th General Hospital, 18 Mar. 1945, subject: Preliminary Report on the Neuritis Complicating Cutaneous Diphtheria.
13Letter, Capt. Daniel J. Perry, MC, Assistant Chief, Dermatology and Syphilology Section, 20th General Hospital, to Consultant in Dermatology, Office of the Surgeon General, 28 Aug. 1945, subject: Follow-Up Studies of a Group of 140 Cases of Cutaneous Diphtheria.
14(1) Letter, Capt. Harvey Blank, MC, Chief, Section of Dermatology and Syphilology, 69th General Hospital, India-Burma Theater, to Commanding Officer, 69th General Hospital, 31 Jan. 1945, subject: Analysis of 40 Additional Cases of Cutaneous Diphtheria. (2) Letter, Capt. Harvey Blank, MC, Chief, Section of Dermatology and Syphilology, 69th General Hospital, Advance Section 3, India-Burma Theater, to Commanding Officer, 69th General Hospital, 1 Apr. 1945, subject: Report of Cutaneous Diphtheria Among the Detachment of a General Hospital.
15Blumgart, Herrman L., and Pike, George M.: History of Internal Medicine in India-Burma Theater. [Official record.]


282

Southwest Pacific.-The group at the 9th General Hospital on Biak16 observed a total of 210 cases of diphtheria between 1 November 1944 and 1 March 1945. There were 102 cases of dermatitis from which C. diphtheriae was isolated. Of the 31 recovered strains tested, 19 were virulent. There were also 60 other cases with wounds, burns, otitis media, otitis externa, and other such lesions, and 48 nasopharyngeal infections from which the C. diphtheriae was isolated. The patients in this group were from nine widely scattered bases in the Southwest Pacific Area, New Guinea, the Netherlands East Indies, and the Philippine Islands. On Biak, where the studies were conducted, 112 patients were from 22 different organizations.

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

Zone of Interior-After prevalence of the condition was recognized, the patients with cutaneous lesions received thorough study in several large centers in the United States. At the Moore General Hospital, Swannanoa, N.C.,17 a skin isolation ward was established to which there were 228 admissions between 1 March and 3 October 1945. Cultures of ulcerated lesions in the skin were positive for corynebacteria in 107, 18 of which proved to be toxigenic. At the Harmon General Hospital, Longview, Tex.,18 a survey was made of 385 admissions; most of the patients in the survey were from the Pacific areas. Seventy persons were proved to have C. diphtheriae either in the nose or throat or in cutaneous lesions. Fifty-eight of these strains of the micro-organism were virulent, but 12 were toxigenic C. diphtheriae. This represented an incidence of 3.1 percent in the population of the hospital at the time of admission. Fifty-six of these patients had tropical ulcers or ulcerated dermatitides. In 8 of these, C. diphtheriae was found to be toxigenic and in 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 the Tropics. [Official record.]
17Bronson, L. M.: Memorandum on Cutaneous Diphtheria at Moore General Hospital. [Official record.]
18(1) Denhoff, E., and Kolodny, M. H.: Studies on Cutaneous Diphtheria and Tropical Ulcers. Arch. Dermat. & Syph. 55: 360-368, March 1947. (2) Denhoff, E., Kolodny, M. H., Daniels. W. B., and Mitchell, L. P.: Plan to Control Diphtheria in an Army General Hospital. Bull. U.S. Army M. Dept. 6: 59-60, July 1946.


283

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

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

Policies-In recognition of the increasing importance of the problem of diphtheria during World War II, information, as it became available, was disseminated by the highest echelon. The diphtheritic nature of certain types of tropical ulcers in the Pacific was first given wide publicity in the May 1944 issue of the Bulletin of the U.S. Army Medical Department. Following a tour of inspection of the Pacific area in October 1944 by Col. Francis R. Dieuaide, MC, Chief, Tropical Disease Treatment Branch, Medical Consultants Division, Office of the Surgeon General, War Department Technical Bulletin (TB MED) 143, entitled "Cutaneous Diphtheria" was issued in February 1945. This bulletin summarized the reports from various tropical areas, gave directions concerning diagnosis and treatment, and emphasized the epidemiological significance of the disease. Similar material on the recognition and treatment of cutaneous diphtheria was published in the March 1945 issue of the Bulletin. A special circular on management of patients with cutaneous diphtheria was prepared by the Medical Consultants Division, Office of the Surgeon General, and was issued to service command medical consultants on 3 August 1945.

The many cases of polyneuritis that had been reported from the Mediterranean theater,21 the South Pacific, Burma,22 and elsewhere, attracted the interest of the Army Epidemiological Board (Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army), which established an investigative commission composed of Dr. George D. Gammon and Maj. (later Lt. Col.) Emanuel B. Schoenbach, MC. The commission arrived in Merano, Italy, on 31 May 1945 and devoted its attention to the many cases among the German prisoners of war, since cases among U.S. soldiers were no longer available in large numbers. A preliminary report of 42 cases considered diphtheritic polyneuritis and of 28 others was submitted in 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, Letterman General Hospital, San Francisco, Calif., to Office of the Surgeon General, 20 Oct. 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 on Investigation of Polyneuritis in the Mediterranean Theater of Operations, U.S. Army, 20 Aug. 1945. [Official record.]


284

MORPHOLOGY

Typical lesions-The characteristic lesion from which C. diphtheriae was demonstrated in highest incidence was rounded with angular irregularities, deep and 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 had this appearance. They were similar to lesions of cutaneous diphtheria seen in temperate zones, to the desert or veldt sores of North Africa and Palestine, to the "Garigha" of northern India, and to the lesions seen among the Melanesians and Tonkinese in the New Hebrides, and the Chamorros in the Marianas Islands. A typical lesion could develop in as short a time as a month.

The margins of the diphtheritic ulcers were declivitous, indurated, and often rolled (figs. 37A and B, and 38). Occasionally, they were slightly undermined but not to the same extent as the tropical phagedenic ulcers described, for example, 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 to that of phenol burns or decubitus ulcers. In other instances, there was a fibrinous crust which when removed after the application of soaks revealed the lesion described. The eschar could usually be loosened at the edges but adhered firmly at the center as if it were a part of the subcutaneous tissue.

Usually, the base was relatively clean, with a moderate serous or serosanguineous discharge, but sometimes there was adherent fibrinopurulent material. The exudate beneath the crust was gray or gray green rather than yellow. Occasionally, there was a gray-green fibrinous membrane, which ordinarily was difficult to scrape from the surface but could be peeled off in some instances. It was present chiefly in lesions of short duration. This membrane was often fitted to the irregularities of the ulcer (fig. 39).

Under advantageous conditions, healing occurred by granulation from below and ingrowth of epithelium from the sides in such a manner that the scar was on a level with, or slightly below, the surrounding skin 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 border of persistent bronze-violet pigmentation (fig. 37D). The latter tended to persist for months or years. Persistent hyposthenia or anesthesia in the scars was emphasized by some observers;25  however, a degree of anesthesia in newly formed 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.-Multiple diphtheritic ulcers of lower extremity acquired in New Zealand. The patient was given 300,000 units of penicillin in 5 doses per day intramuscularly for 18 days. Saline compresses (250 units per cc.) were applied for 4 hours twice daily. A. Appearance of lesions after 1 months' duration, before treatment, 24 May 1944. B. Lesions after 3 days' therapy. C. Appearance of lesions after 17 days' 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 South Pacific series), and in almost all patients at least one lesion was situated on an extremity. In some instances, they were found in bizarre locations, as on the penis (fig. 40) or perianally. A large percentage of lesions were on the feet and as a result the ulcers were frequently disabling, although in other locations 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 be diphtheritic. Recurrences were frequent, as the insensitive layer of newly formed skin was delicate and was subject to such trauma as may have been in part responsible for the ulcer originally. In recurrent lesions, a watery blister often formed at the center, but it usually did not contain C. diphtheriae.

