CHAPTER IX
Meningococcal Infections
Worth B. Daniels, M.D.
HISTORICAL NOTE
Outbreaks of meningococcal infection are known to have occurred during allwars since the illness was first described by Vieusseux1in 1805. Importantmilestones in the development of knowledge of this disease can be brieflysummarized. The isolation of the causative agent by Weichselbaum2in 1887 led to a search for a specific cure. Flexner andJobling3 thoughtthat 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 annualrate of admission to hospital for white enlisted men in the United Statesreached 1.71 per 1,000 troops, and within 7 months an explosive outbreak ofmeningococcal meningitis had begun (chart 12). In January 1918, the rate hadrisen to a peak of 4.48 per 1,000.4 Thisepidemic afforded Herrick5 anopportunity to study the use of antiserum under controlled conditions and tomake observations on pathogenesis. His studies indicated that antiserum givenintravenously reduced the mortality in patients with bacteremia and in thosewith meningitis. In spite of the use of meningococcal antiserum, however, therewere 1,836 deaths among approximately 5,900 cases (31 percent case fatalityratio) among troops throughout the U.S. Army in a period of 33 months during andimmediately following World War I.6 Herrick'sstudies clearly showed that meningitis does not develop as the result ofextension from the nasopharynx but begins as bacteremia with later localizationin the meninges, joints, and other tissues. This concept has greatly influencedtreatment and, together with the development of the sulfonamides, has been afactor in lowering the death rate.
1Vieusseux, M.: M?moire sur la Maladie qui a rēgne ? G?n?ve auprintemps de 1805. J. de m?d., chir. et pharmacol. 11: 163-182, 1805.
2Weichselbaum, A.: Ueber die Aetiologie der akuten Meningitiscerebro-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 CerebrospinalMeningitis. J. Exper. M. 10: 141-203, January 1908.
4The Medical Department of the United States Army in the World War. Washington: U.S. Government PrintingOffice, 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.: EarlyDiagnosis and Intravenous Serum Treatment of Epidemic Cerebrospinal Meningitis.J.A.M.A. 71: 612-617, 24 Aug. 1918. (3) Herrick, W. W.: The Intravenous SerumTreatment of Epidemic Cerebrospinal Meningitis. Arch. Int. Med. 21: 541-563,April 1918.
6See footnote 4.
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CHART 12.-Admissions to U.S. Army hospitals formeningococcal infections among troops in the continental United States, bymonth, World War I1 and World WarII2
Sulfanilamide early proved to be a highly effective agent inthe therapy of these infections.7 In 1940-41, during the outbreak inHalifax, Nova Scotia, Dingle and his coworkers8 showed the effectiveness ofsulfadiazine in a small group of patients.
7Schwentker, F. F., Gelman, S., and Long, P. H.: The Treatment ofMeningococcic 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 ofMeningococcicMeningitis and Meningococcaemia With Sulfadiazine. J.A.M.A. 116: 2666-2668, 14June 1941.
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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 hospitalswith meningococcal infections; 6,370 of these developed theillness in the United States. The incidence rate per 1,000 per annum was 1.0 forthe total U.S. Army, 1.2 for troops in the United States, and 0.4 for troopsoverseas.
For the year 1943, in the United States, the statistical health report ratesper 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 Theaterof Operations, U.S. Army, during 1942 was greater than among troops in theUnited States. During 1943, the rate in the European theater remained about thesame (0.9). In other oversea theaters, the rates in general rose somewhat, butno significant outbreaks occurred.
During September and October 1943, the incidence ofmeningococcal infections among Army troops in the United States fell nearly tothe preepidemic level. A rise to a second, less elevated, peak began in thewinter of 1943-44, with return to the preepidemic rate by summer. It is of someinterest that the peak of the second rise (1.1 per 1,000 in February 1944) came11 months after the height of the epidemic (2.9 in March 1943), table 34. InWorld War I, the second peak (1.2 admissions per 1,000 for white enlisted men inOctober 1918) occurred 9 months after the first peak (4.5
9Sartwell, P. E., and Smith, W. M.: Epidemiological Notes onMeningococcal Meningitis in the Army. Am. J. Pub. Health 34: 40-49, January 1944.
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in January 1918).10 The second rise in incidenceamong troops in the United States during World War II was as intense as thatwhich occurred during World War I, and was more sustained. Attention is calledto this because sulfonamides were widely used prophylactically in the fall andwinter of 1943-44, following distribution of Circular Letter No. 170, Office ofthe Surgeon General, U.S. Army, dated 30 September 1943. This letter establishedas Army policy the administration of sulfadiazine to all newly inducted soldiersduring 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.
| 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 theUnited States, whereas the World War II data represent incidence for all Armypersonnel 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 enlistedmen in the United States and Europe combined. Based on the distribution ofadmissions in the two areas, the incidence in the United States is estimated at3,500 cases.
4Consists of admissions in the entire Army and secondarycases among enlisted men in the United States and Europe. Secondary cases amongofficers and among enlisted men outside the United States and Europe are notavailable, 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 MedicalDepartment of the United States Army in the World War." Washington:Government Printing Office, 1925, vol. XV, pt. 2. (2) Data for World War II arepreliminary. (3) The number of deaths are from complete files of individualmedical records, and incidence is based on sample tabulations of individualmedical records, except for data on peak incidence which are from thestatistical health report.
During the years 1942-45, in spite of the availability ofhighly effective treatment, meningococcal infections caused more deaths (559)than any other infectious disease, except tuberculosis. Table 35 shows thenumber of deaths in the U.S. Army during this period resulting from the moreserious infectious diseases and the death rates from these diseases per 100,000average strength.
10See footnote 4, p. 239.
