U.S. Army Medical Department, Office of Medical History
Skip Navigation, go to content

HISTORY OF THE OFFICE OF MEDICAL HISTORY

AMEDD BIOGRAPHIES

AMEDD CORPS HISTORY

BOOKS AND DOCUMENTS

HISTORICAL ART WORK & IMAGES

MEDICAL MEMOIRS

AMEDD MEDAL OF HONOR RECIPIENTS External Link, Opens in New Window

ORGANIZATIONAL HISTORIES

THE SURGEONS GENERAL

ANNUAL REPORTS OF THE SURGEON GENERAL

AMEDD UNIT PATCHES AND LINEAGE

THE AMEDD HISTORIAN NEWSLETTER

Chapter XI

Contents

CHAPTER IX

Meningococcal Infections

Worth B. Daniels, M.D.

HISTORICAL NOTE

Outbreaks of meningococcal infection are known to have occurred during all wars since the illness was first described by Vieusseux1 in 1805. Important milestones in the development of knowledge of this disease can be briefly summarized. The isolation of the causative agent by Weichselbaum2 in 1887 led to a search for a specific cure. Flexner and Jobling3 thought that the antiserum prepared by them at the Rockefeller Institute in 1908 favorably modified the course of the disease.

Within 1 month of mobilization in World War I, the annual rate of admission to hospital for white enlisted men in the United States reached 1.71 per 1,000 troops, and within 7 months an explosive outbreak of meningococcal meningitis had begun (chart 12). In January 1918, the rate had risen to a peak of 4.48 per 1,000.4 This epidemic afforded Herrick5 an opportunity to study the use of antiserum under controlled conditions and to make observations on pathogenesis. His studies indicated that antiserum given intravenously reduced the mortality in patients with bacteremia and in those with meningitis. In spite of the use of meningococcal antiserum, however, there were 1,836 deaths among approximately 5,900 cases (31 percent case fatality ratio) among troops throughout the U.S. Army in a period of 33 months during and immediately following World War I.6 Herrick's studies clearly showed that meningitis does not develop as the result of extension from the nasopharynx but begins as bacteremia with later localization in the meninges, joints, and other tissues. This concept has greatly influenced treatment and, together with the development of the sulfonamides, has been a factor in lowering the death rate.

1Vieusseux, M.: Mémoire sur la Maladie qui a rēgne à Génève au printemps de 1805. J. de méd., chir. et pharmacol. 11: 163-182, 1805.
2Weichselbaum, A.: Ueber die Aetiologie der akuten Meningitis cerebro-spinalis. Fortschr. d. Med. Berlin 5: (No. 18), 573-583, 15 Sept. 1887; ibid., 5: (No. 19), 620-626, 1 Oct. 1887.
3Flexner, S., and Jobling, J. W.: Serum Treatment of Epidemic Cerebrospinal Meningitis. J. Exper. M. 10: 141-203, January 1908.
4The Medical Department of the United States Army in the World War. Washington: U.S. Government Printing Office, 1928, vol. IX, pp. 203-221.
5(1) Herrick, W. W.: The Epidemic of Meningitis at Camp Jackson. Preliminary report. J.A.M.A. 70: 227, 26 Jan. 1918. (2) Herrick, W. W.: Early Diagnosis and Intravenous Serum Treatment of Epidemic Cerebrospinal Meningitis. J.A.M.A. 71: 612-617, 24 Aug. 1918. (3) Herrick, W. W.: The Intravenous Serum Treatment of Epidemic Cerebrospinal Meningitis. Arch. Int. Med. 21: 541-563, April 1918.
6See footnote 4.


240

CHART 12.-Admissions to U.S. Army hospitals for meningococcal infections among troops in the continental United States, by month, World War I1 and World War II2

Sulfanilamide early proved to be a highly effective agent in the therapy of these infections.7 In 1940-41, during the outbreak in Halifax, Nova Scotia, Dingle and his coworkers8 showed the effectiveness of sulfadiazine in a small group of patients.

7Schwentker, F. F., Gelman, S., and Long, P. H.: The Treatment of Meningococcic Meningitis With Sulfanilamide; Preliminary Report. J.A.M.A. 108: 1407-1408, 24 Apr. 1937.
8Dingle, J. H., Thomas, L., and Morton, A. R.: Treatment of Meningococcic Meningitis and Meningococcaemia With Sulfadiazine. J.A.M.A. 116: 2666-2668, 14 June 1941.


241

INCIDENCE DURING WORLD WAR II

In World War II, mobilization began with the federalization of the National Guard in September 1940, and the induction of large numbers of selectees followed shortly. For over 2 years, only sporadic cases of meningitis occurred in troops. In December 1942, closely following an increase of respiratory disease in the late fall, the incidence of meningococcal infections rose sharply throughout Army installations in the United States. By March 1943, the outbreak had assumed severe proportions, and the incidence rate had reached 2.9 per 1,000 troops (chart 12). The rate among newly inducted soldiers was from 5 to 10 times greater than among soldiers with a year or more of Army service. At one post, where crowding among new inductees was excessive, the weekly rate rose to 42.2 per 1,000 per annum.9

Throughout 1943, the year of most numerous cases, data based on individual medical records show that 7,083 patients were admitted to hospitals with meningococcal infections; 6,370 of these developed the illness in the United States. The incidence rate per 1,000 per annum was 1.0 for the total U.S. Army, 1.2 for troops in the United States, and 0.4 for troops overseas.

For the year 1943, in the United States, the statistical health report rates per 1,000 per annum by service command are as follows:

Service Command

Rate

First

1.2

Second

1.6

Third

1.4

Fourth

1.5

Fifth

1.3

Sixth

1.5

Seventh

1.3

Eighth

.8

Ninth

1.0


The incidence of meningitis (0.8 per 1,000 per annum) in the European Theater of Operations, U.S. Army, during 1942 was greater than among troops in the United States. During 1943, the rate in the European theater remained about the same (0.9). In other oversea theaters, the rates in general rose somewhat, but no significant outbreaks occurred.

During September and October 1943, the incidence of meningococcal infections among Army troops in the United States fell nearly to the preepidemic level. A rise to a second, less elevated, peak began in the winter of 1943-44, with return to the preepidemic rate by summer. It is of some interest that the peak of the second rise (1.1 per 1,000 in February 1944) came 11 months after the height of the epidemic (2.9 in March 1943), table 34. In World War I, the second peak (1.2 admissions per 1,000 for white enlisted men in October 1918) occurred 9 months after the first peak (4.5

9Sartwell, P. E., and Smith, W. M.: Epidemiological Notes on Meningococcal Meningitis in the Army. Am. J. Pub. Health 34: 40-49, January 1944.


242

in January 1918).10 The second rise in incidence among troops in the United States during World War II was as intense as that which occurred during World War I, and was more sustained. Attention is called to this because sulfonamides were widely used prophylactically in the fall and winter of 1943-44, following distribution of Circular Letter No. 170, Office of the Surgeon General, U.S. Army, dated 30 September 1943. This letter established as Army policy the administration of sulfadiazine to all newly inducted soldiers during the seasons when respiratory diseases were prevalent (chart 12).

Again, during the winter months of 1944-45, the admissions to hospital rose, but to a much less degree than during the previous winters.

TABLE 34.-Incidence and deaths due to meningococcal infections, U.S. Army, World War I and World War II

Period

Number of cases

Number of deaths

Case fatality ratio (per cent)

Peak of incidence in the United States1

Period

Rate2

World War I (April 1917-December 1919):

World War I:

     Continental United States

32,878

986

---

     January 1918

4.48

     Total Army

45, 839

1,836

31. 4

     October 1918

1.21

World War II (January 1942-December 1945):

World War II:

     Continental United States

10,619

410

3. 9

     March 1943

2.89

     Total Army

13,922

559

4.0

     March 1944

1.14


1The World War I data pertain to admissions for white enlisted men in the United States, whereas the World War II data represent incidence for all Army personnel in the United States.
2Rate expressed as number per annum per 1,000 average strength.
3Admissions only. Data on secondary cases are available only for enlisted men in the United States and Europe combined. Based on the distribution of admissions in the two areas, the incidence in the United States is estimated at 3,500 cases.
4Consists of admissions in the entire Army and secondary cases among enlisted men in the United States and Europe. Secondary cases among officers and among enlisted men outside the United States and Europe are not available, but the incidence is estimated to be 5,900 cases for the entire Army.

NOTE.-(1) Data for World War I were obtained from "The Medical Department of the United States Army in the World War." Washington: Government Printing Office, 1925, vol. XV, pt. 2. (2) Data for World War II are preliminary. (3) The number of deaths are from complete files of individual medical records, and incidence is based on sample tabulations of individual medical records, except for data on peak incidence which are from the statistical health report.

During the years 1942-45, in spite of the availability of highly effective treatment, meningococcal infections caused more deaths (559) than any other infectious disease, except tuberculosis. Table 35 shows the number of deaths in the U.S. Army during this period resulting from the more serious infectious diseases and the death rates from these diseases per 100,000 average strength.

10See footnote 4, p. 239.


243

Of 13,922 patients attacked by meningococcal infections during 1942-45, only 559 deaths were reported-a case fatality ratio of 4 percent. During World War I, the ratio was nearly eight times as great, 31 percent. Chart 13 indicates the case fatality ratios in the continental United States by month during the two wars. The ratios for World War I are based on white enlisted patients in the continental United States.

CHART 13.-Case fatality ratios for meningococcal infections, by months, in the continental United States during World War I1 and World War II2

TABLE 35.-Comparative mortality of certain infectious diseases in the U.S. Army, 1942-45

[Preliminary data, pending publication of final statistics] 
[Rate expressed as number of deaths per annum per 100,000 average strength]

Cause of death

Rate 1942-45


Number of deaths


1942-45

1942

1943

1944

1945

Tuberculosis

3.16

806

107

192

201

306

Meningococcal infections

2.19

559

73

269

139

78

Bacterial pneumonia

1.59

404

51

121

117

115

Lobar pneumococcal pneumonia

1.41

358

51

121

91

95

Malaria

1.19

302

25

113

89

75

Scrub typhus

1.11

283

---

49

180

54

Poliomyelitis

1.05

267

5

49

66

147

Infectious hepatitis

(1)

(1)

(1)

(1)

68

191

Primary atypical pneumonia

.67

170

38

48

42

42

Diphtheria

.48

123

1

10

22

90

Amebiasis1

.15

39

6

4

7

22

Bacillary dysentery1

.06

16

3

6

3

4


1Other infectious diseases causing more deaths than amebiasis were scarlet fever (61) and syphilis (70). Several other infectious diseases ranked higher than bacillary dysentery as a cause of death. Even though amebiasis and bacillary dysentery had low death rates, both were feared diseases.


244

The organization of medical care in the Army permitted the observation of early cases, resulting in better recognition of the various forms of the disease. It is, therefore, proposed in this chapter to describe the different forms that meningococcal infection assumed in soldiers during World War II, indicating how studies of the early stages contributed to knowledge of its pathogenesis, and to review the methods and results of treatment carried out in Army installations.

PATHOGENESIS

During nonepidemic periods, the rate for meningococcal carriers in troops ranged from 2 to 10 percent.11 In periods of epidemic, carrier rates among troops rose and in studies made during the epidemic were reported as ranging from 2312 to 80 percent.13 The carrier rate was lowest among newly inducted soldiers.