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

26See footnote 12 (4), p. 281.


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FIGURE 39.-Diphtheritic skin ulcers. A. Skin ulcer over left clavicle with adherent green diphtheritic membrane. Patient acquired lesion in the Solomon Islands. B. Diphtheritic ulcer in skin over left iliac crest 13 weeks after onset. The lesion was relatively shallow but punched out with adherent gray-green membrane at the base. The lesion was acquired on the island of Saipan.

Atypical lesions-Although the diphtheritic lesions usually were of the punched-out, ulcerated character described, it was not uncommon in the tropics to 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's discomfort disproportionately great. Five lesions of the interdigital spaces of the feet were noted in the India-Burma series. Any unexplained sinus tract of the feet in soldiers evacuated from the tropics should be suspected of being diphtheritic in origin.

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

Diphtheritic paronychias were occasionally observed, two each in 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 the South Pacific, who daily dressed such a case for many weeks before the diphtheritic 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 have been permanent.

MORPHOLOGY IN RELATION TO THE BACTERIOLOGY OF THE LESIONS

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

FIGURE 40.-Penile ulcers. A. Acute membranous diphtheria of coronal sulcus beginning 4 days post fellationem. B. Diphtheritic ulcer of penis resembling chancre in its firmness but has adherent green membrane from which toxigenic Corynebacterium diphtheriae was cultured. The patient had just returned from the Solomon Islands and had not indulged in sexual intercourse 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, there was an incidence of 26.3 and 23.4 percent of toxigenic micro-organisms in ulcerative lesions of two groups of soldiers, totaling 556 men, who were evacuated some 6 to 8 weeks after combat (when most of the ulcers were acquired), compared to an incidence of 6.2 percent in a group of 224 soldiers evacuated some 20 weeks after combat. In this study, all ulcerative dermatitides were cultured, although the lesion had the typical punched-out appearance. The observers in the India-Burma theater also stated that the chances of a positive culture decreased with the age of the lesion.

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

The duration of the lesions yielding a positive culture seems also to be a determinant of the toxigenicity of the strains recovered. Thus, in the South Pacific series, 40 of 43 (93 percent) diphtheritic ulcers of less than 12 weeks' duration yielded toxigenic micro-organisms, whereas of 25 older ulcers only 17 (68 percent) contained toxigenic bacilli. In one ulcer, a strain recovered on 18 November 1943 was toxigenic in contrast with one morphologically and biochemically identical obtained on 28 January 1944 from the


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FIGURE 42.-Moist, desquamative, and ulcerative dermatitis. Virulent Corynebacterium diphtheriae from scalp and ulcers of leg. Lesion acquired in the Solomon Islands.


291

FIGURE 43.-Cutaneous diphtheria as seen in the India-Burma theater. The resemblance to the lesions shown in figures 37-42 in the South Pacific Area is striking. A. A recent lesion. The ulcer is still shallow and a thin layer of fibrinous material adheres to the base. The surrounding tissue is erythematous and moderately edematous. B. A black adherent eschar forms the center of the well-defined lesion. C. In another instance the eschar has been elevated revealing the punched-out character of the lesion and its relatively clean base. D. A more chronic diphtheritic ulcer retaining the punched-out character with relatively clean granulations at its base. The margin is indurated. The surrounding tissue is slightly edematous and has a bronze-violet color. E. A healed 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 case at the Moore General Hospital,29 and the same general observation was recorded by the Southwest Pacific group, as follows: "In some instances, a culture early in the disease shows virulent organisms. Later, organisms with the same morphology and fermentation reactions were isolated, but were non-virulent by guinea-pig tests.''30 These observations indicate that the longer C. diphtheriae persist in a cutaneous lesion the less likely is the recovered strain to be toxigenic. This probably accounts for the relatively high incidence of atoxic strains in cutaneous lesions when seen in the United States.31 Neuritis in individuals carrying avirulent C. diphtheriae suggests that they may at one time have harbored toxigenic micro-organisms. Carriers in general have a relatively high proportion of atoxic strains. The mechanism of this is not clear but may be based on the formation of atoxic variants.32

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

There is a possibility that C. diphtheriae, which is not toxigenic for the rabbit or guinea pig, may have a destructive activity on the human skin. This is suggested by the work of Pasricha and Panja,33 who injected microorganisms obtained from the "Garigha" sores of Assam, intracutaneously into other men. Ulcers resembling those of the donor patients resulted, while diphtheroids similarly inoculated produced no effect. These experiments require confirmation.

Other bacteria were usually associated with C. diphtheriae in the cutaneous lesions. Considering only the 145 ulcers from which toxigenic C. diphtheriae was obtained in the South Pacific group, 6 yielded pure cultures of C. diphtheriae on blood-agar plates, and in 84 others this was the predominant micro-organism. The associated bacteria in this group were almost invariably staphylococci (65 percent), beta hemolytic streptococci (47 percent), a new hemolytic corynebacterium (9.6 percent) belonging to the common group that includes the animal pathogens Corynebacterium pyogenes and Corynebacterium ovis, and other diphtheroids (4 percent). The new hemolytic corynebacterium was made the subject of a special study and is discussed on pages 293 and 319. The presence of beta hemolytic streptococci 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 Hill Tracts. 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 positive for hemolytic Staphylococcus aureus, but less than 10 percent were positive for beta hemolytic streptococci.

METHODS OF DIAGNOSIS

Early difficulties-Until educative efforts emanating from higher medical echelons became effective, or until suspicion was raised by the development of suggestive complications or nasopharyngeal infection in contacts, there was great delay in accepting any of the cutaneous lesions of the tropics as diphtheritic. In the words of Col. William S. Middleton, MC,35 Chief Consultant in Medicine, Office of the Chief Surgeon, European theater, "a new generation in medicine has grown up without clinical awareness of the disease [diphtheria]." Part of the difficulty resulted from burying reason in the shroud of obscurant nomenclature, such as tropical ulcer, ecthyma, or "Garigha," and veldt or "Naga" sores. These exotic local names for a condition general in the tropics fostered the expectation of an exotic etiology. Part of the difficulty, however, resulted from inadequate bacteriological diagnosis, for few laboratory officers had had extensive experience with C. diphtheriae in the United States. In one general hospital, where an alert clinical staff had correlated expert dermatological knowledge with the observation of a large number of cardiac and neurological complications suggestive of diphtheria, there were no positive reports of skin cultures for C. diphtheriae during the first 6 weeks of observation of a large 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 simplest methods of culture were effective. It was found best to bring the media to the bedside and to remove a small quantity of material from the base of the ulcer with a platinum loop filled with saline or broth, if necessary. It was not important to get beneath overhanging margins or to scrape deeply. The bacteria were everywhere over the surface of the granulations at the base. If the ulcer was relatively clean and not crushed, direct culture of the base was successful without further preparation, and it was not necessary to apply alcohol or other agents. It was far more satisfactory as a routine procedure in hospital cases to apply a warm saline pack to the lesion from 3 to 24 hours, which helped to remove any excessive exudate, fibrinous crust, or ointment that may previously have been applied. Saprophytic bacteria were relatively abundant in the protein material 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 polymorphonuclear leukocytes of the exudate (fig. 43C). Sometimes, the micro-organisms were numerous, and the predominant element of the bacterial population, but usually there 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 classical descriptions, which are based on the appearance of the bacteria on Löffler's medium (fig. 43D). The bacteria from cutaneous lesions assumed the classical forms when grown on this material. In the tropics, great difficulty was encountered in distinguishing C. diphtheriae from the new hemolytic corynebacterium that was so frequently found in these lesions as well as in infections of the throat. C. diphtheriae could usually be differentiated from ordinary diphtheroids, since the former were longer, more pleomorphic, with slender and club-shaped forms, more granular, and less intensely gram positive.