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Of 13,922 patients attacked by meningococcal infectionsduring 1942-45, only 559 deaths were reported-a case fatality ratio of 4percent. During World War I, the ratio was nearly eight times as great, 31percent. Chart 13 indicates the case fatality ratios in the continental UnitedStates by month during the two wars. The ratios for World War I are based onwhite enlisted patients in the continental United States.
TABLE 35.-Comparative mortality of certaininfectious diseasesin 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 |
| ||||
| 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 scarletfever (61) and syphilis (70). Several other infectious diseases ranked higher thanbacillary dysentery as a cause of death. Even though amebiasis and bacillary dysentery had low death rates, both were feared diseases.
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The organization of medical care in the Army permitted theobservation of early cases, resulting in better recognition of the various formsof the disease. It is, therefore, proposed in this chapter to describe thedifferent forms that meningococcal infection assumed in soldiers during WorldWar II, indicating how studies of the early stages contributed to knowledge ofits pathogenesis, and to review the methods and results of treatment carried outin Army installations.
PATHOGENESIS
During nonepidemic periods, the rate for meningococcal carriers in troopsranged from 2 to 10 percent.11 In periods of epidemic, carrier rates amongtroops rose and in studies made during the epidemic were reported as rangingfrom 2312 to 80 percent.13 The carrier rate was lowest among newlyinducted soldiers.
The micro-organism probably invades the body from thenasopharynx, and infection in this region may or may not be accompanied byevidences of respiratory infection. The subsequent manifestations are those ofbacteremia and localization. Observations during World War II supportedconclusions similar to Herrick's in World War I, since they clearly indicatedthat the course of events consisted of invasion of the bloodstream followed bylocalization in the meninges, skin, or other tissues of the body if notprevented by natural resistance or by therapy. The experience of all observersemphasized the necessity of viewing this disease as a bacteremia, which wassometimes overshadowed by the advent of the more dramatic symptoms ofmeningitis. By early recognition of the bacteremic stage and prompt institutionof treatment, the infection might be terminated before its localization in themeninges or before it had become fulminating. If meningitis or other severemanifestation did, notwithstanding, supervene, the chance of recovery still wasbetter than in cases that had not had prompt treatment. When medical officersbecame familiar with the disease, through experience in the epidemic, theyrecognized it in the bacteremic stage and prior to the advent of meningitis in as high as 30 to40 percent of the patients.14
MENINGOCOCCAL BACTEREMIA
Prodromal symptoms-The illness began, as a rule, withprodromalsymptoms of disease of the upper respiratory tract. After an indefinite period
11Dingle, J. H., and Finland, M.: Diagnosis, Treatment andPrevention of Meningococcic Meningitis. With R?sum? of Practical Aspects of Treatment of Other Acute Bacterial Meningitides. War Med. 2: 1-58, January1942.
12Personal communication, C. T. Nelson, Fourth Service CommandLaboratory, 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 ofOutbreak in the Fourth Service Command During the Winter and Spring of1942-1943. J.A.M.A. 123: 264-272, 2 Oct. 1943.
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of from a day to a week or more, the manifestations becamemore acute. There was usually a sudden chill with rapid rise in temperature, butthe onset might be gradual. Malaise, extreme weakness, aching of muscles,moderate headache, nausea, vomiting, pain in joints, or acute inflammation ofjoints, developed. The most characteristic manifestation was the rash. Itspresence was essential to clinical diagnosis before the advent of meningeallocalization.
Rash.-The rash might be so sparse that careful and frequentlyrepeated search was necessary to find it, or it might be obvious and noted bythe patient. It appeared in a wide variety of forms, and knowledge of itsvariations was necessary to the recognition of the disease.
The commonest lesion was petechial or purpuric and variedfrom 1 to 15 mm. diameter. In addition to this type, which has been emphasized in thepast, otherforms of rash, not commonly described, were generally seen. Ill-defined faintpink macules similar to the rose spots of typhoid fever were common. These mightbe evanescent, and not infrequently a scattered few constituted the onlycutaneous manifestation. Maculopapular lesions (fig. 35) were usually present,and in some instances they had a central petechia. The larger ones of this typewere nodular or plaquelike and often tender. When
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on the extremities, these nodules bore a striking resemblanceto the smaller lesions of erythema nodosum. Occasionally, there were petechiaein the conjunctivae and the oral mucous membranes.
Various combinations of the cutaneous manifestations occurred; indeed, mostpatients showed more than one type of lesion. The rash appeared anywhere on thebody but usually spared the face and was less common on the palms and soles. Itwas often evident in crops. The macular lesions sometimes receded with fall intemperature, only to reappear as the temperature again rose. The rapidity withwhich the rash often appeared made it necessary to examine carefully everysuspected patient at hourly intervals; in a few hours, it could advance from afew 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 fewpatients, large areas of hemorrhage developed beneath the conjunctivae and inthe oral mucous membranes. Some of the ecchymotic lesions became vesicular, andulceration occasionally occurred. The rapid disappearance of the maculopapularcomponent of the rash within 12 to 18 hours after the beginning of therapy withsulfadiazine was almost diagnostic of meningococcal bacteremia.
Other symptoms-Herpes simplex was common, usually occurring about thesecond day of illness. Herpes zoster, involving the ophthalmic and maxillarybranches of the fifth cranial nerve, was observed in one patient.
At admission, the temperature of patients with meningococcemia ranged from97? to 106? F. It was generally between 101? and 102?F.