The micro-organism probably invades the body from the nasopharynx, and infection in this region may or may not be accompanied by evidences of respiratory infection. The subsequent manifestations are those of bacteremia and localization. Observations during World War II supported conclusions similar to Herrick's in World War I, since they clearly indicated that the course of events consisted of invasion of the bloodstream followed by localization in the meninges, skin, or other tissues of the body if not prevented by natural resistance or by therapy. The experience of all observers emphasized the necessity of viewing this disease as a bacteremia, which was sometimes overshadowed by the advent of the more dramatic symptoms of meningitis. By early recognition of the bacteremic stage and prompt institution of treatment, the infection might be terminated before its localization in the meninges or before it had become fulminating. If meningitis or other severe manifestation did, notwithstanding, supervene, the chance of recovery still was better than in cases that had not had prompt treatment. When medical officers became familiar with the disease, through experience in the epidemic, they recognized it in the bacteremic stage and prior to the advent of meningitis in as high as 30 to 40 percent of the patients.14

MENINGOCOCCAL BACTEREMIA

Prodromal symptoms-The illness began, as a rule, with prodromal symptoms of disease of the upper respiratory tract. After an indefinite period

11Dingle, J. H., and Finland, M.: Diagnosis, Treatment and Prevention of Meningococcic Meningitis. With Résumé of Practical Aspects of Treatment of Other Acute Bacterial Meningitides. War Med. 2: 1-58, January 1942.
12Personal communication, C. T. Nelson, Fourth Service Command Laboratory, to the author. 
13Cheever, F. S., Breese, B. B., and Upham, H. C.: The Treatment of Meningococcus Carriers With Sulfadiazine. Ann. Int. Med. 19: 602-608, October 1943.
14(1) Daniels, W. B., Solomon, S., and Jaquette, W. A., Jr.: Meningococcic Infection in Soldiers. J.A.M.A. 123: 1-9, 4 Sept. 1943. (2) Thomas, H. M., Jr.: Meningococcic Meningitis and Septicaemia: Report of Outbreak in the Fourth Service Command During the Winter and Spring of 1942-1943. J.A.M.A. 123: 264-272, 2 Oct. 1943.


245

FIGURE 35.-Rash in meningococcal bacteremia showing slightly raised pink macules with petechial centers, case 1.

of from a day to a week or more, the manifestations became more acute. There was usually a sudden chill with rapid rise in temperature, but the onset might be gradual. Malaise, extreme weakness, aching of muscles, moderate headache, nausea, vomiting, pain in joints, or acute inflammation of joints, developed. The most characteristic manifestation was the rash. Its presence was essential to clinical diagnosis before the advent of meningeal localization.

Rash.-The rash might be so sparse that careful and frequently repeated search was necessary to find it, or it might be obvious and noted by the patient. It appeared in a wide variety of forms, and knowledge of its variations was necessary to the recognition of the disease.

The commonest lesion was petechial or purpuric and varied from 1 to 15 mm. diameter. In addition to this type, which has been emphasized in the past, other forms of rash, not commonly described, were generally seen. Ill-defined faint pink macules similar to the rose spots of typhoid fever were common. These might be evanescent, and not infrequently a scattered few constituted the only cutaneous manifestation. Maculopapular lesions (fig. 35) were usually present, and in some instances they had a central petechia. The larger ones of this type were nodular or plaquelike and often tender. When


246

on the extremities, these nodules bore a striking resemblance to the smaller lesions of erythema nodosum. Occasionally, there were petechiae in the conjunctivae and the oral mucous membranes.

Various combinations of the cutaneous manifestations occurred; indeed, most patients showed more than one type of lesion. The rash appeared anywhere on the body but usually spared the face and was less common on the palms and soles. It was often evident in crops. The macular lesions sometimes receded with fall in temperature, only to reappear as the temperature again rose. The rapidity with which the rash often appeared made it necessary to examine carefully every suspected patient at hourly intervals; in a few hours, it could advance from a few vague spots to a widespread eruption.

In fulminating bacteremia, a widespread extensive ecchymotic rash developed, involving, in some patients, as much as 80 percent of the body. In a few patients, large areas of hemorrhage developed beneath the conjunctivae and in the oral mucous membranes. Some of the ecchymotic lesions became vesicular, and ulceration occasionally occurred. The rapid disappearance of the maculopapular component of the rash within 12 to 18 hours after the beginning of therapy with sulfadiazine was almost diagnostic of meningococcal bacteremia.

Other symptoms-Herpes simplex was common, usually occurring about the second day of illness. Herpes zoster, involving the ophthalmic and maxillary branches of the fifth cranial nerve, was observed in one patient.

At admission, the temperature of patients with meningococcemia ranged from 97° to 106° F. It was generally between 101° and 102° F. 

Leukocytosis (15,000 to 50,000 per cubic millimeter), with an increase in polymorphonuclear cells, was the rule, but in a few patients the number of leukocytes was normal.

Variations in Meningococcemia

There was a simple acute form of meningococcemia with fever, malaise, painful joints, rash, and leukocytosis. The progress of this type could be arrested at this stage by therapy with sulfadiazine, as illustrated in case 1.

Case 1.-A soldier, aged 34, had had a slight cold for about 2 weeks before admission. During the afternoon of the day before admission he suddenly began to feel unusually tired and to ache all over. During the night he had chilly sensations alternating with feverishness, and on the morning of the day of admission he had a moderately severe headache. He was acutely, but not seriously, ill. His face was flushed and his temperature was 101.3° F. There was slight inflammation of the nose and throat, and a maculopapular rash (fig. 35) was scattered over the trunk and all extremities. Neurological examination gave entirely normal results. The leukocytes numbered 19,800 per cubic millimeter, with 81 percent polymorphonuclear cells. Blood cultured on admission yielded type I meningococcus. Lumbar puncture was not done. As soon as the blood for culture had been taken, sulfadiazine was given by mouth. The temperature was normal within 2 days. The patient developed no signs of meningitis.


247

The disease at times was relatively mild and subacute, so that the fever, malaise, painful joints, and rash suggested rheumatic fever or erythema multiforme. The following case is illustrative:

Case 2-A soldier, aged 21, had been well until 3 days before admission, when he suddenly had a shaking chill with the development of fever, malaise, and sore throat. The only significant findings were a few erythematous blotches on the chest and the legs and a palpable spleen. There was a continuous fluctuating fever during the succeeding 11 days. A rash consisting of macular, papular, and nodular lesions, with a few petechiae, appeared in crops. These findings suggested erythema multiforme and erythema nodosum. Shortly after admission, redness, tenderness, and swelling of the right ankle developed. The leukocytes numbered 16,300 per cubic millimeter, with 73 percent polymorphonuclear cells. Many erythrocytes were noted in several specimens of urine. The spinal fluid was normal. Cultures of the blood yielded type IIa meningococcus. After the first dose of sulfadiazine by mouth, the temperature became normal and remained so. The rash faded promptly.

The extraordinarily mild character that meningococcal infection occasionally assumed is illustrated in case 3.15

Case 3-The 10-year-old son of an officer was admitted to an Army hospital with minimal headache and fever (100° F.). Admission was granted only on the insistence of his apprehensive mother, who feared poliomyelitis. Because of pressure from the mother, examination of the cerebrospinal fluid and culture of the blood was made. The spinal fluid was normal. Two days later, cultures of both blood and spinal fluid that were made on admission grew meningococci. No specific treatment had been given. At this time, on careful scrutiny, one skin lesion thought to be a small petechial hemorrhage was found: a second examination of the spinal fluid showed a normal fluid and was sterile. Another culture of blood drawn on the third day again yielded meningococci. As the patient had become afrebrile and asymptomatic no sulfonamides were given. Subsequent cultures of the blood were sterile. For 10 days the patient was watched closely and developed no recurrence of symptoms and no manifestations of illness. At this time a course of therapy with sulfadiazine was administered. The patient was discharged well after approximately 3 weeks of observation.

It is probable that, during the periods of increased prevalence of meningococcal infection, some cases of mild character with spontaneous recovery were not detected. We know that recovery from meningococcal bacteremia has occurred after minimal amounts of sulfonamide, in some cases with a total dose of as little as 2 grams. These patients usually had a mild illness with fever and were given a single dose of sulfadiazine by the ward officer, after which no drug was administered. Later, the original cultures of blood taken before therapy were shown to contain meningococci, but the patients had by then become apparently well.

In other patients, the course was chronic and produced a persistent, low-grade, febrile illness, which in case 4 was not severe enough to prevent the performance of military duty.

Case 4-A soldier, aged 23, was admitted to the orthopedic service because of an injured ankle. It was learned that for about 3 weeks he had been suffering from malaise, evening feverishness, and an intermittent eruption of red nodules on his legs. While in

15Personal communication, R. H. Turner, to the author.


248

the hospital his temperature ranged from 98.6° to 102° F. Migrating arthralgia was present, and a scattered erythematous papular rash appeared. This was most apparent on the extremities. The leukocytes numbered 12,600 per cubic millimeter, with 81 percent polymorphonuclear cells. Two cultures of the blood grew type I meningococcus. There were no meningeal symptoms or signs at any time, and the spinal fluid was normal. All manifestations cleared entirely within 24 hours after sulfadiazine was administered by mouth. The patient had been ill 4 weeks prior to treatment.

Transition From Bacteremia To Meningitis

The recognition of meningococcal infection before any evidence of invasion of the meninges was relatively easy during the epidemic, when the index of suspicion was high; it was in the sporadic case that delays in diagnosis and treatment were likely.

Case 5.-A private, aged 20, was admitted with a history of sore throat which had been present for 1 week. On the day before admission there was a sudden onset of shaking chills, fever, and painfulness of joints. A few small erythematous nodular lesions of the skin developed, and the pharynx showed mild inflammation. Both knees and both elbows and the right wrist and ankle were tender and hot-but not red or swollen. The leukocytes numbered 11,500 per cubic millimeter with 78 percent polymorphonuclear cells. A tentative diagnosis of acute rheumatic fever was made, and full dosage of salicylates prescribed. In spite of this medication the temperature ranged from 98.6° to 102.4° F. for the succeeding 13 days. On the 13th hospital day there was a sudden rise in temperature to 105° F., with severe headache, nausea, and vomiting. Within 3 hours the patient was stuporous and presented all of the signs of severe meningitis, with a dozen or so pinkish macules resembling rose spots on the trunk. The spinal fluid contained 1,200 leukocytes per cubic millimeter, with 95 percent polymorphonuclear cells. Treatment with sulfadiazine resulted in recovery. Blood was taken for culture after therapy was begun, and there was no growth.

Case 6 illustrates the importance of cutaneous manifestations, showing how the absence of a persistent rash during the greater part of the bacteremic stage delayed diagnosis.

Case 6.-The patient was admitted to the ward for patients with diseases of the respiratory tract, having had a cold with nasal congestion, slight cough, and sore throat for 1 week. During the day before admission, he had several slight chills and felt feverish; he vomited once. Examination revealed moderate inflammation of the nasopharynx, and a discrete macular rash on the trunk and around the shoulder girdle, which disappeared within a few hours after admission. For about 11 days the patient's temperature was of the septic type, with daily elevations to 102° F., associated with polymorphonuclear leukocytosis. The spleen was palpable. Since a diagnosis of subacute bacterial endocarditis was entertained, repeated cultures of the blood were made. Ten days after admission the temperature rose to 103° F. and the patient appeared worse. There were no meningeal signs or symptoms. On the next day, increasingly severe headache developed, with nausea and vomiting. Examination revealed a slightly stiff neck, positive Kernig's sign, and sparse petechiae on the upper part of the trunk. The spinal fluid was cloudy and contained 9,700 cells per cubic millimeter. Smear and culture of the fluid showed type I meningococcus. A culture of the blood taken on the day before the development of meningeal signs contained the same micro-organism. Recovery was rapid on therapy with sulfadiazine.