With the Saipan group, an attempt was made to determine how well purely morphological criteria would bear the test of subsequent bacteriological investigation. 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 were found in the cultures. In 15 instances, 10 percent, gram-positive pleomorphic bacilli were incorrectly diagnosed as C. diphtheriae from the smears. This demonstrates that, with experience, a reasonably accurate guess can be made, which may apply under field conditions where facilities for culture are not available.

Bacteriological media-With the proper use of blood-agar plates, isolated colonies could be studied and picked for subculture, usually within 24 hours. It was 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 fresh blood. If the blood is overheated, the narrow ring of hemolytis characteristic of C. diphtheriae type mitis may be obscured and the colonies are less readily distinguished from those of staphylococci and diphtheroids.

3. To employ good streaking technique, so that the colonies on the plate were well isolated and did not present the cream cheese confluence too often characteristic of routine plates in badly conducted laboratories. On this medium, the differentiation from the unusual corynebacterium is simple, for the latter produces intensely hemolytic colonies resembling those of the beta hemolytic Streptococcus.

Löffler''s serum was found useful when examined 8 to 12 hours after incubation, for then C. diphtheriae appears in long slender pleomorphic form, permitting a tentative differentiation from the generally much shorter and thicker diphtheroids. It was extremely difficult, however, to distinguish C. diphtheriae from the new hemolytic corynebacterium.


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Tellurite medium, particularly Müller's modification,37 was very successful in some hands. The difficulty with this medium was that some batches of crystalline potassium tellurite supplied early in World War II seemed to have become partly decomposed during the vicissitudes of transportation through the Tropics and were more toxic for C. diphtheriae. On this medium, there was often a delay of up to 48 hours before typical colonies of C. diphtheriae made their appearance. The advantages under ideal circumstances are the selectivity of tellurite aiding differentiation of the type of C. diphtheriae. The new hemolytic corynebacterium generally was markedly inhibited on this material.

In the India-Burma theater, contrary to experience elsewhere where mitis was found, the micro-organisms were described as being of the intermedius variety.38 In the same theater, at the 20th General Hospital, 90 percent of micro-organisms described as virulent C. diphtheriae were said to ferment sucrose but not dextrose or levulose. In the South and Southwest Pacific39 experiences, all of the virulent C. diphtheriae were sucrose nonfermenters.

ASSOCIATED CLINICAL FINDINGS

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

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

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

Suppurative adenitis or lymphangitis were remarkably rare despite the presence not only of virulent C. diphtheriae but frequently of hemolytic Staph. aureus or beta hemolytic streptococci. Moderate local swelling of the lymph nodes without heat, however, was frequent.

In two Schick-positive individuals, a striking erythema and edema occurred about the ulcers following administration of diphtheria antitoxin. This may be analogous to the Francis reaction as observed in pneumococcal infections.

Hyperhidrosis of the hands and feet in association with cutaneous diphtheria 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.


296

RELATION TO THE SCHICK REACTION

The relation of the incidence of the lesions to the Schick reaction of the individual is of considerable interest, as it has both etiological and prophylactic connotations. It was found in the South Pacific experience that individuals with diphtheritic ulcers are much more frequently Schick positive than the general population of which the patients are a part (table 43). This indicates that the Schick-negative stage is in large measure protective. 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 the Harmon General Hospital, however, had negative Schick reactions. In another large group in the India-Burma theater (69th General Hospital), 40 percent of infected individuals were Schick positive, while 20 percent of uninfected individuals in a random sampling of admissions were Schick positive. It is notable that the divisions, after combat service in the Tropics, have a lower incidence of Schick-positive individuals than the 35 to 45 percent before going overseas. On the dermatology ward at a large hospital in the United States, 34 percent of patients from the Pacific admitted with this disease were Schick positive in contrast with the 75 general medical admissions from the Pacific areas, of whom only 13.3 percent were Schick positive. Thirty-two percent of the individuals harboring avirulent C. diphtheriae were Schick positive. This suggests a general, largely subclinical, diphtherization anologous to that which Dudley found in his school studies. Bensted,41 during an outbreak of diphtheria among British troops in northwest India, performed Schick tests on his battalion and observed that all of those subsequently 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


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 Both Cutaneous and Faucial Lesions. J. Roy. Army M. Corps 67: 295-307, November 1936.


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Several instances, however, have been recorded of the development of diphtheritic ulcers in Schick-negative individuals. One patient in the 27th Division had been found Schick negative 1 month before admission for a diphtheritic ulcer of 2 weeks' duration. In the India-Burma theater, one patient, a medical officer, who was known to have had a negative Schick test before he acquired the infection, later developed postdiphtheritic neuritis and myocarditis. In the same group, there was another man, previously Schick negative, from whose ulcers toxigenic C. diphtheriae was cultivated. Two Schick-negative individuals in whom cutaneous diphtheria appeared are mentioned in the April 1945 report from the 69th General Hospital in the India-Burma theater. One had been Schick negative 4½ months before the cutaneous lesion developed at the site where he had been scratched by a psychotic Chinese soldier patient. The other was a cook who had been found Schick negative 3 weeks previously; he had suffered a laceration from tripping over a crate. These cases, as well as others in which the Schick reaction was negative within 1 to 5 days after apparent onset, indicate that a negative Schick reaction does not necessarily imply immunity to cutaneous diphtheria and its complications.

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

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

CUTANEOUS AND EXTRACUTANEOUS DIPHTHERIA

Incidence-The concomitance of cutaneous and extracutaneous diphtheria has been noted previously, especially by Bensted, and Cameron and Muir42 in the Middle East. In the South Pacific studies, routine cultures of the nose and throat of 174 patients with diphtheritic ulcers revealed C. diphtheriae in 19 (11 percent) of them. This is a much higher carrier rate than in the general military population of which these patients were a part. Ten of the nineteen individuals had clinical pharyngeal diphtheria, and two had fibrinous rhinitis. There were also six pharyngeal carriers and one nasal carrier. In the India-Burma series, only 1 of the 119 patients with ulcers had virulent C. diphtheriae in the throat, but 8 others had diphtheroids re-

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


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

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

In 3 of the 12 clinical cases of the South Pacific group mentioned previously, the patients had been sent to the hospital for the treatment of ulcers and were found to be Schick positive. Acute pharyngitis developed while the patients were in strict isolation for periods varying from 2½ to 5 weeks. All three had had negative throat cultures and were not given antitoxin until the pharyngitis became manifest. These cases demonstrate that in all probability autoinfection of the nasopharynx from the skin can occur. The other clinical cases were admitted primarily for pharyngitis or rhinitis, although in five of them ulcers antedated the diphtheria of the throat for periods varying from 3 to 7 weeks.

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

COMPLICATIONS

Incidence-The incidence may be described as actual and apparent.

1. The actual incidence of complications, as well as the severity of the disease, is determined by the toxigenicity of the micro-organisms and by the level of susceptibility of the population. Dudley in particular has pointed out how susceptibility, by a process of latent immunization, tends to fall in an environment where C. diphtheriae is widely disseminated. Evidence that this has occurred in the Tropics is the Schick reaction of veterans of the Pacific campaigns as compared with those of trainees.

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


299

pharyngitis or tonsillitis; common colds were not included in this series. So mild had the diphtheria been that it was actually the presence of typical complications that first drew attention to the existence of the infection, which previously had escaped bacteriological detection. This mildness is probably the result of latent immunization. Obviously, the apparent incidence of 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 or toxigenicity and susceptibility have determined the stated incidence of complications, but all of these possibilities should be kept in mind.