Leukocytosis (15,000 to 50,000 per cubic millimeter), with an increase inpolymorphonuclear cells, was the rule, but in a few patients the number ofleukocytes 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 bearrested 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 2weeks before admission. During the afternoon of the day before admission hesuddenly began to feel unusually tired and to ache all over. During the night hehad chilly sensations alternating with feverishness, and on the morning of theday of admission he had a moderately severe headache. He was acutely, but notseriously, ill. His face was flushed and his temperature was 101.3? F. Therewas slight inflammation of the nose and throat, and a maculopapular rash (fig.35) was scattered over the trunk and all extremities. Neurological examinationgave entirely normal results. The leukocytes numbered 19,800 per cubicmillimeter, with 81 percent polymorphonuclear cells. Blood cultured onadmission yielded type I meningococcus. Lumbar puncture was not done. As soonas the blood for culture had been taken, sulfadiazine was given by mouth. Thetemperature was normal within 2 days. The patient developed no signs ofmeningitis.
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The disease at times was relatively mild and subacute, sothat the fever, malaise, painful joints, and rash suggested rheumatic fever orerythema multiforme. The following case is illustrative:
Case 2-A soldier,aged 21, had been well until 3 daysbefore admission, when he suddenly had a shaking chill with the development offever, malaise, and sore throat. The only significant findings were a fewerythematous 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 ofmacular, papular, and nodularlesions, with a few petechiae, appeared in crops. These findings suggestederythema multiforme and erythema nodosum. Shortly after admission, redness, tenderness,and swellingof the right ankle developed. The leukocytes numbered 16,300 per cubicmillimeter, with 73 percent polymorphonuclear cells. Many erythrocytes were noted in severalspecimens of urine. The spinal fluid was normal. Cultures of the blood yielded typeIIa meningococcus. After thefirst dose of sulfadiazine by mouth, the temperature became normal andremained so. The rash faded promptly.
The extraordinarily mild character that meningococcal infection occasionallyassumed is illustrated in case 3.15
Case 3-The10-year-old son of an officer was admittedto an Army hospital with minimal headache and fever (100? F.). Admission was grantedonly on the insistence of his apprehensive mother, who feared poliomyelitis. Because of pressure from themother, examination of the cerebrospinal fluid and culture of the blood wasmade.The spinal fluid was normal. Two days later, cultures of both blood andspinal fluid that were made on admission grew meningococci. No specifictreatment had been given. At this time, on careful scrutiny, one skinlesion thought to be a small petechial hemorrhage was found: a secondexamination of the spinal fluid showed a normal fluid and was sterile. Another culture of blood drawn on the third day again yieldedmeningococci. As the patient had become afrebrile and asymptomatic nosulfonamides were given. Subsequent cultures of the blood were sterile. For10 days the patient was watched closely and developed no recurrence ofsymptoms and no manifestations of illness. At this time a course of therapywith sulfadiazine was administered. The patient was discharged well afterapproximately 3 weeks of observation.
It is probable that, during the periods of increasedprevalence of meningococcal infection, some cases of mild character withspontaneous recovery were not detected. We know that recovery from meningococcalbacteremia has occurred after minimal amounts of sulfonamide, in some caseswith a total dose of as little as 2 grams. These patients usually had a mildillness with fever and were given a single dose of sulfadiazine by the wardofficer, after which no drug was administered. Later, the original cultures ofblood taken before therapy were shown to contain meningococci, but the patientshad by then become apparently well.
In other patients, the course was chronic and produced apersistent, low-grade, febrile illness, which in case 4 was not severe enoughto prevent the performance of military duty.
Case 4-A soldier,aged 23, was admitted to theorthopedic service because of an injured ankle. It was learned that for about3 weeks he had been suffering from malaise, evening feverishness, and an intermittent eruption of red noduleson his legs. While in
15Personal communication, R. H. Turner, to the author.
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the hospital his temperature ranged from98.6? to 102? F.Migrating arthralgia was present, and a scattered erythematous papular rashappeared. This was most apparent on the extremities. The leukocytes numbered12,600 per cubic millimeter, with 81 percent polymorphonuclear cells. Twocultures of the blood grew type I meningococcus. There were no meningealsymptoms or signs at any time, and the spinal fluid was normal. Allmanifestations cleared entirely within 24 hours after sulfadiazine wasadministered 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 ofthe meninges was relatively easy during the epidemic, when the index ofsuspicion was high; it was in the sporadic case that delays in diagnosis andtreatment were likely.
Case 5.-A private, aged 20, was admitted with a history of sore throat whichhad been present for 1 week. On the day before admission there was a suddenonset of shaking chills, fever, and painfulness of joints. A fewsmall erythematous nodular lesions of the skin developed, and the pharynxshowed mild inflammation. Both knees and both elbows and the right wrist andankle were tender and hot-but not red or swollen. The leukocytes numbered 11,500per cubic millimeter with 78 percent polymorphonuclear cells. A tentativediagnosis of acute rheumatic fever was made, and full dosage of salicylatesprescribed. In spite of this medication the temperature ranged from 98.6? to102.4? F. for the succeeding 13 days. On the 13th hospital day there was asudden rise in temperature to 105? F., with severe headache, nausea, andvomiting. Within 3 hours the patient was stuporous and presented all of thesigns of severe meningitis, with a dozen or so pinkish macules resembling rosespots on the trunk. The spinal fluid contained 1,200 leukocytes per cubicmillimeter, with 95 percent polymorphonuclear cells. Treatment withsulfadiazine resulted in recovery. Blood was taken for culture after therapy wasbegun, and there was no growth.
Case 6 illustrates the importance of cutaneous manifestations, showing howthe absence of a persistent rash during the greater part of the bacteremic stagedelayed diagnosis.