249

The speed with which meningitis could develop in a patient with meningococcemia was extremely variable. The next patient reported (case 7) was one in whom early meningitis was present on admission, as indicated by recovery of meningococci on culture from an otherwise normal spinal fluid. The history, however, gave clear-cut evidence that bacteremia had existed for about 24 hours before admission. This case also illustrates how rapidly meningitis can advance in spite of prompt and adequate therapy with sulfadiazine.

Case 7-A private, aged 37, was well until the morning of the day before admission, when he suddenly had a shaking chill and began to feel extremely weak. Headache was moderately severe but subsided during the evening. On the morning of the day of admission the patient's headache was gone, but he noticed that he was covered with tiny dark purplish spots. His right knee was moderately painful on walking. Severe frontal headache again developed on his admission to the ward. He was obviously acute and seriously ill, although alert and well oriented. Scattered over the trunk and all extremities were myriads of dark petechiae, all less than 2 mm. in diameter. There was no stiffness of the neck, and Kernig's and Brudzinski's signs were not present. A specimen of spinal fluid contained 3 lymphocytes per cubic millimeter, a normal concentration of sugar, and a smear of it was negative for micro-organisms. By the following day, however, type I meningococcus grew in the culture of this fluid. Immediately after the initial lumbar puncture, 5 gm. of sodium sulfadiazine (in 1,500 cc. of saline and dextrose solution) was given intravenously.

Four hours after admission the patient developed projective vomiting and rapidly became stuporous. All the signs of meningitis were present. Five and one-quarters hours after the first lumbar puncture another specimen of spinal fluid was obtained. The fluid was under greatly increased pressure and contained 17,700 leukocytes per cubic millimeter, with 99 percent polymorphonuclear cells. The concentration of sugar had fallen to a level too low to read with accuracy and the level of sulfadiazine had reached 8.2 mg. per 100 cubic centimeters. Smear and culture of this second specimen were negative for meningococci in spite of the addition of para-aminobenzoic acid to the culture media. After an extremely stormy course, the patient recovered.

Although the culture of blood on admission was contaminated and no meningococci were found, the history of a shaking chill, the presence of a purpuric rash extensive enough to be noticed by the patient, and a painful knee joint-all at a time when the patient was entirely free of headache-were believed to be evidence that invasion of the bloodstream occurred several hours before admission. That meningitis was in the earliest phase at the time of admission was shown by the fact that the spinal fluid was normal in every respect except that meningococci were grown on culture. There were no meningeal signs except severe headache.

FULMINANT MENINGOCOCCAL BACTEREMIA

Without adrenal hemorrhage-A form of fulminant, rapidly fatal meningococcal infection occurred, with little or no evidence of meningitis either during life or at necropsy, and without the clinical manifestations of the Waterhouse-Friderichsen syndrome, while the adrenals, (at necropsy,


250

showed no abnormality. The rash was widespread and frequently as extensive as that seen in patients who had massive bilateral hemorrhage into the adrenals. The following is a case in point:

Case 8-A 20-year-old soldier was admitted at 4:30 a.m. after an illness of a few hours, with chills, fever, headache, and weakness. On admission the temperature was 107° F. Stupor was marked. The pulse was strong, pounding, and rapid. The blood pressure was 120 systolic and 70 diastolic. There was no stiffness of the neck or other evidence of meningeal irritation. Widely scattered over the skin were myriads of petechial and purpuric lesions, some of which coalesced to form areas of ecchymosis. The cerebrospinal fluid was normal. A culture of the blood later grew type I meningococcus. Sodium sulfadiazine, 4.0 gm., was promptly given intravenously. Stupor deepened, and only terminally did cyanosis develop. Death occurred 8 hours after admission.

At autopsy neither the adrenals nor the leptomeninges showed abnormalities. There were small scattered hemorrhages throughout most of the organs.

Instances of a fatal form of fulminating bacteremia associated with so-called tubular degeneration of the adrenal cortex, as described by Rich,16 occurred among Army personnel. The adrenals in these patients were not the site of hemorrhage. These cases occurred with and without meningitis. The following case, reported by Kinsman, D'Alonzo, and Russi,17 is illustrative:

Case 9-A 29-year-old white soldier was admitted to the hospital at 3:30 p.m. on 22 January 1944, about 2 hours after sudden onset of weakness, shaking chills, fever, headache, pain in the back, and exhaustion. The temperature on admission was 104.6° F. The leukocytes numbered 11,950, with 84 percent neutrophils. Physical examination revealed nuchal rigidity of minimal degree, but Kernig's sign was absent. The pharynx was moderately injected. Type I meningococcus was later recovered from the spinal fluid. Early the next morning (23 January) the patient developed an increasingly widespread, mottled purpuric and ecchymotic rash over the entire body, including the face and neck. About 80 percent of the surface of the body eventually became involved. There were scattered hemorrhagic spots, most of them large, an inch or more in diameter. These were also observed in the conjunctivae and mouth; the uvula was completely black from hemorrhage. In spite of treatment, the eruption continued to spread. The patient became restless, complaining of chilliness, and of the burning and soreness of the eruption. His lips, fingernails, and entire skin became cyanotic, the pulse was 110, and blood pressure was 130 systolic and 100 diastolic. Nuchal rigidity had not increased and Kernig's sign was still absent. The leukocytes numbered 27,200, with 87 percent neutrophils. The temperature was 105° F. At 1:10 p.m. he became comatose and markedly cyanotic, with rapid respirations. The temperature climbed to 107.8° F., and the respirations dropped to 8 per minute. A direct smear of his blood showed diplococci lying within the cytoplasm of the neutrophils. The culture of the blood was later reported positive for type I meningococcus. The patient expired at 3:10 p.m., 26 hours after onset. A second spinal puncture was done at the time of the necropsy and showed 2,200 cells.

Necropsy revealed widespread focal hemorrhages in the pulmonary parenchyma and petechial hemorrhages in the pleura, pericardium, and endocardium. Examination of the adrenals showed no gross hemorrhages. Microscopically, there was marked congestion

16Rich, A. R.: A Peculiar Type of Adrenal Cortical Damage Associated With Acute Infections, and Its Possible Relation to Circulatory Collapse. Bull. Johns Hopkins Hosp. 74: 1-15, January 1944. 
17Kinsman, J. M., D'Alonzo, C. A., and Russi, S.: Fulminating Meningococcic Septicemia Associated With Adrenal Lesions; An Analysis and Discussion of Seven Cases. Arch. Int. Med. 78: 139-169, August 1946.


251

of the sinusoids but no extravasation of blood. The cells in the glomerular zone displayed a vacuolated cytoplasm, and appeared of average size, while those in the inner part of the fascicular and reticular zones had shrunk, their cytoplasm being homogeneous, dark, and sprinkled with brown pigment. In this case the tubular changes in the outer half of the fascicular layer were prominent. The lesion was similar to that described by Rich. The cords in the outer third of the fascicular zone were converted into tubules lined by vacuolated cells, many of which had undergone degeneration with fraying of the cytoplasm and pyknotic changes of the nuclei. In some instances, the adrenal cells had disappeared entirely from the inner layer of the cortex, leaving only a reticular stroma between the congested capillaries. The medulla was not abnormal.

The meninges were not conspicuously involved on gross examination. Microscopically, there was a fair amount of acute inflammatory cellular exudate in the subarachnoid spaces.

Fulminating meningococcal bacteremia, without meningitis, occurred with the clinical manifestations of the Waterhouse-Friderichsen syndrome, and yet no hemorrhage or other abnormality of the adrenals was found at necropsy. Four such cases were found among 300 fatal cases analyzed (table 36).18 In a number of others, the history suggested this syndrome, but the case abstracts were not full enough to allow reliable deductions. Thomas19 has reported 3 such cases in a series of 49 fatal cases.

TABLE 36.-Cause of death1in 300 cases of meningococcal infection reviewed at the Armed Forces Institute of Pathology

Cause of death

Number

Percent

Fulminating bacteremia:

 

 

    

Without adrenal hemorrhage2

30

10

    

With adrenal hemorrhage3

126

42


Total

156

52

Meningitis

144

48


Total

300

100


1With renal complications (estimated case fatality in the total U.S. Army, 0.04 percent) in three cases, due to sulfonamide therapy.
2Four of these patients showed the clinical manifestations of the Waterhouse-Friderichsen syndrome.
3Five of these patients did not exhibit the clinical manifestations of the Waterhouse-Friderichsen syndrome.

Case 10-A soldier, aged 21, suddenly became ill 24 hours before admission with severe headache, stiffness, generalized aching, nausea, and vomiting. On examination, aside from fever, dusky cyanosis, and petechiae scattered over the skin, no other deviation from normal was found. About 18 hours after admission, in spite of a concentration of 9 mg. percent of sulfadiazine in the blood, the patient became rapidly worse. The skin eruption spread and pallor, with cyanosis, became extreme. The extremities were clammy

18Daniels, W. B.: The Cause of Death in Meningococcic Infection: An Analysis of 300 Fatal Cases. Am J. Med. 8: 468-473, April 1950.
19Thomas, H. M., Jr.: The Treatment of Fulminating Meningococcic Infections. Bull. U.S. Army M. Dept. No. 73, pp. 78-84, February 1944.


252

and there was evidence of marked shock. A culture of blood was positive for meningococci. Stained films of blood from the fingertip showed diplococci within the leukocytes; smears from punctured purpuric skin lesions revealed gram-negative diplococci. The patient died in shock 30 hours after admission.

Necropsy showed no adrenal hemorrhage or evidence of meningitis. Petechiae were scattered over all serous surfaces. The interstitial tissues of the myocardium showed a diffuse infiltration with polymorphonuclear leukocytes.

The records of 300 of the soldiers who died as the result of meningococcal infection between September 1940 (mobilization) and 31 December 1945 were reviewed at the Army Institute of Pathology (now the Armed Forces Institute of Pathology), Washington, D.C. (table 36). Ten percent were cases of fulminating bacteremia without adrenal hemorrhage. Of these, 13 had no meningitis, 16 had slight meningitis, and the autopsy record of 1 was incomplete. The average duration of life after admission to hospital was 33 hours, ranging from 2 to 101 hours. Four of these patients satisfied all the clinical criteria of the Waterhouse-Friderichsen syndrome, but at autopsy, the adrenals were not abnormal. The average duration of life in these 4 cases was 40 hours from time of admission to hospital.

With adrenal hemorrhage-Fulminating meningococcal bacteremia with peripheral vascular failure and hemorrhage into the adrenals evident at necropsy-the so-called Waterhouse-Friderichsen syndrome-was described first in 1894 by Voelcker.20 Additional cases were later reported by the authors whose name the syndrome bears.21 No more dramatic or catastrophic situation requiring immediate therapy can face the physician.

From the beginning of the epidemic, patients with this syndrome were admitted to Army hospitals. Some died before specific treatment was instituted. In the analysis of 300 fatal cases, it was found that in 121 cases (40 percent) death was due to this form of infection. (Five additional cases in this series had adrenal hemorrhage without the clinical syndrome (p. 254).) In view of the rarity of this disease, it is not surprising that, of the whole series of 126 fatal cases with adrenal hemorrhage, 14 (11 percent) came to necropsy lacking correct diagnosis. Ante mortem, these were classified as follows: Rocky Mountain spotted fever, 3; heat stroke, 2; purpura hemorrhagica, 2; endemic typhus, l; acute leukemia, 1; pachymeningitis, l; and no diagnosis, 4. A few more than 100 instances of this form of meningococcal infection had been reported in the world literature before World War II.