Diphtheritic neuritis-Diphtheritic neuritis was reported from many parts of the world, especially from tropical regions, during World War II. Such factors as have been mentioned in the preceding section probably account for the following variations in the stated incidence of the postcutaneous form: South Pacific Area, 3 of 85 patients (4 percent); Southwest Pacific Area, 6 of 102 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 69th General Hospital.

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

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

In contrast to the nature of the complication following pharyngeal diphtheria, the cranial nerves, particularly the ninth, were rarely involved in cases proved to be purely cutaneous. It was generally true also in Samp-

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 Following Cutaneous Diphtheria. Lancet 2: 232-233, 24 Aug. 1918.
45Perkins, R. F., and Laufer, M. W.: Clinical Study of Postdiphtheritic Polyneuritis. J. Nerv. & Ment. Dis. 104: 59-65, July 1946.


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son's series of 20 cases, and a similar impression was held by Quillinan,46 although no detailed evidence was presented. This may be less true of paralysis of accommodation, which is transient, and in which especially skillful observation is necessary, than of pharyngeal paralysis. There is no doubt that diphtheritic neuritis can occur in individuals with positive Schick reactions. Apparently, in some instances, the toxin is absorbed upon the nervous tissues sufficiently to result in neuritis, while not enough antitoxin is stimulated to reverse the Schick reaction. Generally speaking, a single clinical attack of nasopharyngeal diphtheria fails to reverse the Schick reaction in approximately 60 percent of cases. Low antibody levels do not preclude previous, even relatively recent, diphtheritic infections, as Bronson47 would imply. This is pointed out by the observations of Gammon and Schoenbach. In Bronson's series, it is mentioned that 80 percent of proved cutaneous diphtheria, even of long duration, had positive Schick reactions. Also, Bronson mentioned a patient with nasopharyngeal diphtheria who was Schick positive 3 months after the infection and who had had antitoxin for treatment in the meantime. Three in Sampson's series had positive Schick reactions at the time the neuritis was diagnosed, but in these cases C. diphtheriae was not demonstrated. In the 20th General Hospital group, all patients with definite complications had negative Schick tests.

In most cases of undoubted diphtheritic neuritis, there is an elevation of spinal fluid protein, sometimes with changes in the colloidal gold curve, but almost always without pleocytosis.48 In Delp, Sutherland, and Hashinger's49 cases, the spinal fluid protein levels varied between 57 and 230 mg. percent. The average in Perkins and Laufer's50 series of 21 cases was 114 mg. percent, but some were as high as 200 mg. percent. In Sampson's group of 20 instances, most of which were postcutaneous, approximately one-third were below 40 mg. percent, the others were higher, and the maximum was 134 mg. percent. In the India-Burma series, the proteins were described as elevated in nearly every case and in general "proportional to the severity of the neurological disease."51 This so-called albuminocytological dissociation has caused a great deal of confusion, and much neuritis of diphtheritic origin has been classified under the Guillain-Barré syndrome, rather than under the etiological diagnosis. Often, this has been in flagrant disregard of the principle that eponyms should be applied only to the syndrome as originally described. A part of the confusion has arisen from lack of 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 Following Infections 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 Simulating Guillain-Barré'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 been ignorance of the fact that a positive Schick reaction is not incompatible with diphtheritic neuritis. The greatest cause of the difficulty, however, has been inadequate bacteriological diagnosis of cutaneous and mild nasopharyngeal diphtheria. These remarks must not be construed to imply that there were no other causes of neuritis among U.S. soldiers; some had all of the features of the syndrome as originally described by Guillain, Barré, and Strohl.52 It is desired to emphasize here, however, that the vast majority of cases of neuritis seen in the tropics were diphtheritic in origin.

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

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

Group B.-Neuritis associated with ulcers of the skin unhealed at the time of admission 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 of sore throat.

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

Group F.-Other cases of neuritis clinically indistinguishable from diphtheritic neuritis.

After the diphtheritic nature of certain tropical ulcers became apparent, there was no instance of neuritis of the type discussed that could not be related either to the ulcers, sore throat, or to proved diphtheritic pharyngitis or dermatitis.

Notable in cutaneous diphtheria is the long incubation period of neuritis. In the three cases in group A of the South Pacific series, the symptoms began between 3 and 7 months after the lesion was first noted by the patient. In two of the patients, the lesion occurred 2 and 4 months, respectively, from the time that the toxigenic C. diphtheriae was first cultured from the lesion. In pharyngeal diphtheria, neuritis most commonly begins within 6 weeks after onset of sore throat. In a series of 21 cases of neuritis observed at a neurological center in the United States, the average time of appearance of the neurological symptoms after onset of the nasopharyngeal disease was 26 days, whereas it was 2½ months after the onset of the cutaneous lesion.53 There is some variation in this, since in another group at the Baxter General Hospital54 the incubation period of the cutaneous cases varied between 30 and 77 days, and of the pharyngeal cases between 30 and 72 days. The interval between the onset of the ulcers and the onset of the

52Guillain, G., Barré, J. A., and Strohl, A.: Sur un syndrome de radiculo-névrite avec hyperalbuminose du liquide cephalo-rachidien sans réaction cellulaire. Remarques sur les caractères cliniques et graphiques des réflexes tendineux. Bull. et mém. Soc. méd. d. hôp. 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 20th General Hospital group and 73 days in the referred patients. It was of the same order of magnitude at the 69th General Hospital in the same theater.55 In a reported British experience in North Africa,56 an interval of 6 to 10 weeks elapsed in most cases after the skin lesions were noted and before the neurological symptoms appeared.

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

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

Carditis in cutaneous diphtheria-Myocarditis has come to be the most important cause of death in diphtheria. During World War II, tissues from 221 cases of diphtheria were sent to the Army Institute of Pathology (now the Armed Forces Institute of Pathology), Washington, D.C., for study.57 There was evidence of myocarditis in 143 or 65 percent of these cases. By 1945, postdiphtheritic myocarditis had become an important cause of death among troops in the army of occupation in Germany. At the 7th Medical Laboratory,58 Gräfelfing, Germany, it was the cause of death in 12 of the 285 post mortem examinations 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, if at all. Cutaneous diphtheria also was complicated by myocarditis, as seen in eight of the deaths in the Army Institute of Pathology series with such a pathogenesis.

In the India-Burma group of 14160 cases of cutaneous diphtheria, indubitable evidence of carditis existed in four instances, one of which came to autopsy, and of probable myocarditis in three, a total incidence of 5 per cent. In seven others, there were suggestive findings in the electrocardiographic tracings, but the diagnosis could not be definitely established. All individuals with definite myocarditis had extensive skin lesions. A program of case finding was instituted which included a careful physical examina-

55See footnote 14 (1), p. 281. 
56See footnote 7 (2), p. 279.
57Gore, I.: Myocardial Changes in Fatal Diphtheria; Summary of Observations in 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 Cutaneous Diphtheria. [Official record.] (2) Kay, C. F., and Livingood, C. S.: Myocardial Complications 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 possible after the diagnosis of cutaneous diphtheria was made, and at intervals of 15 to 30 days thereafter until well after the lesions had become inactive. In the same group of 141 individuals, the incidence of neurological complications was 43.5 percent. All four of those with definite myocarditis had neuritis. Neuritis usually preceded myocarditis except in the one fatal case. The earliest appearance of the electrocardiographic changes was on the 20th day of the existence of the cutaneous lesion; in the fatal case, the severe symptoms appeared on the 38th day, followed by death 3 days later; and in another case, myocarditis appeared on the 60th day. The duration of electrocardiographic changes was from 60 to 90 days among those in whom the diagnosis was certain and approximately 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 in the India-Burma group were asymptomatic, two complained of dyspnea and faintness on slight exertion, and the one who died first suffered abdominal pain with nausea and dyspnea on exertion. Eighteen hours before death, discomfort extended upward into the chest, then there was vomiting, collapse, fall in blood pressure, gallop rhythm, and leukocytosis. The electrocardiographic tracings usually did not show a P-R interval in excess of 0.20 second, nor were abnormalities in the QRS segment striking. The most consistent abnormalities were depression or frank inversion of T-waves in the C-R3 lead. These occurred in all but the fatal case of the India-Burma group. This was also the experience of Ball who emphasized depression of the S-T interval. Conduction defects apparent in the two cases of myocarditis that followed nasopharyngeal diphtheria were not observed among the postcutaneous cases in the India-Burma group, but they were described in other instances that apparently followed diphtheria of the skin.62

Several writers have stressed the importance of serial electrocardiographic tracings to diagnosis.63 Careful observations of pulse and blood pressure must, however, not be forgotten.