Case 6.-The patient was admitted to the ward for patients with diseases ofthe respiratory tract, having had a cold with nasal congestion, slightcough, and sore throat for 1 week. During the day before admission, he hadseveral slight chills and felt feverish; he vomited once. Examination revealedmoderate inflammation of the nasopharynx, and a discrete macular rash on thetrunk and around the shoulder girdle, which disappeared within a few hours afteradmission. 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 ofsubacute bacterial endocarditis was entertained, repeated cultures of theblood were made. Ten days after admission the temperature rose to 103? F.and the patient appeared worse. There were no meningeal signs or symptoms. Onthe next day, increasingly severe headache developed, with nausea and vomiting.Examination revealed a slightly stiff neck, positive Kernig's sign, and sparsepetechiae on the upper part of the trunk. The spinal fluid was cloudy andcontained 9,700 cells per cubic millimeter. Smear and culture of the fluidshowed type I meningococcus. A culture of the blood taken on the day before thedevelopment of meningeal signs contained the same micro-organism. Recovery wasrapid on therapy with sulfadiazine.
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The speed with which meningitis could develop in a patient withmeningococcemia was extremely variable. The next patient reported (case 7) wasone in whom early meningitis was present on admission, as indicated by recoveryof meningococci on culture from an otherwise normal spinal fluid. The history,however, gave clear-cut evidence that bacteremia had existed for about 24 hoursbefore admission. This case also illustrates how rapidly meningitis can advancein spite of prompt and adequate therapy with sulfadiazine.
Case 7-A private,aged 37, was well until the morning of theday before admission, when he suddenly had a shaking chill and began tofeel extremely weak. Headache was moderately severe but subsided during theevening. On the morning of the day of admission the patient's headache wasgone, but he noticed that he was covered with tiny dark purplish spots. Hisright knee was moderately painful on walking. Severe frontal headache againdeveloped on his admission to the ward. He was obviously acute and seriouslyill, although alert and well oriented. Scattered over the trunk and allextremities were myriads of dark petechiae, all less than 2 mm. in diameter. There was no stiffness of the neck, andKernig'sand Brudzinski's signs were not present. A specimen of spinal fluid contained 3lymphocytes per cubic millimeter, a normal concentration of sugar, and a smearof it was negative for micro-organisms. By the following day, however, type Imeningococcus grew in the culture of this fluid. Immediately after the initiallumbar puncture, 5 gm. of sodium sulfadiazine (in 1,500 cc. of saline anddextrose solution) was given intravenously.
Four hours after admission the patient developed projective vomiting andrapidly became stuporous. All the signs of meningitis were present. Five andone-quarters hours after the first lumbar puncture another specimen of spinalfluid was obtained. The fluid was under greatly increased pressure andcontained 17,700 leukocytes per cubic millimeter, with 99 percentpolymorphonuclear cells. The concentration of sugar had fallen to a level toolow to read with accuracy and the level of sulfadiazine had reached 8.2 mg. per100 cubic centimeters. Smear and culture of this second specimen were negativefor meningococci in spite of the addition of para-aminobenzoic acid to theculture media. After an extremely stormy course, the patient recovered.
Although the culture of blood on admission was contaminatedand no meningococci were found, the history of a shaking chill, the presenceof a purpuric rash extensive enough to be noticed by the patient, and a painfulknee joint-all at a time when the patient was entirely free ofheadache-werebelieved to be evidence that invasion of the bloodstream occurred several hoursbefore admission. That meningitis was in the earliest phase at the time ofadmission was shown by the fact that the spinal fluid was normal in everyrespect except that meningococci were grown on culture. There were no meningealsigns except severe headache.
FULMINANT MENINGOCOCCAL BACTEREMIA
Without adrenal hemorrhage-A form of fulminant, rapidly fatalmeningococcal infection occurred, with little or no evidence of meningitiseither during life or at necropsy, and without the clinical manifestations ofthe Waterhouse-Friderichsen syndrome, while the adrenals, (at necropsy,
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showed no abnormality. The rash was widespread and frequentlyas extensive as that seen in patients who had massive bilateral hemorrhage intothe adrenals. The following is a case in point:
Case 8-A 20-year-old soldier was admitted at 4:30 a.m. afteran illnessof a few hours, with chills, fever, headache, and weakness. On admission thetemperature was 107? F. Stupor was marked. The pulse was strong, pounding, andrapid. The blood pressure was 120 systolic and 70 diastolic. There was nostiffness of the neck or other evidence of meningeal irritation. Widelyscattered over the skin were myriads of petechial and purpuric lesions, some ofwhich coalesced to form areas of ecchymosis. The cerebrospinal fluid wasnormal. A culture of the blood later grew type I meningococcus. Sodiumsulfadiazine, 4.0 gm., was promptly given intravenously. Stupor deepened, andonly 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 bacteremiaassociated with so-called tubular degeneration of the adrenal cortex, asdescribed by Rich,16 occurred among Army personnel. The adrenals in these patientswere not the site of hemorrhage. These cases occurred with and withoutmeningitis. The following case, reported by Kinsman, D'Alonzo, and Russi,17is illustrative:
Case 9-A 29-year-old white soldier was admitted to the hospital at3:30p.m. on 22 January 1944, about 2 hours after sudden onset of weakness, shakingchills, fever, headache, pain in the back, and exhaustion. The temperature onadmission was 104.6? F. The leukocytes numbered 11,950, with 84 percentneutrophils. Physical examination revealed nuchal rigidity of minimal degree,but Kernig's sign was absent. The pharynx was moderately injected. Type Imeningococcus was later recovered from the spinal fluid. Early the next morning(23 January) the patient developed an increasingly widespread, mottled purpuricand ecchymotic rash over the entire body, including the face and neck. About 80percent of the surface of the body eventually became involved. There werescattered hemorrhagic spots, most of them large, an inch or more in diameter.These were also observed in the conjunctivae and mouth; the uvula was completelyblack from hemorrhage. In spite of treatment, the eruption continued to spread.The patient became restless, complaining of chilliness, and of the burning andsoreness of the eruption. His lips, fingernails, and entire skin becamecyanotic, the pulse was 110, and blood pressure was 130 systolic and 100diastolic. Nuchal rigidity had not increased and Kernig's sign was stillabsent. The leukocytes numbered 27,200, with 87 percent neutrophils. Thetemperature 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 therespirations dropped to 8 per minute. A direct smear of his blood showeddiplococci lying within the cytoplasm of the neutrophils. The culture of theblood was later reported positive for type I meningococcus. The patient expiredat 3:10 p.m., 26 hours after onset. A second spinal puncture was done at thetime of the necropsy and showed 2,200 cells.