In two published series of 214 and 182 patients with meningococcal infection, the Waterhouse-Friderichsen syndrome occurred in 3.3 and 2.2 percent, respectively.22 As noted, the records of the 300 cases studied at the

20Voelcker, A. F.: Pathological Report. Abstract. Middlesex Hospital Reports, 1894. p. 279.
21(1) Waterhouse, R.: A Case of Suprarenal Apoplexy. Lancet 1: 577-579, 4 Mar. 1911. (2) Friderichsen, C.: Nebennierenapoplexie bei kleinen Kindern. Jahrb. f. Kinderh. 87: 109-125, 1918.
22(1) See footnote 17, p. 250. (2) Bernhard, W. G., and Jordan, A. C.: Bilateral Adrenal Hemorrhage (Waterhouse-Friderichsen Syndrome) Associated With Meningococcal Septicemia; Report of Four Cases in Adults With a Review of the Literature. J. Lab. & Clin. Med. 29: 357-365, April 1944.


253

Armed Forces Institute of Pathology showed that 126 (42 percent) of the soldiers with adrenal hemorrhage died (table 36). More than 50 instances of this syndrome were reported in the literature by U.S. Army Medical Corps officers. This is an incomplete list as many cases were described only because of unusual features, long survival period, or recovery.23

Meningitis was usually absent or extremely slight in these patients. In analysis of the 126 cases of fulminating bacteremia with adrenal hemorrhage, no post mortem evidence of meningitis was found in 61; in 48, the meningitis was early and minimal; in 7, it was moderately severe; in another 7, severe; in 3 cases, the grade of meningitis was not clear from the records. Early death may have been responsible for the slight degree or absence of meningeal inflammation.

Clinical course-As with other meningococcal infections, prodromal respiratory symptoms usually preceded the onset. These were followed by general aching, painful joints, headache, weakness, nausea, vomiting, chills, and fever. Within a few hours there was a dramatic, sudden change, with the development of apprehension, restlessness, and often an initial delirium. At a later stage, there were frequent lucid intervals. A previously insignificant rash suddenly became widespread, purpuric, and ecchymotic, and often covered two-thirds of the body. The conjunctivas and buccal mucous membranes showed hemorrhages. As a rule, there were no signs of involvement of the meninges, but meningitis, usually of mild degree, might be present. Cyanosis, low blood pressure, rapid, thready or imperceptible pulse, cold, wet extremities, and all evidences of extreme shock supervened. Anuria with retention of nitrogen was usual. Within a few hours to a day or more, pulmonary edema usually supervened, and death generally occurred in spite of heroic therapy. In fatal cases, the average duration of life from admission to death was 24 hours.24

A classical instance of this clinical course follows.

Case 11.-A 21-year-old soldier developed headache, weakness, general aching, and vomiting 1½ hours before admission to hospital at 5 p.m. on 17 April 1943. By midnight,

23(1) Wright. D. O., and Reppert, L. B.: Fulminating Meningococcemia With Vascular Collapse (Waterhouse-Friderichsen Syndrome); Report on Four Adult Patients Who Recovered. Arch. Int. Med. 77: 143-150, February 1946. (2) Kasich, M., and Disick, S.: Meningococcemia With Bilateral Adrenal Hemorrhage (Waterhouse-Friderichsen Syndrome): Report of Two Cases. J. Tennessee M.A. 36: 464-467, December 1943. (3) Marangoni, B. A., and D'Agati, V. C., Hepatorenal Failure in the Waterhouse-Friderichsen Syndrome; Clinico-Pathologic Observations in Two Cases With Prolonged Survival Periods. Am. J.M. Sc. 207: 385-393, March 1944. (4) D'Agati, V. C., and Marangoni, B. A.: The Waterhouse-Friderichsen Syndrome. New England J. Med. 232: 1-7, 4 Jan. 1945. (5) Park, F. R., and Taplin, G. V.: Meningococcic Meningitis With Waterhouse-Friderichsen Syndrome. Report of a Case With Recovery. [Official record.] (6) Felder, S. L., and Stacy, A., Jr.: Meningococcemia With Waterhouse-Friderichsen Syndrome. [Official record.] (7) Leichliter, J. W., and Fish, C. E.: The Waterhouse-Friderichsen Syndrome; A Report of a Case in a Soldier. Mil. Surgeon 93: 77-81, July 1943. (8) Bush, F. W., and Bailey, F. R.: The Treatment of Meningococcus Infections With Especial Reference to the Waterhouse-Friderichsen Syndrome. Ann. Int. Med. 20: 619-631, April 1944. (9) Potter, H. W., and Bronstein, L. H.: The Waterhouse-Friderichsen Syndrome; Report of a Case Terminating in Recovery. J. Lab. & Clin. Med. 29: 703-708, July 1944.
24See footnote 18, p. 251.


254

fever of 106° F., a purpuric skin eruption, and an irrational mental state had developed. Because of obvious meningococcal bacteremia, 4 gm. of sodium sulfadiazine was given parenterally. By 5 a.m. on 18 April, he was stuporous, cyanotic, cold, and in collapse, with a pulse rate of 160 and blood pressure of 70 systolic and 35 diastolic. In spite of large doses of sulfadiazine, adrenal cortical extract, dextrose, sodium chloride and plasma, the purpuric rash spread and large areas of ecchymosis developed (fig. 36). Circulatory collapse increased, the pulse became imperceptible, and the blood pressure fell to 40 systolic and 0 diastolic. Coma developed. The patient died, in pulmonary edema, 36 hours after admission and 26 hours after the institution of specific therapy. There had been no clinical evidence of meningitis and the patient's condition did not warrant spinal puncture. The cerebrospinal fluid at autopsy contained two cells and was sterile. Cultures of the blood during life contained meningococci, and many micro-organisms were seen in leukocytes in smears of the peripheral blood and of purpuric lesions of the skin. Chemical analyses of the blood were as follows: Nonprotein nitrogen 75, creatinine 1.7, chlorides 478, sugar 126, sulfadiazine 20 mg. per 100 cubic centimeters. Autopsy revealed massive hemorrhage in both adrenals and no evidence of meningitis.

FIGURE 36.-Widespread ecchymotic rash in a patient with fulminating bacteremia and hemorrhages into the adrenals, case 11.

Waterhouse-Friderichsen syndrome.-The analysis shown in table 37 suggests that the grade of adrenal hemorrhage has a direct relationship to duration of life. There is, however, ample evidence that shock and circulatory collapse incident to fulminating bacteremia may occur without adrenal hemorrhage. As has been stated, fulminating infection with no evident adrenal abnormality at autopsy (case 10) can produce a clinical picture identical with the classical Waterhouse-Friderichsen syndrome. (See also table 36.) Profound injury to other organs as a result of toxemia and widespread hemorrhage, frequently with marked cellular infiltration of the myocardium,


255

might well be the sole cause of death. Marangoni and D'Agati,25 following observation of two patients with long survival periods (80 and 88 hours), have expressed the opinion that there are two distinct stages in the Waterhouse-Friderichsen syndrome: First, the phase of profound shock and circulatory collapse; if this is survived, the second, or hepatorenal, phase begins. Clinically, it is characterized by marked oliguria with azotemia, and pathologically, by severe central necrosis of the liver associated with changes in the glomeruli and tubules of the kidney. A number of observers26 believe that circulatory collapse in the Waterhouse-Friderichsen syndrome is primarily the result of widespread hemorrhages and changes in tissue, rather than of adrenal insufficiency secondary to hemorrhage into these glands. It is pointed out that (1) in this condition death requires but a few hours, whereas adrenalectomized animals live for several days; (2) classical clinical manifestations of the Waterhouse-Friderichsen syndrome can occur in patients with fulminating bacteremia without abnormality of the adrenals at necropsy; (3) conversely, among the 126 patients found to have had adrenal hemorrhage at necropsy, in 5 the clinical manifestations were not those of the Waterhouse-Friderichsen syndrome27 (table 36); (4) some recovered patients had been given no adrenocortical hormone; and (5) in patients who recovered, the discontinuation of adrenocortical hormone after a few days did not lead to a recurrence of symptoms. If there were adrenal insufficiency secondary to hemorrhagic destruction of the adrenals in these cases, such temporary therapy would scarcely have been curative.

Accordingly, although the severity of adrenal hemorrhage appears in direct correlation with the length of life in the series of fatal cases shown in table 37, it cannot be assumed that there is a direct causal relation between them. The severity of the adrenal lesion may be regarded rather as an index of the severity of the whole pathological process, in which it occurs as an end result.

The Waterhouse-Friderichsen syndrome before the development of sulfonamides was invariably fatal. In 1945, Weinberg and McGavack collected from the literature 11 instances of recovery and reported an additional case with recovery.28 Thirteen other patients who recovered have been either Army personnel or cases observed by the author.29 Undoubtedly, a number

25See footnote 23 (3), p. 253.
26(1) See footnotes 17, p. 250; 19, p. 251; and 23 (1) and (3), p. 253. (2) Thomas, H. B., and Leiphart, C. D.: Septicemia and Purpura With Adrenal Hemorrhage in Adult (Waterhouse-Friderichsen Syndrome); A Discussion of the Role Played by the Adrenal Gland in the Production of the Syndrome; Report of Two Adult Cases. J.A.M.A. 125: 884-890, 29 July 1944.
27See footnote 18, p. 251.
28Weinberg, L. D., and McGavack, T. H.: Waterhouse-Friderichsen Syndrome; Report of Case With Recovery. New England J. Med. 232: 95-101, 25 Jan. 1945.
29(1) See footnotes 17, p. 250; and 23 (1), (4), (5), (6), (8), and (9), p. 253. (2) Wechsler, H. F., and Rosenblum, A. H.: Meningococcic Meningitis. Mil. Surgeon 95: 132-135, August 1944. (3) Meyer, R. R.: Meningococcal Meningitis; A Report of Thirty-Three Cases With No Deaths. New England J. Med. 230: 452-455, 13 Apr. 1944.


256

of additional cases were not reported. Probably some of the recovered patients, although clinically examples of the Waterhouse-Friderichsen syndrome, actually had fulminating bacteremia without adrenal hemorrhage, but when a patient has recovered, there is no way to ascertain the nature or location or extent of tissue damage that was associated with the clinical syndrome.

TABLE 37.-Severity of adrenal hemorrhage and duration of life in 126 of 300 fatal cases of meningococcal infection

Grade of hemorrhage

Number of cases

Percent


Number of cases with relevant data

Number of hours from admission to death

Average

Maximum

Minimum

Mild

21

16.7

20

48

120

Moderate

47

37.3

44

22

60

1/6

Massive

56

44.4

53

16

49

1

Not recorded

2

1.6

1

53

53

53


Total

126

100.0

118

24

120

1/6


MENINGOCOCCAL MENINGITIS

Although it was clearly demonstrated in many patients that meningococcemia preceded the onset of meningitis, the commonest type of meningococcal infection in all Army installations was that exemplified by case 12. Here, the results of meningeal involvement were so dramatic as to overshadow completely those of bacteremia. Bacteremia and meningitis set in almost simultaneously.