Delp and Dimond, who were successful in treating two severe cases of myocarditis, emphasized the importance of putting the patients at absolute rest, elevating the foot of the bed, applying external heat, and slowly administering glucose solution by vein.

61(1) Ball, D.: Diphtheritic Myocarditis; With Report of 2 cases. Am. Heart J. 29: 704-707, June 1945. (2) Craig, C. McK., and Manch, M. D.: A Study of the Aetiology of the "Desert," Septic, or Veldt Sore Amongst European Troops; 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 in Cutaneous Diphtheria. Am. Heart J. 32: 250-256, August 1946. (2) Solomon, S., and Irwin, C. W.: Cutaneous Diphtheria With Toxic Myocarditis; Report of Fatal Case 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 cutaneous diphtheria in tropically acquired cutaneous infections was recognized, and particularly after the dangers of contact cases were realized, relatively efficient methods of case finding were instituted. These consisted in temporarily isolating all patients with ulcerative dermatitis and making cultures designed to detect C. diphtheriae. In some institutions, new patients were held on a special admission ward. Routine cultures were made from material from the cutaneous lesions and from the nose and throat. If the culture was positive for C. diphtheriae, the patient was treated specifically in isolation until virulent organisms were no longer recovered. The other patients were released for treatment in a general dermatological ward. Such a method was found valuable in the South Pacific study in handling the heavily infected 27th Division in the New Hebrides rest area. After a series of talks designed to acquaint the battalion surgeons with diphtheria of the skin, a centrally located clinic was established to which all patients with tropical ulcers were referred for culture. Those found positive were hospitalized. In this way, many patients were put under treatment, and the dissemination of the organisms was checked. This procedure was especially effective in curbing contact cases. Oppel and his coworkers reported that a similar method was adopted in the Southwest Pacific Area. Individuals who were found to have cutaneous lesions infected with C. diphtheriae and were Schick positive were treated with antitoxin. The procedure at Moore General Hospital and at Harmon General Hospital was similar. The desirability of making nose and throat cultures in such cases was stressed in these institutions, as was also the use of Schick-negative attendants in caring for them.

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


305

sified or transferred to the Zone of Interior, none had had diphtheria antitoxin within 32 days after onset of the lesions. These statements are to be regarded as suggestive, rather than final, statistically proved conclusions. According to Livingood,64 the most important factors in preventing complications, loss of man-days, and loss of life from cutaneous 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 healing the ulcers seen in the South and Southwest Pacific and in Burma seem to have been bed rest and the application of moist dressings. Outpatient treatment results in the lesions remaining unhealed for many weeks and continuing as a prolific source of diphtheria bacilli. Although C. diphtheriae is sensitive in vitro to sulfonamides, in ulcers it seemed to be almost unaffected by these drugs. In many instances in the South Pacific, the organisms were cultured directly 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 per cubic centimeter in physiological saline, has certain very definite indications that became evident during the course of a series of controlled observations in the South Pacific Area on Schick-negative individuals whose lesions contained toxigenic bacilli. The actual healing time of the ulcers was not significantly reduced. Results of treatment of lesions containing toxigenic C. diphtheriae in Schick-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 more initial improvement and afforded more relief from pain, but after 2 weeks its effect was not superior to those of other measures. Nevertheless, in the South Pacific, in each of six instances where an ulcer treated locally with penicillin was compared bacteriologically with a saline-treated control in the same individual, it was found that the toxigenic bacilli invariably disappeared from the former within 48 hours after the application of penicillin, whereas, in the latter, they persisted until the lesion was almost healed. The observations at Harmon General Hospital were similar, pathogenic organisms being eliminated in cases treated parenterally with penicillin in an average of 4 days; in those treated with saline alone, only 25 percent were cleared of the organisms in an average period of 8 days. Penicillin reduced not only the hazard of long contact with C. diphtheriae to the patient himself but to the community at large.

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

Surgical measures-The experience of the India-Burma group indicated that operation should be considered if the ulcer fails to heal in 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 most successful methods in a small group treated by Royster66 seemed to be excision of the ulcer and a small margin of normal skin, followed by application of a split-thickness skin graft, rather than of the sliding flap, or extensive undermining and simple closure. The skin adjacent to the graft became more pliable. Skin grafts simply applied to large ulcers, even after they had begun to granulate cleanly, failed to take.

Factors in healing time-If an atoxic organism was present, the healing time seemed to be significantly reduced. The following tabulation shows the relation of toxigenicity of C. diphtheriae to healing 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 Postdiphtheritic Ulcers. Plast. & Reconstruc. Surg. 3: 294-302, May 1948.


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Conclusions-These observations suggest that the most efficient way of handling the patients is to put them at rest in bed and to apply penicillin locally in continuous soaks of 250 units per cubic centimeter. Most clinicians recommend the administration of antitoxin, at least if the individual is Schick positive. In retrospect, it would probably have been best to send only Schick-negative individuals into combat in the Tropics.

COST OF CUTANEOUS DIPHTHERIA TO THE ARMY

A substantial amount of disability was caused by cutaneous diphtheria during World War II. The lesions were present in all tropical areas, but the exact incidence is difficult to estimate. In the 35th Infantry, 25th Division, 6 weeks after evacuation from the New Georgia campaign, 19.4 percent of 200 men who were carefully questioned and examined had either active lesions or scars suggestive of previous infection with C. diphtheriae. Two of these were actually proved to have the organisms in their lesions. At the 54th General Hospital on Biak, 29 percent of admissions to the medical service were because of skin disease. It can be assumed that a considerable proportion of this was of diphtheritic etiology. In the South Pacific Base Command between 1 January and 30 June 1944, skin disease was the primary diagnosis of 9 percent of all medical evacuations to the United States. Many of these skin cases that had been studied at the 39th General Hospital were proved to be diphtheritic.

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

In a followup study of 140 patients in the India-Burma series, a total of 18,783 man-days were lost, an average of 4½ months per man, not including the days lost by 30 patients after their return to the Zone of Interior.67 The total duration of skin lesions from appearance to healing averaged 91 days in another series in the India-Burma theater.68

The chief causes of prolonged hospitalization were breakdown of the thin scars when activity was resumed, or the neuritic or cardiac complications of the disease. In 53 of the 140 cases in the India-Burma group, the scars broke down upon resumption of activity and 13 of these showed no tendency to heal. This was the final result reported in August 1945. At the end of January 1945, in that group,69 the causes of hospitalization in excess of 70 days in a total 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-Burma theater showed that 60 percent of the men had returned to full duty; 18 percent had been reassigned, 12 of 25 because of cutaneous diphtheria alone; 22 percent had been returned to the Zone of Interior, 13 of 30 because of cutaneous diphtheria alone. It seemed, however, that prolonged inactivity occasioned by the cutaneous diphtheria had predisposed to the development of psychoneurosis which was listed as the primary diagnosis in some cases. When this is added to the followup study, the results are that 20 of 25 were reassigned and 22 of the 30 were returned to the Zone of Interior for causes ascribable to cutaneous diphtheria.