Necropsy revealed widespread focal hemorrhages in thepulmonary parenchyma and petechial hemorrhages in the pleura, pericardium, andendocardium. Examination of the adrenals showed no gross hemorrhages.Microscopically, there was marked congestion
16Rich, A. R.: A Peculiar Type of Adrenal Cortical Damage Associated WithAcute Infections, and Its Possible Relation to Circulatory Collapse. Bull. JohnsHopkins Hosp. 74: 1-15, January 1944.
17Kinsman, J. M., D'Alonzo, C. A., andRussi, S.: Fulminating Meningococcic Septicemia Associated With AdrenalLesions; An Analysis and Discussion of Seven Cases. Arch. Int. Med. 78: 139-169,August 1946.
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of the sinusoids but no extravasation of blood. The cells inthe glomerular zone displayed a vacuolated cytoplasm, and appeared of averagesize, while those in the inner part of the fascicular and reticular zones hadshrunk, their cytoplasm being homogeneous, dark, and sprinkled with brownpigment. In this case the tubular changes in the outer half of the fascicularlayer were prominent. The lesion was similar to that described by Rich. Thecords in the outer third of the fascicular zone were converted into tubuleslined by vacuolated cells, many of which had undergone degeneration withfraying of the cytoplasm and pyknotic changes of the nuclei. In someinstances, the adrenal cells had disappeared entirely from the inner layer ofthe cortex, leaving only a reticular stroma between the congested capillaries.The medulla was not abnormal.
The meninges were not conspicuously involved on grossexamination. Microscopically, there was a fair amount of acute inflammatory cellular exudate in thesubarachnoid spaces.
Fulminating meningococcal bacteremia, without meningitis,occurred with the clinical manifestations of the Waterhouse-Friderichsensyndrome, and yet no hemorrhage or other abnormality of the adrenals was foundat necropsy. Four such cases were found among 300 fatal cases analyzed (table36).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.
Cause of death | Number | Percent |
Fulminating bacteremia: |
|
|
| Without adrenal hemorrhage2 | 30 | 10 |
| With adrenal hemorrhage3 | 126 | 42 |
|
| 156 | 52 |
Meningitis | 144 | 48 |
|
| 300 | 100 |
1With renal complications (estimated case fatality in the totalU.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 theWaterhouse-Friderichsen syndrome.
Case 10-A soldier, aged 21, suddenly became ill 24 hoursbefore admission with severe headache, stiffness, generalized aching, nausea, andvomiting. 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 ofsulfadiazine in the blood, the patient became rapidly worse. The skin eruptionspread and pallor, with cyanosis, became extreme. The extremities were clammy
18Daniels, W. B.: The Cause of Death in Meningococcic Infection: AnAnalysis of 300 Fatal Cases. Am J. Med. 8: 468-473, April 1950.
19Thomas, H. M., Jr.: The Treatment of Fulminating MeningococcicInfections. Bull. U.S. Army M. Dept. No. 73, pp. 78-84, February 1944.
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and there was evidence of marked shock. A culture of bloodwas positive for meningococci. Stained films of blood from the fingertip showeddiplococci within the leukocytes; smears from punctured purpuric skin lesionsrevealed gram-negative diplococci. The patient died in shock 30 hours afteradmission.
Necropsy showed no adrenal hemorrhage or evidence ofmeningitis. Petechiae were scattered over all serous surfaces. The interstitialtissues of the myocardium showed a diffuse infiltration with polymorphonuclearleukocytes.
The records of 300 of the soldiers who died as the result of meningococcalinfection between September 1940 (mobilization) and 31 December 1945 werereviewed at the Army Institute of Pathology (now the Armed Forces Institute ofPathology), Washington, D.C. (table 36). Ten percent were cases of fulminatingbacteremia without adrenal hemorrhage. Of these, 13 had no meningitis, 16 hadslight meningitis, and the autopsy record of 1 was incomplete. The averageduration of life after admission to hospital was 33 hours, ranging from 2 to 101hours. Four of these patients satisfied all the clinical criteria of theWaterhouse-Friderichsen syndrome, but at autopsy, the adrenals were notabnormal. The average duration of life in these 4 cases was 40 hours from timeof admission to hospital.
With adrenal hemorrhage-Fulminating meningococcalbacteremia with peripheral vascular failure and hemorrhage into the adrenals evident atnecropsy-the so-called Waterhouse-Friderichsen syndrome-was described first in1894 by Voelcker.20 Additional cases were later reported by theauthors whose name the syndrome bears.21 No more dramatic or catastrophicsituation requiring immediate therapy can face the physician.
From the beginning of the epidemic, patients with thissyndrome were admitted to Army hospitals. Some died before specific treatmentwas instituted. In the analysis of 300 fatal cases, it was found that in 121cases (40 percent) death was due to this form of infection. (Five additionalcases 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 thewhole series of 126 fatal cases with adrenal hemorrhage, 14 (11 percent) came tonecropsy lacking correct diagnosis. Ante mortem, these were classified asfollows: 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 hadbeen reported in the world literature before World War II.