Case 12-A soldier, aged 20, was admitted in violent delirium. The history obtained after the patient had improved indicated that he had been perfectly well until the evening of the day before admission, when severe occipital headache suddenly developed, with a feeling of great fatigue. During the night, pain in the left elbow and ankle began. Early on the day of admission he lost consciousness and regained it only after 12 hours of treatment in the hospital. Examination revealed a gravely ill patient, who had many small erythematous macules scattered over the trunk and extremities. Several of the lesions were hemorrhagic. There was pronounced rigidity of the neck, positive Kernig's and Brudzinski's signs, and slight weakness of the right side of the face. The leukocytes numbered 18,800 per cubic millimeter with 80 percent polymorphonuclear cells. Culture of the blood was later reported as sterile; the spinal fluid showed 9,900 leukocytes per cubic centimeter, of which 99 percent were polymorphonuclear cells. Gram-negative intracellular diplococci were seen on smear, and type I meningococcus was present on culture of the spinal fluid. Immediate therapy with sulfadiazine resulted in complete recovery.

The review of 300 of the fatal cases of meningococcal infection showed that 144 (48 percent) were classified as dying of meningitis (table 36). Only


257

6 of these patients came to necropsy without correct diagnosis, as follows: No diagnosis, 2; endemic typhus, 1; malaria, 1; pachymeningitis, 1; and psychosis, 1. It is of interest that only 26 of the 144 patients lived 96 hours or longer after admission to hospital. The average duration of life of the 118 patients who lived less than 96 hours was 36 hours, the range being from 1 to 95 hours (table 38). Since meningococcal meningitis itself, before the use of sulfonamides, rarely killed in so short a period, one might reasonably expect other lesions due to the meningococcal infection to play some role. Of the 118 patients who died within 96 hours after admission, evidence of lesions other than those in the meninges was reported in 62. Certain lesions associated with the death of those patients are listed, as follows:

Lesions

Number of patients

Pneumonia

26

Encephalitis

11

Myocarditis

11

Pressure cone

4

Purulent pericarditis

4

Periadrenal hemorrhage

1

Tubular degeneration of adrenals

1

Meningococcal peritonitis

1

Purulent arthritis

1

Subarachnoid hemorrhage

1

Bleeding peptic ulcer

1


Total

62


A pressure cone was noted 4 times, myocarditis 11 times, and pneumonia 26 times. Encephalitis was found in 11 cases, its occurrence indicating an organic basis for the changes in personality occasionally reported in patients who recover from meningitis. It seems probable that the majority died of the concomitant bacteremia with toxemia or some complication.

TABLE 38.-Duration of life in relation to severity of illness in 118 of 144 cases of meningitis studied at the Armed Forces Institute of Pathology

Severity of lesion

Number of cases

Percent

Number of cases of known duration

Number of hours from admission to death

Average

Maximum

Minimum

Moderate

10

8

10

23

62

1

Severe

93

79

93

38

95

1

Not recorded

15

13

10

30

90

2


Total

118

100

113

36

95

1



258

The duration of life in relation to severity of meningitis in the patients who lived less than 96 hours after admission to hospital is shown in table 38. 

Those patients with a moderately severe grade of meningitis died on the average of 15 hours earlier than those classified as severe on the basis of spinal fluid and autopsy findings. This is additional evidence that these patients died from bacteremia before the meningitis had reached severe proportions. 

Among the 144 cases of meningitis studied at the Armed Forces Institute of Pathology, the cause of death of the 26 patients who lived longer than 96 hours is shown, as follows:

Meningitis

9

Meningoencephalitis

3

Pneumonia and meningitis

4

Sulfonamide nephrosis

3

Adrenal infarction

1

Myocarditis

1

Brain abscess due to Neisseria intracellularis

1

Hemoglobinuric nephrosis after transfusion

1

Pulmonary infarction

1

Multiple lung abscesses

1

Recurrent fulminating meningococcal sepsis

1


The duration of life ranged from 4 days to 4 months: 10 died on the 5th day of illness, 3 on the 7th, 2 on the 8th, 3 on the 9th, 2 on the 10th, 1 on the 11th, 1 on the 13th, 1 on the 15th, and the other 3 lived 1, 1, and 4 months, respectively. It is seen that only 9 of these 26 patients died of meningitis alone (1 patient was treated inadequately beginning on the 7th day of disease, and sulfonamides were stopped in 1 after good response because of assumed drug fever). Three patients died of myocarditis, brain abscess due to Neisseria intracellularis, and pulmonary infarction after recovery from meningitis. It will be noted that there was no instance of chronic basilar meningitis or of hydrocephalus, the common sequelae of meningococcal meningitis in the past.

COMPLICATIONS

In the various series of cases of meningococcal meningitis reported during World War II, complications of the disease occurred in approximately 10 percent. The most common were transient paralyses of the fourth, sixth, seventh, and eighth cranial nerves. Herpes zoster involving the trigeminal nerve appeared in one patient. Aside from occasional residual nerve deafness and a rare instance of persistent diplopia, these lesions cleared completely with recovery. Paralysis of the serratus anterior was reported.30

In fulminating bacteremia, electrocardiograms were rarely made because of the critical condition of the patient and the emphasis placed on needed therapy. However, two instances of changing electrocardiograms with T-wave inversions and abnormalities in the S-T segment have been de-

30See footnote 14, p. 244.


259

scribed.31 Both patients recovered. Sudden and unexpected death from myocarditis occurred in one patient after apparent recovery from meningitis. In this case, Holman reported marked degenerative changes throughout one-third of the myocardium at necropsy. Myocarditis of significant grade was present at necropsy in 28 of 126 fatal cases with adrenal hemorrhage. Bronchopneumonia terminally was not uncommon. Optic atrophy, corneal ulceration, conjunctivitis due to N. intracellularis, pericarditis, and osteoperiostitis have each been noted in published reports.

Spontaneous glycosuria at onset was reported as occurring in one-third of 26 patients with meningococcal meningitis,32 but rarely among Army personnel during the Second World War.33 It may be accompanied by ketosis, hyperglycemia, and diminished sugar tolerance. Coma with glycosuria and ketosis at the onset of meningitis might lead to the erroneous diagnosis of diabetic acidosis.

In meningococcemia, inflammatory joint affections occurred in from one-third to one-half of the cases. These were usually simple inflammatory reactions but occasionally effusion into the joint, and rarely pyarthrosis developed. The latter required aspiration, but surgical drainage was not necessary in any reported case during the Second World War. Residual joint stiffness, persisting for some weeks after recovery, was noted.34

Some of the ecchymotic skin lesions ulcerated, but sloughing of large ecchymotic lesions rarely occurred. These were slow to heal. In almost all fatal cases of bacteremia and many of meningitis, pulmonary edema and effusion into the pleural sacs were terminal complications of the illness.

Renal complications of meningitis are discussed in the section on treatment.

OTHER MENINGOCOCCAL INFECTIONS

Only one instance of meningococcal pneumonia was reported during World War II.35 This followed 5 weeks after a classical attack of primary atypical pneumonia. The patient developed severe, diffuse pneumonia with high fever. The sputum on two occasions contained about 75 percent meningococci (proved bacteriologically and serologically) and 25 percent hemolytic streptococci, group A. The course of the disease, ending in recovery, was apparently not influenced by the adequate doses of sulfadiazine given. The patient gave no evidence of bacteremia or meningitis.

31(1) Rappaport, J. N., and Zuckerbrod, M.: Recovery From Fulminating Meningococcic Infection With Myocarditis Proved by Electrocardiography. J. Lab. & Clin. Med. 30: 307-316, April 1945. (2) Holman, D. V., and Angevine, D. M.: Meningococcus Myocarditis; Report of Two Cases With Anatomical and Clinical Characteristics. Am. J. M. Sc. 211: 129-137, February 1946.
32Ferguson, F. C., and Barr, D. P.: Glycosuria in Meningitis. Ann. Int. Med. 21: 173-186, August 1944.
33(1) See footnote 17, p. 250. (2) Federer, J. J.: Glycosuria and Hyperglycemia Associated With Acute Meningitis; Report of a Case. New England J. Med. 233: 342-343, 20 Sept. 1945. 
34See footnote 15, p. 247.
35Roberg, N. B.: Meningococcic Pneumonia. Bull. U.S. Army M. Dept. 4: 97-99, July 1945.


260

Thirteen cases of proved meningococcal conjunctivitis were described among U.S. Army personnel during World War II.36 All occurred during the period of increased incidence of meningococcal infection, and only one was associated with bacteremia or meningitis. The response of all these patients to therapy with sulfadiazine was excellent.

LABORATORY DIAGNOSIS

In meningococcal infections, the assistance of the laboratory in arriving at the correct etiology and confirming the clinical diagnosis was directly proportional to the adequacy of methods of culture, the care with which studies were carried out, and the cooperation between the wards and the laboratory. At the beginning of the epidemic, laboratory officers in the Army hospital, like the clinicians, had had relatively little experience in the study of this disease. The standard operating procedure consisted of directing the ward nurse or attendant to send the tubes of cerebrospinal fluid obtained from the patient to the laboratory for examination. The laboratory, as a rule, made no great speed in examining this fluid or inoculating media. Under these conditions, the percentage of positive cultures and of bacteriologically confirmed diagnoses was not enviable. As the number of cases rose, however, there was rapid improvement in this situation in most hospitals, with better coordination between the clinician and the laboratory. In some hospitals, a representative of the laboratory came immediately to the bedside when a lumbar puncture was to be done. Inoculations with blood and cerebrospinal fluid were made directly into previously warmed culture media, and these were promptly incubated in proper atmosphere. The improvement in results was striking. With this method, it was possible to achieve bacteriological confirmation in 95 percent of the patients who had not received treatment with sulfonamides prior to obtaining material for smear or culture.37

The micro-organisms isolated from patients during the outbreak have, as is usual in these infections, been predominantly type I. The distribution of types of meningococci recovered by the Fourth Service Command Laboratory from 1,436 known cases of meningococcal infections from August 1942 to December 194538 is shown in table 39.

In the majority of patients ill with the Waterhouse-Friderichsen syndrome or with fulminating sepsis, careful examination of films of blood taken from the fingers for differential counts revealed diplococci within the leukocytes. Smears and cultures made from petechial, purpuric, or even

36(1) Bauer, C. E., Gall, E. A., and Cox, C. D.: Meningococcal Conjunctivitis; Report of Three Cases. Mil. Surgeon 95: 24-27, July 1944. (2) Theodore, F. H., and Kost, P. F.: Meningococcic Conjunctivitis. Arch. Ophth. 31: 245-247, March 1944. (3) Reid, R. D., and Bronstein, L. H.: Meningococcic Conjunctivitis. J.A.M.A. 124: 703, 11 Mar. 1944. (4) Thygeson, P.: Primary Meningococcic Conjunctivitis Treated by Sulfadiazine. Am. J. Ophth. 27: 400-401, April 1944.
37See footnote 14 (1), p. 244. 
38See footnote 12, p. 244.


261

macular skin lesions showed meningococci in many instances. Tompkins39 obtained positive cutaneous smears in 39 of 48 cases. In some patients, smears showed bacteria at a time when culture of the blood was sterile. Bernhard and Jordan40 compared the results of concomitant examination of smears and cultures of material from purpuric lesions with cultures of the blood and of the spinal fluid in 40 patients. The smears from the purpuric lesions were positive in 68 percent and the cultures in 88 percent, while the cultures of the blood and cerebrospinal fluid were positive in 75 and 82 percent, respectively.

TABLE 39.-Distribution of types of meningococci in 1,436 cases of meningococcal infection, Fourth Service Command Laboratory, August 1942-December 1945

Types of meningococci

Number

Percent

Group I

1,288

89.7

Group II

27

1.9

Group IIa

108

7.5

Polyvalent1

13

.9


Total

1,436

100.0


1Includes micro-organisms with the biological characteristics of meningococci that agglutinate in polyvalent anti-meningococcal serum but not in group-specific serum.