ROLE OF CUTANEOUS LESIONS IN THE SPREAD OF DIPHTHERIA

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

Evidence from contacts in hospitals-In the late spring and summer of 1943 at the 39th General Hospital, in the South Pacific group, there were six instances of apparent contact infections among members of the staff or patients before tropical ulcers were recognized to be diphtheritic. A nurse attending an officer with widespread desquamative and ulcerative lesions had paronychia and an abscess in her arm from which C. diphtheriae and beta hemolytic streptococci were isolated. Another nurse attending the same patient contracted a sore throat which was not of membranous type. This nurse was known to have been Schick negative previously. Another officer, who had been admitted for jaundice 2 weeks before and who did not have a sore throat at the time of admission, was placed in the cubicle next to the first case and developed an extensive membranous nasopharyngeal diphtheria. A wardman on another ward, where many patients with tropical ulcers were kept, developed a paronychial granulomatous and ulcerative lesion from which the toxigenic corynebacteria were cultured (fig. 44), and shortly


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thereafter another attendant on the same ward developed diphtheritic pharyngitis. Pharyngeal diphtheria developed in a wardman on another dermatology ward where there were many ulcer cases. All of these members of the hospital staff had been on wards caring for patients with cutaneous lesions. After isolation procedure was instituted for diphtheritic tropical ulcers, no other contact cases appeared except one in a nurse, attending an isolated patient with diphtheritic pharyngitis, who acquired a severe 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-Burma group,70 11 patients acquired cutaneous diphtheria after a period of hospitalization for another disease or injury. Faucial diphtheria developed in another patient in the 20th General Hospital 4 weeks after admission to the dermatology ward. Two of the patients with cutaneous diphtheria acquired pharyngitis and tonsillitis. In one patient, virulent organisms were isolated 3 weeks after admission, and in the other nontoxigenic bacilli were found 6 weeks after admission. Similarly, in a British experience in North Africa,71 one nursing sister and one orderly in the dermatology ward contracted faucial diphtheria, and the medical officer in charge developed cutaneous diphtheria.

At the 13th General Hospital,72 Finschhafen, two cases of diphtheria were recognized in the dermatology ward. Within the next 8 days, 7 clinical cases and 33 carriers were found by culture and were isolated, and in the following 7 days, 3 cases and 2 carriers were discovered. Seven patients in the 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 pharyngeal diphtheria appeared in wards devoted exclusively to dermatological cases and similar outbreaks centered around these wards.

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

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


310

severe except the first, which was fulminating, with hemorrhagic 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 patients and personnel of the dermatology and physiotherapy sections and in the castroom were also cultured and 14 were found to harbor toxigenic C. diphtheriae. Six of the fourteen were Schick positive. These observations emphasize the menace of unrecognized cutaneous diphtheria.

GENERAL CONSIDERATIONS OF DIPHTHERIA IN THE TROPICS

Diphtheria among the natives-In the course of investigating the cutaneous diphtheria among the soldiers in the New Hebrides and later on Saipan, it was noted that the natives, particularly young children, had cutaneous lesions resembling those of the soldiers. Many of these were found to contain C. diphtheriae. Two of four Melanesian natives (figs. 43E and 45), one with apparently superinfected yaws, yielded atoxic C. diphtheriae. Six of fifty-three Tonkinese children had multiple punched-out lesions generally more superficial but like those observed in the soldiers (fig. 44). Four of these yielded organisms that had the morphological and biochemical characteristics of C. diphtheriae type mitis but were not toxigenic. Lesions of identical appearance were found in large numbers among Chamorro children on Saipan. Fifteen strains of C. diphtheriae type mitis derived from these were tested for toxigenicity and one was found to be toxigenic. It is of some interest to note, and not easy to explain, that some of these ulcers occurred in older children who were Schick negative. The lesions were most numerous where trauma was likely to occur, as about the knees, but they also were found elsewhere. Scars of such lesions were abundant in children more than 7 months of age, and they were almost universal above the age of 3 years.

Many studies have been made of Schick reactions of the natives in the Tropics. All have shown a high level of immunity. This has been found to be true among Filipinos, Malayans, Javanese, Hondurans, Brazilians, and the Bantu of Africa.75 During World War II, in the British Army, the incidence of Schick-positive individuals among 900 sepoys was 1.1 percent, whereas among the British troops it was 27 percent.76 In the South Pacific Area, the Schick reactions of natives more than 5 years of age were almost 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 of Schick positives, in excess of 50 percent, among

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


311

FIGURE 44.-Diphtheritic paronychiae. The patient was a wardman and, for several weeks, had attended an officer with lesions resembling those shown in figure 42. This was a contact case that occurred at the 39th General Hospital in New Zealand, 1943.

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


312

the natives of the various races investigated. The theory was advanced for the first time, that the rapid reversal of Schick reaction was the result of immunization by the cutaneous route. It appears that the antitoxin level falls sufficiently to give a positive Schick reaction for only a short time, after loss of the transplacentally acquired immunity. This probably accounts for the rarity of severe nasopharyngeal diphtheria among natives of the Tropics.

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

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

2. The lack of facilities for washing.

3. The intimate crowding of the population.

4. The numerous opportunities for minor trauma produced mechanically or by insects.

5. The abundance of flies.

All of these conditions are extremely favorable for the spread of cutaneous diphtheria. Among the soldiers, where there are many individuals with low antitoxin titers, in contrast with the natives, there was a high incidence of nasopharyngeal as well as cutaneous infection. The barrier of cleanliness accounts for the fact that colonizers living in the Tropics under peacetime conditions are generally more susceptible than the natives, as indicated by the results of Schick tests, and that the former sometimes have nasopharyngeal diphtheria in epidemic form. One such epidemic is recorded by Fox and MacDonald (quoted by Forbes),77 in a school at Shillong, Assam, the very region 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 the determining factor in the spread of the cutaneous varieties of diphtheria. The original source of C. diphtheriae is difficult to determine. Carriers are always present in our own population, and the native reservoir may at times be important.

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

As in the desert campaigns described so well by Bensted,78 and Cameron and Muir,79 nasopharyngeal diphtheria has been coexistent with, 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. This was 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 in the India-Burma theater80 relatively few nasopharyngeal cases were diagnosed. The course of the epidemic in the 27th Division while at the rest area 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 cases had previously been diagnosed on Saipan, shortly after the campaign on that island. In a more general way, the incidence of skin disease and diphtheria and tonsillitis was closely parallel also in the Afrika Korps (chart 14).

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

Skin-to-skin contact seems the most usual method of the spread of the bacilli among the crowded combat troops in the Tropics. This is supported 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 men from two divisions tested in the South Pacific Area. In a series of 174 patients with ulcers, the incidence of asymptomatic carriers was 4 percent.

80See footnote 15, p. 281.


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TABLE 45.-Cases of diphtheria in the 27th Division in rest area in the New Hebrides, 16 September-28 October 1944

Date of admission


Skin cases

Throat carrier

Throat case

Total


Throat negative

Throat carrier

Throat case

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

 


315

The one group in which the carrier rate has been extremely high in the absence of clinical diphtheria was among German prisoners of war81 at the camp in Merano. Here, it was 17 percent in apparently healthy individuals in a camp where there were many cases of neuritis. This carrier rate was exceeded only in convalescents from clinical diphtheria at the same camp. Evidence has been presented that diphtheria can be spread not only from skin to skin but also from skin to pharynx and from pharynx to skin. The same or other individuals can be involved in this process.

Other factors were considered in Burma. Investigators cultured rice paddies as possible sources of C. diphtheriae among soldiers in the Myitkyina area but found them to be negative.82 Flies, in places where cutaneous diphtheria was prevalent, were cultured in the Southwest Pacific Area.83 They 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 have for them possibly may make them important in spreading the organism in the Tropics.