In two published series of 214 and 182 patients withmeningococcal infection, the Waterhouse-Friderichsen syndrome occurred in 3.3and 2.2 percent, respectively.22 As noted, the records of the 300cases studied at the
20Voelcker, A. F.: Pathological Report. Abstract. MiddlesexHospital Reports, 1894. p. 279.
21(1) Waterhouse, R.: A Case of Suprarenal Apoplexy. Lancet1: 577-579, 4 Mar. 1911. (2) Friderichsen, C.: Nebennierenapoplexie bei kleinenKindern. 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-FriderichsenSyndrome) Associated With Meningococcal Septicemia; Report of Four Cases inAdults With a Review of the Literature. J. Lab. & Clin. Med. 29: 357-365,April 1944.
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Armed Forces Institute of Pathology showed that 126 (42percent) of the soldiers with adrenal hemorrhage died (table 36). More than 50instances of this syndrome were reported in the literature by U.S. Army MedicalCorps officers. This is an incomplete list as many cases were described onlybecause of unusual features, long survival period, or recovery.23
Meningitis was usually absent or extremely slight in thesepatients. In analysis of the 126 cases of fulminating bacteremia with adrenalhemorrhage, no post mortem evidence of meningitis was found in 61; in 48, themeningitis 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 ofmeningeal inflammation.
Clinical course-As with other meningococcal infections,prodromal respiratory symptoms usually preceded the onset. These were followedby general aching, painful joints, headache, weakness, nausea, vomiting, chills,and fever. Within a few hours there was a dramatic, sudden change, with thedevelopment of apprehension, restlessness, and often an initial delirium. At alater stage, there were frequent lucid intervals. A previously insignificantrash suddenly became widespread, purpuric, and ecchymotic, and often coveredtwo-thirds of the body. The conjunctivas and buccal mucous membranes showedhemorrhages. As a rule, there were no signs of involvement of the meninges,but meningitis, usually of mild degree, might be present. Cyanosis, low bloodpressure, rapid, thready or imperceptible pulse, cold, wet extremities, and allevidences of extreme shock supervened. Anuria with retention of nitrogen wasusual. 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, theaverage 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 1? hours before admission to hospital at 5 p.m. on 17 April1943. 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 BilateralAdrenal Hemorrhage (Waterhouse-Friderichsen Syndrome): Report of TwoCases. J. Tennessee M.A. 36: 464-467, December 1943. (3) Marangoni, B. A., andD'Agati, V. C., Hepatorenal Failure in the Waterhouse-Friderichsen Syndrome; Clinico-Pathologic Observations in Two Cases With Prolonged SurvivalPeriods. 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.: MeningococcicMeningitis With Waterhouse-Friderichsen Syndrome. Report of a Case WithRecovery. [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; AReport 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 WithEspecial 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 anirrational mental state had developed. Because of obvious meningococcalbacteremia, 4 gm. of sodium sulfadiazine was given parenterally. By 5 a.m. on18 April, he was stuporous, cyanotic, cold, and in collapse, with a pulse rateof 160 and blood pressure of 70 systolic and 35 diastolic. In spite of largedoses of sulfadiazine, adrenal cortical extract, dextrose, sodium chloride andplasma, the purpuric rash spread and large areas of ecchymosis developed (fig.36). Circulatory collapse increased, the pulse became imperceptible, and theblood pressure fell to 40 systolic and 0 diastolic. Coma developed. Thepatient died, in pulmonary edema, 36 hours after admission and 26 hours afterthe institution of specific therapy. There had been no clinical evidence ofmeningitis and the patient's condition did not warrant spinal puncture. Thecerebrospinal fluid at autopsy contained two cells and was sterile. Cultures of the blood during life containedmeningococci, andmany micro-organisms were seen in leukocytes in smears of the peripheral bloodand of purpuric lesions of the skin. Chemical analyses of the blood wereas follows: Nonprotein nitrogen 75, creatinine 1.7, chlorides 478, sugar 126,sulfadiazine 20 mg. per 100 cubic centimeters. Autopsy revealed massivehemorrhage in both adrenals and no evidence of meningitis.
Waterhouse-Friderichsen syndrome.-Theanalysis shown intable 37 suggests that the grade of adrenal hemorrhage has a direct relationshipto duration of life. There is, however, ample evidence that shock andcirculatory collapse incident to fulminating bacteremia may occur withoutadrenal hemorrhage. As has been stated, fulminating infection with no evidentadrenal abnormality at autopsy (case 10) can produce a clinical pictureidentical with the classical Waterhouse-Friderichsen syndrome. (See also table36.) Profound injury to other organs as a result of toxemia and widespreadhemorrhage, frequently with marked cellular infiltration of the myocardium,
255
might well be the sole cause of death. Marangoni and D'Agati,25following observation of two patients with long survival periods (80 and 88hours), have expressed the opinion that there are two distinct stages in theWaterhouse-Friderichsen syndrome: First, the phase of profound shock andcirculatory collapse; if this is survived, the second, or hepatorenal, phasebegins. Clinically, it is characterized by marked oliguria with azotemia, andpathologically, by severe central necrosis of the liver associated with changesin the glomeruli and tubules of the kidney. A number of observers26 believethat circulatory collapse in the Waterhouse-Friderichsen syndrome is primarilythe result of widespread hemorrhages and changes in tissue, rather than ofadrenal insufficiency secondary to hemorrhage into these glands. It is pointedout that (1) in this condition death requires but a few hours, whereasadrenalectomized animals live for several days; (2) classical clinicalmanifestations of the Waterhouse-Friderichsen syndrome can occur in patientswith fulminating bacteremia without abnormality of the adrenals at necropsy; (3)conversely, among the 126 patients found to have had adrenal hemorrhage atnecropsy, in 5 the clinical manifestations were not those of the Waterhouse-Friderichsen syndrome27 (table36); (4) some recovered patients had been given no adrenocortical hormone; and(5) in patients whorecovered, the discontinuation of adrenocortical hormone after a few days didnot lead to a recurrence of symptoms. If there were adrenal insufficiencysecondary to hemorrhagic destruction of the adrenals in these cases, suchtemporary therapy would scarcely have been curative.