The importance of careful bacteriological studies should not be underestimated. However, during an outbreak of meningococcal infection, the diagnosis of bacteremia can and must be made on clinical grounds long before there is any report of culture of the blood if one hopes to prevent meningitis or fulminant infection. The finding of diplococci in leukocytes in smears of blood or smears from purpuric lesions is of importance, but in patients with rash the clinical impression of a trained observer should be relied upon in instituting treatment. Since, during the epidemic, 92 percent of the patients with meningococcal meningitis showed a characteristic rash,41 a high degree of diagnostic accuracy could be attained on purely clinical grounds. In neither meningitis nor bacteremia should initiation of treatment be delayed by waiting for laboratory reports.

TREATMENT

At the beginning of the epidemic, although Circular Letter No. 170 had been issued, there was little standardization of treatment in U.S. Army hospitals. To a great extent, this was due to the dearth of published reports

39Tompkins, V. N.: The Diagnostic Value of Smears From Purpuric Lesions of the Skin in Meningococcic Disease. J.A.M.A. 123: 31-32, 4 Sept. 1943.
40Bernhard, W. G., and Jordan, A. C.: Diagnosis of Meningococcic Infections, Use of Material From Skin Lesions. Mil. Surgeon 95: 405-409, November 1944.
41See footnote 14 (1), p. 244.


262

on the use of sulfadiazine in large groups of patients with meningitis, to difficulties in obtaining the drug, and to the inability of some installations to acquire the sodium salt of sulfadiazine. Early cases were treated with sulfanilamide, sulfapyridine, sulfathiazole, or sulfadiazine alone or in conjunction with antisera or antitoxin. Thomas,42 of the Fourth Service Command, reported a mortality of 20 percent in 40 cases treated during the first week of the epidemic (the week ending 1 January 1943) and 8.8 percent in 317 cases early in the epidemic. However, during February and March 1943, this was lowered to 2.1 percent in 761 cases. The fall in mortality was not the result of a decrease in virulence of the micro-organism. While 108 soldiers were being treated in one Army hospital in the Fourth Service Command with a mortality of less than 3 percent, there were 4 deaths among 8 civilians in the same county. The early high mortality was probably due to inexperience of the medical officers with the disease and delay in instituting treatment. Correction of these conditions was prompt, with dramatic reduction in mortality.

Meningococcemia-The treatment of soldiers with simple meningococcemia became relatively standardized in Army installations and was highly effective. Under clinical observation, it became obvious that those with uncomplicated meningococcemia who were treated early did not require large doses of sulfadiazine. An initial dose of 4 gm. was given followed by 1 gm. every 4 hours until the temperature had been normal for at least 2 days. Parenteral administration was resorted to in patients who were vomiting.

Renal complications-Treatment of patients with meningitis varied somewhat at different Army hospitals. Massive dosage of sulfadiazine reaching more than 20 gm. in the first 24 hours43 was used, with the achievement of concentrations in the blood of 18 to 24 mg. percent. Among 134 patients so treated, complications of therapy (86 percent of which were renal) occurred in 28 percent. At another hospital, a loading dose (of sodium sulfadiazine) of 0.1 gm. per kilogram of body weight was given intravenously in 1,000 cc. of isotonic sodium chloride solution. Following this, one-half the initial dose was given parenterally every 8 hours until the patient could retain the drug by mouth. Concentrations in the blood and cerebrospinal fluid of 13 and 11 mg. percent, respectively, were obtained with excellent therapeutic results. However, gross hematuria occurred in 15 percent and anuria in 6.6 percent of the patients. When dosage was reduced to 0.05 gm., followed by 0.025 gm. per kilogram of body weight 4 hours later, and the latter dose repeated every 8 hours thereafter, no renal complications were noted.44 With this dosage, the average concentrations of sulfadiazine in the blood and spinal fluid were 8.5 and 6.5 mg. percent, respectively. In

42See footnote 14 (2), p. 244.
43(1) Ochs, L., Jr., and Peters, M.: Management of Meningococcic Infections at the Station Hospital, Fort Benning, Ga. War Med. 4: 599-605, December 1943. (2) Kaplan, G.: Massive-Dose Sulfadiazine Therapy in Meningococcus Meningitis. New York State J. Med. 43: 2210-2212, 15 Nov. 1943.
44See footnote 13, p. 244.


263

this connection, it is of interest that Dowling and Lepper45 reported that no urinary calculi appeared in their patients with pneumonia when the concentration in the blood did not exceed 9.2 mg. percent.

Ochs and Peters,46 while treating patients with an initial intravenous dose of 10 gm. of sodium sulfadiazine in 5 percent solution, encountered renal complications in 5 of 23 patients. Later, 2,000 cc. of 1/6 molar sodium lactate was given intravenously before administering the sulfadiazine with the complete elimination of renal complications.

Drug of choice-Sulfanilamide, sulfathiazole, and sulfapyridine were used early in the epidemic because of the scarcity of sulfadiazine. The latter became the standard drug for treatment because of its efficiency and relatively low toxicity. Sulfanilamide retained an important place in therapy until penicillin became available. When gross hematuria, renal colic, oliguria, or anuria developed during sulfadiazine therapy, sulfanilamide was an effective substitute, since its use was not associated with the deposition of acetylated material in the urinary tract.

In analyzing the records of 300 of the patients who died of meningococcal infection,47 only 3 instances of death as a result of sulfonamide medication were found. All of these were due to renal complications caused by therapy. Since it can be assumed that virtually all patients who received any specific treatment were given sulfonamides, the case fatality ratio from complications of therapy with sulfonamides in the 13,922 cases treated during the Second World War was estimated to be about 0.04 percent (the total mortality from renal complications). This is astounding when one considers that massive dosage was administered to very ill, and often seriously dehydrated, patients. No death from hemolytic anemia or agranulocytosis was encountered.

Since the close of World War II, other sulfonamides have proved curative. Gantrisin has been shown to be effective in two small series of cases of meningococcal infection.48 It has the virtue of greater solubility and, in consequence, rarely causes renal complications. If extensive trials justify the promise of this drug, it may be preferred to sulfadiazine. Its dosage is similar to that of sulfadiazine.

Fulminating infections-The treatment of soldiers with fulminating bacteremia and with the Waterhouse-Friderichsen syndrome may be considered together as, in general, their treatment was identical. Among the 300 deaths analyzed, 156 patients died of fulminating meningococcal bacteremia, 126 with and 30 without adrenal hemorrhage (table 36). Of these, 30 had

45Dowling, H. F., and Lepper, M. H.: Toxic Reactions Following Therapy With Sulfapyridine, Sulfathiazole and Sulfadiazine. J.A.M.A. 121: 1190-1194, 10 Apr. 1943.
46See footnote 43 (1), p. 262. 
47
See footnote 18, p. 251.
48(1) Brickhouse, R. L., Lepper, M. H., Stone, T. E., and Dowling, H. F.: The Treatment of Pneumonia and Other Infections With a Soluble Sulfonamide, Gantrosan (NU-445; 3,4-dimethyl-5-sulfanilamido-isoxazole). Am. J.M. Sc. 218: 133-137. August 1949. (2) Rhoads, P. S., Svec, F. A., and Rohr, J. H.: Bacterial Meningitis: Results of Treatment in Seventeen Cases With a New Sulfonamide (Gantrisin). Arch. Int. Med. 85: 259-264, February 1950.


264

had no specific therapy, 98 were treated with sulfadiazine, 14 with other sulfonamides, and in 14 there was no record of treatment. Penicillin was given concurrently with sulfadiazine to at least 16 patients. The records concerning antiserum, antitoxin, and extracts of adrenal cortex were not adequate for analysis.

Thomas,49 early in the epidemic, stated that the three major objectives of treatment were to combat bacteremia, toxemia, and shock. He advocated 3 to 5 gm. of sodium sulfadiazine intravenously with 1,000 cc. of 1/6 molar sodium lactate and the maintenance of a concentration of sulfadiazine in the blood of 10 to 15 mg. percent. Intravenous administration of 20,000 units of meningococcal antitoxin was advised as an initial dose, followed by the same amount every 4 hours until 100,000 units had been given. Plasma, isotonic sodium chloride, and aqueous extract of adrenal cortex in large doses (30 cc.) at frequent intervals was advocated. In instances where pulmonary edema supervened, it was suggested that 500 cc. of 1.5 percent solution of sodium chloride containing 25 gm. of dextrose be given. A goodly number of patients were treated by a regimen of this type with certain variations. Many received no antitoxin and others either insignificant amounts of adrenocortical extract or none. In the treatment of 13 recovered cases of the Waterhouse-Friderichsen syndrome, the only constant and recurrent features of therapy were the administration of sulfadiazine in adequate amounts, intravenous isotonic sodium chloride and dextrose, and oxygen. Penicillin, adrenocortical extract, desoxycorticosterone acetate, plasma, adrenalin, adrenalin in oil, meningococcal antitoxin, or antimeningococcal serum were given in some. It would appear from the description of treatment that recovery occurred in any case where early adequate antibacterial therapy and proper antishock measures were carefully carried out. The major objective was very early recognition of bacteremia with prompt treatment before the infection became fulminating.

Cortisone, which has become available since World War II, offers an additional potent agent in combating the adrenal insufficiency incident to adrenal hemorrhage. Too few instances of its use have been recorded clearly to evaluate its place in therapy. However, its use in the Waterhouse-Friderichsen syndrome with adrenal hemorrhage is rational, in view of its proved value in critical episodes occurring in Addison's disease with complicating infection. The number of circulating eosinophils should be determined to assist in differentiating this syndrome from fulminating bacteremia without adrenal hemorrhage; the former may show more, and the latter less, than 50 cells per cubic millimeter. Therapy with cortisone should consist of an additional dose of 200 mg. divided into four 50 mg. doses injected intramuscularly into four separate sites to hasten absorption.50 Subsequent

49See footnote 19, p. 251.
50(1) Personal communication, P. H. Forsham, to the author. (2) Forsham, P. H., and Thorn, G. W.: The Diagnosis and Treatment of Adrenal Cortical Insufficiency. Veterans Admin. Tech. Bull. TB 10-62, pp. 1-23, 30 Mar. 1950.


265

dosage may be guided by following the level of circulating eosinophils. These should be kept at 15 per cubic millimeter or below.51 This will probably require 50 mg. or more every 6 hours for the first 2 days and 25 mg. at the same interval for the next 3 days. Thereafter, the dose should be gradually reduced and discontinued over the period of 1 week.