DIPHTHERIA TRANSMITTED FROM MILITARY TO CIVILIAN POPULATIONS

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

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

A specific example is cited in a case investigated by the New York State Department of Health. 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 was returned to this country and was again hospitalized at Fort Dix, [N.J.] in June 1945. 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 son born in the household on July 26 was circumcised on July 31. This child was noted to be ill on August 18 and on inspection, the circumcision wound was found to be unhealed and covered with a diphtheritic membrane. Virulent diphtheria bacilli were recovered from the wound, and the child responded to specific therapy.

An adult female, the captain's wife, developed sore throat on 24 August. Virulent diphtheria organisms were found in her throat and she responded promptly 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 on August 30 and responded promptly to treatment. Virulent diphtheria organisms were recovered from his throat. The captain developed no sore throat and there was no mention of any change in the ulcers on the left hand and arm. It was reported that a culture taken from his hand on August 23, 1945 at Fort Dix was negative. These lesions were cultured in Hornell on September 6, and pure culture of diphtheria organisms were recovered. On the whole, it appears highly probable that the infection was introduced by the captain but, as you will note from the dates, the case was not proved beyond doubt.

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

Diphtheria had a high incidence in the summer months of 1941 and 1942 in the Afrika Korps, and in each year it waned during the fall and winter months. This information is derived from captured German documents in the European Order-of-Battle Section, G-2, Headquarters, Army Ground Forces. The epidemic began late in July 1941. In September, there were 416 diagnosed cases, largely in the 21st Panzer Division, but there were some also in the 15th Panzer Division.84 In the report of the chief surgeon of the Panzer Army in 1941, the following statement appears (translated):85 "There were four outstanding diseases, which in increasing measure had an uncommonly high incidence: Dysentery, jaundice (infectious icterus), diphtheria, and ulcers of the skin, especially of the lower extremities." In the next year, the table of incidence taken from the corresponding report, is very similar (chart 14). Diphtheria of the skin among German soldiers was reported in several papers in Der deutsche Militärarzt.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 Merano and the associated diphtheria there have been discussed previously. The evacuation of Germans from the North African campaign was progressing continuously in 1941 by hospital ship to Naples, Italy, thence by train to Germany, where Munich was the usual debarkation point. From April to December 1941, 8,400 were sent from Italy to Germany by train.

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

84Deutsches Afrika Korps. Tätigkeitsbericht der Abt. IVb, 30 Sept. 1941. [Captured German document.]
85Armeearzt, Hauptquartier Panzerarmee Afrika. Erfahrungsbericht, 28 Feb. 1942. [Captured German document.]
86(1) Binhold, (NFI): Über Wundiphtherie. Deut. Militärarzt 8: 521-527, September 1943. (2) Funk, C. F.: Die chrönisch-ulcerosen flächenhaften Pyodermien: Ecthyma simplex, Pyodermia papillaris vegetans et exulcerans, sowie das Ulcus cruris ohne Ulcus varicosum. Deut. Militärarzt 9: 401-404, September 1944. (3) Quartiermeister (Rom) IVb, Zurzer Tätigkeitsund Erfahrungsbericht für die Zeit von 6.2.1941 bis 31.12.1941 des Danitätssoffz. bei QM. Rom (Heer). Sect. VI. Abtransport Verwundeter und Kranker der Panzergruppe Afrika, 28 Jan. 1942. [Captured German document.]


317

ber 1941 (chart 15), at the same time the diphtheria epidemic was at its height among the German soldiers in North Africa and while troops were being continually evacuated from that theater. In France, the increase occurred largely in the northern, occupied parts of the country.87 It was not until after a considerable interval of time that the disease became prevalent in neutral countries, such as Sweden and Switzerland, to which travel from 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 countries were poor. However, a similar increase in incidence of diphtheria occurred in New Zealand where the diet was more than adequate. Here, it was associated, at least in time, with the return of U.S. Marines and later U.S. Army troops from campaigns in the Solomon Islands. Diphtheria among the Marines has been described by Norris and others. The influx into the country began after the middle of 1942. The 25th Division appeared en masse in New Zealand in 1943; the 43d Division arrived later. Diphtheria among these soldiers is described in detail in this chapter. Thus, the stream of individuals infected with C. diphtheriae had been uninterrupted until the middle of

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


318

1944. Therefore, the morbidity from diphtheria in the New Zealand civilian population 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 have been associated with the return of soldiers at that time from Gallipoli and the Desert.

It is of interest that the great pandemics of previous centuries appear to have come from the South.88 According to Friederich Löffler, quoted by Nuttall,89 "The disease appears to have been perfectly well known in Egypt, Syria, and Palestine even in ancient times. This is proved by repeated references to it in the Babylonian Talmud." Also, according to Rolleston,90 in the first century A.D., "an unmistakable description of diphtheria is given by Aretaeus of Cappadocia under the name of Syriac or Egyptian ulcers owing to its having originated in Syria and Egypt whence it spread to all European countries." The "ulcers" refer to the appearance of the throat and not to the skin in this instance.

These correlations are not held up as final proof of the importance of cutaneous diphtheria among the military as the ultimate source of the epidemic in 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 of Diphtheria. Oxford: Cambridge University Press, 1908.
90Rolleston, J. D.: Acute Infectious Diseases. London: William Heinemann, Ltd., 1925.


319

importance as both, owing to their innocent appearance, may widely spread disease before their true nature is recognized." Streptococci may be similarly introduced since they abound in cutaneous lesions in the Tropics.

Part III. A New Hemolytic Corynebacterium in Man

A hemolytic corynebacterium was frequently cultivated from nasopharyngeal and cutaneous infections in soldiers evacuated from tropical islands of the Pacific and from natives of the New Hebrides and the Marianas. This organism which was given the tentative designation "Corynebacterium hemolyticum" is similar to a large group91 of hemolytic corynebacteria, such as C. ovis and C. pyogenes, known to be pathogenic for animals. This organism is important because:

1. It may readily be confused with C. diphtheriae in direct smears of exudates and on Löffler's slants, and with beta hemolytic streptococci on blood-agar plates.

2. There is suggestive evidence of its pathogenicity for man. In smears of exudates and Löffler's slants, the new organism closely resembles C. diphtheriae, although it tends to be more slender. It is pleomorphic and granular, but the granules are not metachromatic. On filtered sugar media enriched 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, in slowly liquefying gelatin, and in not reducing nitrates. When inoculated intracutaneously into guinea pigs or rabbits, C. hemolyticum produces lesions resembling those caused by C. diphtheriae, but these are not prevented by diphtheria antitoxin, in the standard virulence test of Fraser and Weld. C. hemolyticum produces hemolytic and skin necrotizing toxins in broth that will not pass the Seitz filter.

On 24-hour blood-agar plates (pH 7.4), the organism is more hemolytic than C. diphtheriae type mitis, and its colonies resemble those of the beta hemolytic streptococcus. When the plates are allowed to incubate for 48 to 72 hours the colonies of C. hemolyticum continue to grow and become discoid, contrary to those of the Streptococcus, and the zone of hemolysis becomes enormous, usually after passing through a double phase. Other colonial characteristics are a lenticular dark spot visible by transillumination and etching of the surface of the blood-agar plates. Both of these phenomena are manifest in colonies more than 24 hours old and are not seen with the beta hemolytic streptococcus (fig. 46-55).

91Brooks, R. F., and Hucker, G. J.: A Study of Certain Members of the Genus Corynebacterium. J. Bact. 48: 295-312, September 1944.