Accordingly, although the severity of adrenal hemorrhageappears in direct correlation with the length of life in the series of fatalcases shown in table 37, it cannot be assumed that there is a direct causalrelation between them. The severity of the adrenal lesion may be regarded ratheras an index of the severity of the whole pathological process, in which itoccurs as an end result.
The Waterhouse-Friderichsen syndrome before the development of sulfonamideswas invariably fatal. In 1945, Weinberg and McGavack collected from theliterature 11 instances of recovery and reported an additional case withrecovery.28 Thirteen other patients who recovered have been eitherArmy personnel or cases observed by the author.29 Undoubtedly, anumber
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 PurpuraWith Adrenal Hemorrhage in Adult (Waterhouse-Friderichsen Syndrome); ADiscussion of the Role Played by the Adrenal Gland in the Production of theSyndrome; Report of Two Adult Cases. J.A.M.A. 125: 884-890, 29July 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 CasesWith No Deaths. New England J. Med. 230: 452-455, 13 Apr. 1944.
256
of additional cases were not reported. Probably some of therecovered patients, although clinically examples of the Waterhouse-Friderichsensyndrome, actually had fulminating bacteremia without adrenal hemorrhage, butwhen a patient has recovered, there is no way to ascertain the nature orlocation or extent of tissue damage that was associated with the clinicalsyndrome.
Grade of hemorrhage | Number of cases | Percent |
| Number of hours from admission to death | ||
Average | Maximum | Minimum | ||||
Mild | 21 | 16.7 | 20 | 48 | 120 | 1? |
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 |
|
| 126 | 100.0 | 118 | 24 | 120 | 1/6 |
MENINGOCOCCAL MENINGITIS
Although it was clearly demonstrated in many patients thatmeningococcemia preceded the onset of meningitis, the commonest type ofmeningococcal infection in all Army installations was that exemplified by case12. Here, the results of meningeal involvement were so dramatic as to overshadowcompletely those of bacteremia. Bacteremia and meningitis set in almostsimultaneously.
Case 12-A soldier, aged 20, was admitted in violentdelirium. The history obtained after the patient had improved indicated thathe had been perfectly well until the evening of the day before admission, whensevere 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 ofadmission he lost consciousness and regained it only after 12 hours of treatmentin the hospital. Examination revealed a gravely ill patient, who had many smallerythematous macules scattered over the trunk and extremities. Several of thelesions were hemorrhagic. There was pronounced rigidity of the neck, positiveKernig's and Brudzinski's signs, and slight weakness of the right side of theface. The leukocytes numbered 18,800 per cubic millimeter with 80 percentpolymorphonuclear cells. Culture of the blood was later reported as sterile; thespinal fluid showed 9,900 leukocytes per cubic centimeter, of which 99 percentwere polymorphonuclear cells. Gram-negative intracellular diplococci were seenon 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 that144 (48 percent) were classified as dying of meningitis (table 36). Only
257
6 of these patients came to necropsy without correctdiagnosis, as follows: No diagnosis, 2; endemic typhus, 1; malaria, 1;pachymeningitis, 1; and psychosis, 1. It is of interest that only 26 of the 144patients lived 96 hours or longer after admission to hospital. The averageduration 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 meningitisitself, before the use of sulfonamides, rarely killed in so short a period, onemight reasonably expect other lesions due to the meningococcal infection to playsome 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. Certainlesions 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 |
|
| 62 |
A pressure cone was noted 4 times, myocarditis 11 times, andpneumonia 26 times. Encephalitis was found in 11 cases, its occurrenceindicating an organic basis for the changes in personality occasionally reportedin patients who recover from meningitis. It seems probable that the majoritydied of the concomitant bacteremia with toxemia or some complication.
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 |
|
| 118 | 100 | 113 | 36 | 95 | 1 |
258
The duration of life in relation to severity of meningitis in the patientswho 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 averageof 15 hours earlier than those classified as severe on the basis of spinal fluidand autopsy findings. This is additional evidence that these patients died frombacteremia before the meningitis had reached severe proportions.
Among the 144cases of meningitis studied at the Armed Forces Institute of Pathology, thecause of death of the 26 patients who lived longer than 96 hours is shown, asfollows:
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 diedon the 5th day of illness, 3 on the 7th, 2 on the 8th, 3 on the 9th, 2 on the10th, 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 ofmeningitis alone (1 patient was treated inadequately beginning on the 7th day ofdisease, and sulfonamides were stopped in 1 after good response because ofassumed drug fever). Three patients died of myocarditis, brain abscess due to Neisseriaintracellularis, and pulmonary infarction after recovery from meningitis. Itwill be noted that there was no instance of chronic basilar meningitis or ofhydrocephalus, the common sequelae of meningococcal meningitis in the past.
COMPLICATIONS
In the various series of cases of meningococcal meningitisreported during World War II, complications of the disease occurred inapproximately 10 percent. The most common were transient paralyses of thefourth, sixth, seventh, and eighth cranial nerves. Herpes zoster involving thetrigeminal nerve appeared in one patient. Aside from occasional residual nervedeafness and a rare instance of persistent diplopia, these lesions clearedcompletely with recovery. Paralysis of the serratus anterior was reported.30
In fulminating bacteremia, electrocardiograms were rarely made because of thecritical condition of the patient and the emphasis placed on needed therapy.However, two instances of changing electrocardiograms with T-wave inversions andabnormalities in the S-T segment have been de-
30See footnote 14, p. 244.