Potent new pressor agents have become available since the Second World War. Norepinephrine by continuous intravenous infusion has proved helpful in maintaining blood pressure and combating shock in two instances of the Waterhouse-Friderichsen syndrome.52

Serum

In meningitis, antimeningococcal serum in conjunction with sulfadiazine was employed intravenously and occasionally intrathecally in some hospitals.53 Serum was often given to patients who had not shown an adequate response to therapy with sulfonamide 36 to 48 hours after the initiation of treatment. It became rapidly apparent, however, that patients treated with sulfonamides alone fared as well as those to whom serum was given in addition.54

Antitoxin

Meningococcal antitoxin, originally advocated by Ferry55 and used extensively by Hoyne,56 was given to a few patients with meningitis, especially those with fulminating infections. In the early period of the epidemic, antitoxin was employed in some installations, particularly those in the Fourth Service Command, in patients ill with fulminating bacteremia. At 10 station hospitals, 134 patients were treated with this material. It was thought by Thomas57 that benefit was observed in 56 of these patients. In retrospect, it appears that mortality in cases of fulminating bacteremia treated with antitoxin is not lower than in cases treated with sulfadiazine alone. The excellent therapeutic results with sulfadiazine alone led the Council on Pharmacy and Chemistry of the American Medical Association

51Faloon, W. W., Reynolds, R. W., and Beebe, R. T.: The Use of the Direct Eosinophil Count in the Diagnosis and Treatment of Waterhouse-Friderichsen Syndrome. New England J. Med. 242: 441-445, 23 Mar. 1950.
52(1) Personal communication, P. B. Beeson, to the author. (2) Unpublished observations of the author.
53(1) See footnote 43 (1), p. 262. (2) Borden, W. B., and Strong, P. S.: Epidemic Meningitis; A Report of 15 Cases at Fort Eustis, Virginia. Mil. Surgeon 91: 517-522, November 1942. (3) Kasich, M., and Shulman, B.: Thirteen Cases of Meningitis Treated With Serum and Sulfonamides at Station Hospital, Fort Dix, New Jersey. Mil. Surgeon 90: 419-424, April 1942.
54See footnote 14 (2), p. 244.
55Ferry, N. S.: Meningococcus Antitoxin; Prophylactic and Therapeutic Tests on Guinea Pigs. J. Immunol. 23: 315-324, October 1932.
56Hoyne, A. L.: Intravenous Treatment of Meningococcic Meningitis With Meningococcus Antitoxin. J.A.M.A. 107: 478-481, 15 Aug. 1936.
57See footnote 19, p. 251.


266

to remove antimeningococcal serum and meningococcal antitoxin from the accepted preparations listed in "New and Nonofficial Remedies."58

Penicillin

During the early period of the war, penicillin was in its experimental stage and not in sufficient production for use in treatment of meningococcal infections. Beginning late in 1943, small amounts first became available at some Army hospitals for the treatment of patients with this infection. TB MED (War Department Technical Bulletin) 9, dated 12 February 1944, first advocated the use of penicillin in conjunction with sulfadiazine in patients with fulminating infection and in those who failed to respond to, or should not receive, sulfadiazine. Therapy both intrathecally and by the usual parenteral routes was advised in meningitis.

There were relatively few published reports on the use of penicillin in meningococcal infections. Kolmer59 reported that in 96 collected cases treated by intravenous, intramuscular, and intrathecal injections, the mortality was about 8.5 percent. Of these 96 cases, 76 were described by Drs. D. H. Rosenberg and P. A. Arling, who stated that 75 recovered, a death rate of 1.3 percent. This is comparable to the mortality in similar series of patients treated with sulfadiazine.60 Although the reports from the Army61 do not represent studies of the use of this antibiotic in large numbers of patients, they quite clearly indicate its place in therapy.

Rammelkamp and Keefer62 found no penicillin in the cerebrospinal fluid after constant intravenous administration over a 24-hour period, and as a result of their observations, the intrathecal together with other parenteral routes have been used in patients with meningitis. Rosenberg and Sylvester63 reported the finding of penicillin in the spinal fluid in patients with meningitis, and Price and Hodges reported the cure of four patients, following intramuscular and intravenous administrations alone.

58Status of Antimeningococcic Serum and Meningococcus Antitoxin; Report of the Council on Pharmacy and Chemistry. J.A.M.A. 124: 95, 8 Jan. 1944.
59Kolmer, John A.: Penicillin Therapy. New York: D. Appleton-Century Co., Inc., 1945, p. 202.
60(1) See footnote 14 (1), p. 244. (2) Hill, L. W., and Lever, H. S.: Meningococcic Infection in an Army Camp. J.A.M.A. 123: 9-13, 4 Sept. 1943.
61(1) Kinsman, J. M., and D'Alonzo, C. A.: Meningococcemia; A Description of the Clinical Picture and a Comparison of the Efficacy of Sulfadiazine and Penicillin in the Treatment of Thirty Cases. Ann. Int. Med. 24: 606-617, April 1946. (2) Kinsman, J. M., and D'Alonzo, C. A.: The Penetration of Penicillin Through Normal and Inflamed Meninges. New England J. Med. 234: 459-463, 4 Apr. 1946. (3) Letter, Lt. Col. J. Murray Kinsman, MC, Chief, Medical Service, Regional Hospital, Fort Bragg, N.C., to The Surgeon General, 27 Mar. 1945, subject: Transmittal of Report [Penicillin Studies]. (4) Rammelkamp, C. H., and Kirby, W. M. M.: Factors Determining the Dosage of Penicillin in the Treatment of Infections. Bull. New York Acad. Med. 21: 656-672, December 1945. (5) Dotterer, J. E.: A Fatal Case of Meningococcal Meningitis Treated With Sulfadiazine and Penicillin. ETO Med. Bull. 31: 36-38, May-June 145. (6) Lo Vetere, A. A.: Penicillin's Application to Meningitis, Meningococcemia and Septicemia. Kentucky M.J. 43: 24-27, January 1945. (7) Price, A. H., and Hodges, J. J.: Treatment of Meningitis With Penicillin Injected Intravenously and Intramuscularly. New York State J. Med. 44: 2012-2014, 15 Sept. 1944.
62Rammelkamp, C. H., and Keefer, C. S.: The Absorption, Excretion, and Distribution of Penicillin. J. Clin. Investigation 22: 425-437, May 1943.
63Rosenberg, D. H., and Sylvester, J. C.: The Excretion of Penicillin in the Spinal Fluid in Meningitis. Science 100: 132-133, 11 Aug. 1944.


267

Studies were undertaken at the Regional Hospital at Fort Bragg, N.C., to obtain further information on the most efficient mode of therapy. In 20 patients with primary or secondary syphilis given 20,000 to 40,000 units of penicillin every 3 hours from 1 to 8 days, no penicillin appeared in the spinal fluid. In six patients with meningococcemia uncomplicated by meningitis, 25,000 to 40,000 units of penicillin were given at the same interval. Twelve specimens of spinal fluid obtained 8 and 24 hours after institution of therapy and on the fifth and ninth days of treatment showed no penicillin. One patient with tuberculous meningitis showed a trace of penicillin at the 11th hour after 200,000 units of penicillin, and none at the 23d hour. Another patient with the same disease was given comparable amounts and showed no penicillin in the spinal fluid at 18 hours, and only a trace at 23 hours when the blood level was 0.4 units per cubic centimeter. Two patients with meningococcal meningitis were treated intramuscularly only. One showed a measurable amount of penicillin in the spinal fluid only at 24 hours, and in the other assays revealed none at 1½, 2½, 10, and 16 hours after treatment was begun. Both patients showed initial improvement but relapsed after 24 hours. In one, culture of the spinal fluid remained positive for meningococci. Both patients recovered promptly when sulfadiazine was administered. In seven other patients with meningococcal meningitis, penicillin was administered (intramuscularly) in large doses in the early part of their illness prior to beginning the usual therapy with sulfadiazine. The range of penicillin in the spinal fluid was from 0 to 0.5 units per cubic centimeter, 1½ to 27 hours after treatment was started. It is clear that, without intrathecal administration, penicillin may penetrate into the spinal fluid, but irregularly and in low concentrations. This work did not invalidate reported recoveries, but it indicated the hazards of modes of therapy that exclude the intrathecal route.

It was demonstrated64 that, following the administration of 10,000 units of penicillin intrathecally, from 4 to 20 units per cubic centimeter were still present in the spinal fluid 8 hours later and from 0.08 to 0.31 units after 24 hours.

In a study65 of comparable cases of uncomplicated meningococcal bacteremia, 18 were treated with penicillin and 12 with sulfadiazine. All patients recovered and were free of symptoms within 24 hours. Those treated with penicillin had normal temperatures at 12 hours while, in the sulfadiazine group, the temperatures remained elevated for 24 hours. The rash faded in both groups in 2 days. Penicillin was apparently more effective than sulfadiazine in rapidly controlling symptoms in this group. However, its inconstant appearance in the spinal fluid after intramuscular injection made it a less desirable mode of therapy, since bacteriostatic levels of penicillin in

64See footnote 61 (2), p. 266. 
65See footnote 61 (1), p. 266.


268

the spinal fluid could not be depended upon to prevent meningitis, or to control early meningitis if it occurred in these cases.

In eight patients with meningococcal meningitis, alternate cases were treated either with sulfadiazine in the usual dosage, or with 25,000 to 40,000 units of penicillin every 3 hours intramuscularly and 10,000 units intrathecally daily for 3 days.66 All patients recovered. Those treated with sulfadiazine developed normal temperatures more rapidly, became free of headache and meningeal manifestations sooner, and were out of bed earlier than those who received penicillin. One patient who received intrathecally 10,000 units of a dark-colored penicillin in 10 cc. of normal saline promptly developed extreme headache, stiffness of the neck, opisthotonos, and increasing fever associated with a rise of leukocytes in the spinal fluid from a few hundred to 50,000 within a few hours. It became necessary to stop the intrathecal penicillin and resort to sulfadiazine therapy. One other patient given the same dark-colored penicillin developed meningeal irritation of less marked grade.

In reviewing 300 fatalities due to meningococcal infection (table 36), instances of the administration of 20,000 to 25,000 units of penicillin intrathecally were noted. In one, following a large cisternal dose, hemorrhage in the medulla was found at necropsy.67 Several instances of pleocytosis and actual hemorrhage have attended doses in excess of 10,000 units.68

Meningitis developed in two patients69 while on intramuscular penicillin. One was being treated for meningococcemia and one for abdominal wounds. From the history of the first patient it is possible that meningitis already existed in spite of a normal spinal fluid.

In rare instances, penicillin was effective when sulfadiazine failed. A native of New Guinea (at Aitape) was seen at the 30th Evacuation Hospital by the author and Col. Vernon J. Erkenbeck, MC, in a moribund condition with meningococcal meningitis. He had been under treatment with massive doses of sulfadiazine for 5 days, and concentrations of sulfadiazine in blood and spinal fluid were high. In spite of this, there was extreme opisthotonos and hyperpnea, and death seemed imminent. Penicillin intrathecally and intravenously produced rapid improvement and ultimate recovery.

Since World War II, it has been shown that satisfactory cerebrospinal fluid levels of penicillin can be attained by the intramuscular route alone if enough penicillin is given. Dowling and his coworkers70 found that 1 million units of aqueous penicillin intramuscularly every 2 hours resulted in adequate concentrations in the cerebrospinal fluid.

66See footnote 52, (2), p. 265. 
67See footnote 18, p. 251.
68Annual Report, Professional Service Division, Medical Consultation Service, Office of the Chief Surgeon, Headquarters, European Theater of Operations, U.S. Army, 30 Dec. 1944, p. 13.
69(1) See footnote 61 (5), p. 266. (2) Personal communication, W. M. M. Kirby, to the author.
70Dowling, H. F., Sweet, L. K., Hirsh, H. L., and Lepper, M. H.: Specific Therapy of Bacterial Infections of the Central Nervous System. J.A.M.A. 139: 755-758, 19 Mar. 1949.


269

It becomes clear that sulfadiazine has proved to be the drug of choice in the mild or average instance of meningococcal infection. Penicillin should not be used as a routine measure. It should be given in massive dosage in conjunction with sulfadiazine in fulminating bacteremia or meningitis, and to replace it when intolerance to, or complications from, sulfadiazine develop. When improvement is not noted after 36 hours of treatment with sulfadiazine, massive parenteral penicillin therapy should be instituted without discontinuing sulfadiazine.

Therapy With Other Drugs

Certain new antibiotics that have become available since World War II are highly effective in the treatment of both bacteremia and meningitis. Aureomycin (chlortetracycline),71 chloramphenicol,72 and Terramycin (oxytetracycline)73 have been used successfully in the treatment of small groups of patients. Should a patient demonstrate clear-cut evidence of sensitivity to the sulfonamides and penicillin, one of these other drugs can be used with confidence.