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The pathogenicity of C. hemolyticum for man is indicated by its capacity for producing lesions when inoculated into the skin. Its low invasiveness, however, is inferred by the absence of complications after intracutaneous injections in man and by the failure of development of significant symptoms when sprayed on the normal throat. It readily becomes parasitic in the nasopharynx, where it may persist for many weeks. In conjunction with another infectious agent or a lowering of resistance of the host, however, it is possible that C. hemolyticum may become an "opportunist pathogen" for man. This is supported by the evidence of clinical cases in which C. hemolyticum was the dominant organism during the course of an acute respiratory illness, was unassociated with a known pathogen, and disappeared with the subsidence of the disease.

FIGURE 46.-Exudate from diphtheritic ulcer. Corynebacterium diphtheriae within 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 sometimes observed 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 Espíritu Santo, New Hebrides Islands.

Part IV. Use of Penicillin in Treatment of Diphtheria

Interest in penicillin as a possible therapeutic agent against diphtheria was high since it was known from earlier observations of the British that C. diphtheriae was sensitive to penicillin in vitro. Some evidence of variation in the susceptibility of various strains has been pointed out by McDaniels. In the European theater, investigation of the subject was stimulated by Administrative Memorandum No. 151, Office of the Chief Surgeon, dated 27 November 1944, outlining a tentative program for the observation of the efficacy of penicillin in the treatment of diphtheria.

All observers were agreed that following use of the drug in the active nasopharyngeal form of diphtheria there was often evidence of clinical improvement,92 but some ascribed this to the effect on the frequently concomitant streptococcal infection. It soon became obvious by the review of fatalities and serious complications that penicillin, even when given early and abundantly, did not prevent myocarditis.93 In the words of Colonel Middleton, Chief Consultant in Medicine, European theater:94 "There is no substitute for antitoxin administration on suspicion without undue reliance

92Karelitz, S., Moloshok, R. E., and Wasserman, L. R.: Penicillin in the Treatment 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. Melanesian child in New Hebrides Islands with typical punched-out ulcers of the skin and yaws of the right foot. Ulcerative lesions in both instances contained nontoxigenic Corynebacterium diphtheriae. B. Tonkinese child, about 2 years old, with multiple ulcers. Some appear punched out; others are partly or completely 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 is complete, the clinician may himself perpetrate a virulence test on Homo sapiens with irreversible effect.95

Penicillin seemed particularly promising for use in the treatment of carriers, and was given study in various quarters with somewhat diverse results. There was variation in the definition of carrier and in the methods of application and dosage of penicillin. Among the criteria for checking the results of these experiments should be consideration of (1) whether an adequate number of cases was used, (2) whether a check was made on the natural decline of the carrier state, and (3) whether the recurrence of organisms was tested.

For these reasons, the work of Karelitz and his coworkers must be considered inconclusive. 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 from 18 to 24 hours. Hemolysis is beginning. (X 4) Inset shows actual size of colonies.

FIGURE 51.-Cornyebacterium diphtheriae 24 hours on 5 percent human blood agar, for contrast with C. hemolyticum. (X 4) Inset shows actual size.

FIGURE 52.-Corynebacterium hemolyticum 48 hours on 5 percent human blood agar contrasted with beta hemolytic streptococcus. Note greater translucency and less sharply defined border of Streptococcus colony. In the original, the latter has a silvery rather than pink color. Zone of hemolysis is now relatively smaller in contrast with appearance at 24 hours. Note minute pit at apex of C. hemolyticum colony. (X 4) Inset shows actual size of colony.

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


324

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

FIGURE 54.-Corynebacterium hemolyticum, 48 hours on Löffler's serum at 37° C. Gram stain. (X 1,100)

FIGURE 55.-Corynebacterium diphtheriae, 48 hours on Löffler's serum at 37° C. Gram stain. (X 1,100) (Compare with fig. 54.)

Bagnall and Bain97 of the No. 14 Canadian General Hospital, in the Mediterranean, performed careful experiments using 175 patients and giving penicillin intramuscularly. Two groups were used: Group A received a total of 600,000 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 25,000 units every 3 hours. The percentage of success was higher in group B than in group A, which was no better than the control group. Bagnall and Bain pointed out that, in seven instances, positive cultures recurred after three consecutive negative cultures and in four instances, after four consecutive negative cultures. The writers' conclusions were that the results were disappointing.

Even less satisfactory were the results of intramuscular treatment of individuals 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 of 2,100,000 units. The cultures remained positive in their subjects.

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


325

These observers concluded, however, on the basis of another experiment, that local therapy is effective. Their method was to use glycerine-gelatine lozenges, which required 20 to 30 minutes for solution, one each hour for 12 doses. The early patients in the series received lozenges containing 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 individuals cleared promptly in 1 to 10 days after treatment was started, and eight cases that were persistently positive had large tonsils. After tonsillectomy, however, these became consistently negative. Scrutiny of the table presented by these workers, however, shows that 10, rather than 8, cases must be considered failures. Furthermore, in seven others, the cultures were already negative before local treatment was started and are therefore "no test."

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

Part V. Problems Remaining for Investigation

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

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

2. Of special interest would be an investigation of whether cutaneous diphtheria has a significant incidence in the poorer parts of the Southern United States where it may account for the high levels of Schick immunity observed there.

3. Further information should be gathered concerning the occurrence of cutaneous 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 capable of producing lesions in the human skin requires careful investigation. The factor of hypersensitivity may have significance in this connection.

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

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


326

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

Part VI. Summary

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

The lesions, which usually were preceded by trauma or insect bites, most commonly assumed the form of punched-out ulcers with declivitous margins and relatively clean bases, to which occasionally a grey-green membrane or fibrinous crust was adherent. The borders were usually indurated and blue or bronze violet in appearance. Exanthematous or moist desquamative lesions of entirely different appearance could, however, harbor large numbers of C. diphtheriae.

The complication of neuritis or myocarditis occurred occasionally, or in some groups of cases frequently, but usually there 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 military efficiency 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 cutaneous and nasopharyngeal diphtheria for others. This is demonstrated by evidence of spread of diphtheria from patients on dermatology wards to other patients and to ward personnel; concomitance of nasopharyngeal and cutaneous diphtheria in military populations in the Tropics; and suggestive evidence that unrecognized cutaneous diphtheria in Rommel's soldiers was responsible for the epidemic in Europe where, on account of climatic conditions, the diphtheria took the respiratory form. The epidemic in Europe began in September 1941, when both cutaneous and nasopharyngeal diphtheria was at its height in the Afrika Korps and while large numbers of German soldiers were being returned to Germany as patients. It involved first those countries under direct occupation by the Germans and the neutral countries not until much later.

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

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


327

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 the Tropics, who constitute a tremendous reservoir of C. diphtheriae. Among them, cutaneous diphtheria is universal by the fourth year of age. Only between the ages of 9 and 24 months is there a high incidence of Schick-positive reactions among these people. Immunization by the cutaneous route probably accounts for the rapid conversion to the Schick-negative state. The level of immunity 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 vicissitudes of combat in the Tropics into the same epidemiological conditions as the natives, then severe faucial as well as the more common cutaneous forms of diphtheria become widespread.

The best treatment for cutaneous diphtheria appears to be to put the patient at rest in bed and to apply penicillin locally in continuous, moist saline compresses. Diphtheria antitoxin intramuscularly may prevent the consequences of autoinfection of the pharynx and possibly may diminish the incidence of complications.

The best measure of prevention of a cutaneous diphtheria is to send only Schick-negative troops into combat in the Tropics. The fact that more individuals who have diphtheritic ulcers are Schick positive than the general population, 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 the Tropics, hemolytic corynebacteria are common which may resemble C. diphtheriae in direct smears and on Löffler's media. These require further investigation.

More study is necessary concerning the use of penicillin in terminating the carrier state and in the therapy of clinical nasopharyngeal diphtheria. Penicillin alone, even when given early and abundantly, does not prevent the complications of the disease.

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