Adjuvant Therapy

Fluid balance-Patients admitted with meningitis, or severely ill with bacteremia, are almost invariably dehydrated, so that careful attention to fluid balance is necessary for its own sake as well as to prevent the renal complications of sulfonamide therapy. Urine flow should not be less than 1,200 cc. per day. Attention to this detail of therapy was often painfully learned by medical officers when gross hematuria or oliguria developed during administration of sulfadiazine. It was soon found that the use of sodium sulfadiazine in 5 percent solution, as suggested in Circular Letter No. 170, was fraught with danger unless a large amount of fluid had preceded treatment. When the patient's condition permits slight delay, Ochs' recommendation74 of 2,000 cc. of 1/6 molar sodium lactate prior to sulfadiazine may be wise. He also advocated using the same quantity of this solution following the drug and the maintenance of an alkaline urine. However, renal complications were rare when the initial dose of sodium sulfadiazine was administered in 1,000 cc. of isotonic sodium chloride or the same volume of 1/6 molar sodium lactate. In some hospitals, the major portion of the intake of fluid was administered to comatose patients by Levin tube and in others by a parenteral route. The latter is preferable when there is vomiting.

71Conn, Howard F. (editor): Current Therapy. Philadelphia: W. B. Saunders Co., 1951, p. 19. 
72McCrumb, F. R., Jr., Hall, H. E., Merideth, A. M., Deane, G. E., Minor, J. V., and Woodward, T. E.: Chloramphenicol in the Treatment of Meningococcal Meningitis. Am. J. Med. 10: 696-703, June 1951.
73Hoyne, A. L., and Riff, E. R.: Terramycin Therapy for Meningitis; A Report of Fourteen Recoveries Without Other Medication. J. Pediat. 39: 151-154, August 1951.
74See footnote 43 (1), p. 262.


270

Sedation.-Restlessness is common and when mild can be disregarded or allayed by simple sedatives, such as the barbiturates. Great restlessness and almost maniacal delirium occur frequently with meningitis, often making lumbar puncture or intravenous treatments difficult or impossible. Paraldehyde, 16 cc., proved the most effective sedative. Intravenous barbiturates are occasionally necessary, though undesirable. Morphine, though considered hazardous by some because of its depressant effect on respiration, is at times essential. Extreme restlessness and even delirium can often be relieved by lumbar puncture with the reduction of pressure of the spinal fluid. Catheterization with relief of bladder distention often quiets a restless, thrashing patient who is hard to keep in bed. It has been noted that the delirium is frequently a resistive one, so that attempts to restrain the patient's movements result in a heightening of delirium. Freedom to thrash about in bed for a few minutes without restraint is often followed by quiet and relaxation. In fulminating bacteremia, morphine appears to be the most effective drug for restlessness and is indicated if shock supervenes.

Lumbar puncture-Initial diagnosis may be the only occasion for the use of this procedure in patients who show prompt and continued improvement following treatment. As a therapeutic procedure for reduction of intracranial pressure, lumbar puncture is of great importance when headache is excessive, restlessness intractable, coma deepening, and hyperpnea, Biot's breathing, or other respiratory abnormalities are marked. Striking improvement has been noted in patients following reduction in intracranial pressure.

Complete recovery with return to full duty after an average hospitalization for 1 month and a similar period on sick furlough or reconditioning has been usual. Data as to actual days lost are not available. In mild and uncomplicated bacteremia, many soldiers have been returned to full duty within 2 weeks from onset.

Preliminary tabulations of individual medical records, during 1942-45, indicate that 105 U.S. Army personnel were separated for disability due to meningococcal infection.

PATHOLOGICAL FINDINGS

The vast amount of pathological material available at the Armed Forces Institute of Pathology is being carefully studied by the medical officers assigned there. The major lesions disclosed at autopsy in those patients who died of meningitis were inflammatory changes in the leptomeninges of the brain and cord, usually without evidence of organization of exudate. True encephalitis was present in relatively few cases (p. 257). The pathological findings in patients with meningitis who died early were comparable with those who died of bacteremia.

Of the 156 patients who died from fulminating bacteremia (table 36), 126 showed hemorrhage in the adrenal glands ranging from mild extravasa-


271

tions to the conversion of both glands into sacs of blood. There was no evidence of meningitis in 74 of these 156 patients and in 64 others the meningeal inflammation was minimal. Pulmonary edema was striking in almost all and gross hemorrhage into the lung was not unusual. There were small effusions into one or both pleural cavities in about half of the patients. Widespread focal hemorrhages were scattered over the serous surfaces in most cases and sometimes involved the myocardium. Interstitial myocarditis, occasionally severe but usually of mild focal character, occurred in 28 of the 126 patients with adrenal hemorrhage. Renal changes indicative of shock were observed in 6 of 26 patients analyzed by Thomas.75 As has been noted (p. 263), in only 3 of the 300 patients who died of meningococcal infection was death the result of renal lesions due to sulfonamides.

TREATMENT OF MENINGOCOCCAL INFECTIONS

It seems worthwhile to outline briefly recommendations for treatment based on the published reports and the experience of many medical officers with about 14,000 patients ill with meningococcal infection during World War II, and on advances in therapy since the war ended.

Acute or chronic bacteremia-Sulfadiazine, 4.0 gm., should be given by mouth and be followed by 1 gm. every 4 hours until fever, symptoms, and other manifestations of infection have been absent for at least 48 hours. When there is vomiting, comparable amounts of sodium sulfadiazine dissolved in a liter of normal saline solution should be administered intravenously. These dosages are usually sufficient to maintain a concentration in blood from 5 to 11 mg. per 100 cc. of plasma, and as a rule prevent the development of fulminating bacteremia or meningitis.

Fulminating bacteremia with peripheral circulatory failure-This is a major medical emergency requiring immediate action and continued, constant observation by resourceful physicians and nurses. Even though meningitis is present or suspected, it is of quite secondary importance, and the patient should not be subjected to the strain of lumbar puncture.

An hourly chart of pulse, respiration, temperature, and blood pressure is begun. The patient is placed in the shock position. Oxygen is administered continuously to combat cyanosis. External warmth is applied. An infusion of sodium sulfadiazine, 0.1 gm. per kilogram of body weight dissolved in 1,000 cc. of normal saline solution, is begun in an antecubital vein of one arm; in the other arm, an infusion of 500 cc. of 10 percent dextrose in water is begun; 500,000 units of penicillin dissolved in 20 cc. of normal saline solution are injected into the tubing and then 100 cc. of aqueous adrenocortical extract. This is followed by 500 cc. of plasma or blood, if it appears necessary. Meanwhile, the following intramuscular injections are given: (1) Cortisone, 200 mg. divided into four 50 mg. doses injected into

75See footnote 14 (2), p. 244.


272

four separate sites, and (2) penicillin, 1 million units divided into two 500,000-unit doses injected into two separate sites. If the systolic blood pressure is 80 mm. of mercury or less, a 4-cc. ampule of l-norepinephrine (levofed bitartrate, each cubic centimeter containing 1 mg. of levofed base) should be added to the flask of 10 percent glucose and given at a rate necessary to maintain adequate blood pressure. This is usually about 2 to 4 μg. per minute.

Further therapy may include: (1) Plasma, or 25 gm. of concentrated human albumin administered in 5 percent solution, if indicated for shock; (2) sodium sulfadiazine, 0.05 gm. per kilogram of body weight every 4 hours intravenously until the drug (approximately 1 to 1.5 gm. every 4 hours) is tolerated by the oral route; (3) penicillin, 1 million units every 2 hours intramuscularly; (4) cortisone, 50 mg. intramuscularly every 6 hours for the first 2 days and 25 mg. every 6 hours for the next 3 days; thereafter, the dose should be gradually discontinued over the course of a week; and (5) small quantities of ginger ale or sweetened fruit juice, orally, as soon as possible amounting to 3,000 cc. of fluids or more daily.

The dosage of sulfadiazine should be guided by frequent determinations of drug level in the blood, 15 to 20 mg. per 100 cc. being the optimum range. Full chemotherapy should be continued for at least 4 days after the patient has recovered from the acute phase of his disease, counted from the first day of normal temperature.

After the first day, no more than 1,000 cc. of normal saline need be given daily intravenously. Should pulmonary, sacral, or peripheral edema appear, however, the quantity of normal saline solution should be markedly reduced. If marked pulmonary edema develops, 1 to 3 units of plasma or 25 to 50 gm. of concentrated human albumin may be administered slowly. Positive pressure oxygen may be helpful.

If the patient is failing, hypoglycemia and hypopotassemia should be considered. The appropriate blood determinations should be made, and their abnormalities corrected. An electrocardiogram might show evidence of potassium deficiency.

In those patients with fulminating bacteremia whose manifestations are not those of shock, the use of plasma, norepinephrine, oxygen, and adrenocortical compounds should be omitted.

A count of circulating eosinophils should be performed to assist in differentiation of the Waterhouse-Friderichsen syndrome from fulminating sepsis without adrenal insufficiency; the former may show more, and the latter less, than 50 cells per cubic millimeter. Cortisone dosage should be adequate to maintain the number of eosinophils at 15 per cubic millimeter or less.

Meningitis-The potential seriousness of this condition is such that, regardless of its severity, all patients should receive a liter of saline containing sodium sulfadiazine intravenously-6 gm. for a heavyweight, 5 gm. for


273

a mediumweight, and 4 gm. for a lightweight adult. It is wise to administer half the original dose parenterally 4 hours later, but, in conscious and cooperative patients who are not vomiting, the oral route may be used at this time. If, following this, continued parenteral therapy is needed, 2 gm. of sulfadiazine dissolved in saline should be injected intravenously or subcutaneously every 8 hours. In comatose patients, the drug may be administered by stomach tube. Sulfadiazine, in doses of 1 to 1.5 gm. orally every 4 hours, will usually maintain the concentration in blood around 8 mg. and concentration in the spinal fluid around 6 mg. per 100 cc. A concentration in blood of 6 to 10 mg. is adequate. In fulminating cases, the dosage should be adjusted to maintain the concentration in the blood between 15 and 20 mg. per 100 milliliter. In the gravely sick cases, penicillin should also be used, in the doses just mentioned. If the patient is known to be sensitive to, or develops complications of, sulfonamide treatment, penicillin in massive dosage (1 million units every 2 hours) should replace it. If sensitivity to both of these agents should be present, chloramphenicol, Aureomycin, and Terramycin are effective drugs.

DISCUSSION

The experiences of medical officers who have treated meningococcal infection during the Second World War have clarified and extended knowledge of the various forms which this infection may assume. These observations amply confirmed the opinion of Herrick and others in the World War I epidemic that the disease begins as a bacteremia and, if not prevented by spontaneous resistance or therapy, involves the meninges, skin, and other organs, or it may be fatal in the bacteremic form.

The major contribution has been the development of a tried therapeutic plan, which has reduced the case fatality to 4 percent in contrast to about 31 percent in World War I (table 34). In the Zone of Interior, where no problem of evacuation existed, the case fatality was 3.9 percent compared to 4.5 percent for oversea areas. The ratios for the continental United States in 1944 and 1945 were, respectively, 2.9 and 4.9 percent, based on 2,577 and 815 cases. It is not probable that with our present therapeutic tools mortality can be further significantly reduced, unless some means can be found which will enable the physician to recognize incipient meningococcal bacteremia during the phase of prodromal respiratory symptoms.

RETURN TO TABLE OF CONTENTS