259
scribed.31 Both patients recovered. Sudden andunexpecteddeath from myocarditis occurred in one patient after apparent recovery frommeningitis. In this case, Holman reported marked degenerative changesthroughout one-third of the myocardium at necropsy. Myocarditis of significantgrade 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 osteoperiostitishave each been noted in published reports.
Spontaneous glycosuria at onset was reported as occurring inone-third of 26 patients with meningococcal meningitis,32 but rarely among Armypersonnel during the Second World War.33 It may be accompanied byketosis, hyperglycemia, and diminished sugar tolerance. Coma with glycosuria andketosis at the onset of meningitis might lead to the erroneous diagnosis ofdiabetic acidosis.
In meningococcemia, inflammatory joint affections occurred infrom one-third to one-half of the cases. These were usually simple inflammatoryreactions but occasionally effusion into the joint, and rarely pyarthrosisdeveloped. The latter required aspiration, but surgical drainage was notnecessary in any reported case during the Second World War. Residual jointstiffness, persisting for some weeks after recovery, was noted.34
Some of the ecchymotic skin lesions ulcerated, but sloughingof large ecchymotic lesions rarely occurred. These were slow to heal. In almostall fatal cases of bacteremia and many of meningitis, pulmonary edema andeffusion 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 reportedduring World War II.35 This followed 5 weeks after a classical attack of primaryatypical pneumonia. The patient developed severe, diffuse pneumonia with highfever. The sputum on two occasions contained about 75 percent meningococci(proved bacteriologically and serologically) and 25 percent hemolyticstreptococci, group A. The course of the disease, ending in recovery, wasapparently not influenced by the adequate doses of sulfadiazine given. Thepatient 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 ClinicalCharacteristics. 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 amongU.S. Army personnel during World War II.36 All occurred during the period ofincreased incidence of meningococcal infection, and only one was associated withbacteremia or meningitis. The response of all these patients to therapy withsulfadiazine was excellent.
LABORATORY DIAGNOSIS
In meningococcal infections, the assistance of the laboratoryin arriving at the correct etiology and confirming the clinical diagnosis wasdirectly proportional to the adequacy of methods of culture, the care with whichstudies were carried out, and the cooperation between the wards and thelaboratory. At the beginning of the epidemic, laboratory officers in the Armyhospital, like the clinicians, had had relatively little experience in the studyof this disease. The standard operating procedure consisted of directing theward nurse or attendant to send the tubes of cerebrospinal fluid obtained fromthe patient to the laboratory for examination. The laboratory, as a rule, madeno great speed in examining this fluid or inoculating media. Under theseconditions, the percentage of positive cultures and of bacteriologicallyconfirmed diagnoses was not enviable. As the number of cases rose, however,there was rapid improvement in this situation in most hospitals, with bettercoordination between the clinician and the laboratory. In some hospitals, arepresentative of the laboratory came immediately to the bedside when a lumbarpuncture was to be done. Inoculations with blood and cerebrospinal fluid weremade directly into previously warmed culture media, and these were promptlyincubated in proper atmosphere. The improvement in results was striking. Withthis method, it was possible to achieve bacteriological confirmation in 95percent of the patients who had not received treatment with sulfonamides priorto obtaining material for smear or culture.37
The micro-organisms isolated from patients during the outbreak have, as isusual in these infections, been predominantly type I. The distribution of typesof meningococci recovered by the Fourth Service Command Laboratory from 1,436known cases of meningococcal infections from August 1942 to December 194538 isshown in table 39.
In the majority of patients ill with the Waterhouse-Friderichsen syndrome orwith fulminating sepsis, careful examination of films of blood taken from thefingers 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.: MeningococcalConjunctivitis; 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.: MeningococcicConjunctivitis. J.A.M.A. 124: 703, 11 Mar. 1944. (4) Thygeson, P.: PrimaryMeningococcic 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 somepatients, smears showed bacteria at a time when culture of the blood wassterile. Bernhard and Jordan40 compared the results of concomitant examinationof smears and cultures of material from purpuric lesions with cultures of theblood and of the spinal fluid in 40 patients. The smears from the purpuriclesions were positive in 68 percent and the cultures in 88 percent, while thecultures of the blood and cerebrospinal fluid were positive in 75 and 82percent, respectively.
Types of meningococci | Number | Percent |
Group I | 1,288 | 89.7 |
Group II | 27 | 1.9 |
Group IIa | 108 | 7.5 |
Polyvalent1 | 13 | .9 |
|
| 1,436 | 100.0 |
1Includes micro-organisms with the biological characteristics ofmeningococci that agglutinate in polyvalent anti-meningococcal serum but not ingroup-specific serum.
The importance of careful bacteriological studies should notbe underestimated. However, during an outbreak of meningococcal infection, thediagnosis of bacteremia can and must be made on clinical grounds long beforethere is any report of culture of the blood if one hopes to prevent meningitisor fulminant infection. The finding of diplococci in leukocytes in smears ofblood or smears from purpuric lesions is of importance, but in patients withrash the clinical impression of a trained observer should be relied upon ininstituting treatment. Since, during the epidemic, 92 percent of the patientswith meningococcal meningitis showed a characteristic rash,41 a high degree ofdiagnostic accuracy could be attained on purely clinical grounds. In neithermeningitis nor bacteremia should initiation of treatment be delayed by waitingfor laboratory reports.
TREATMENT
At the beginning of the epidemic, although Circular LetterNo. 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 publishedreports
39Tompkins, V. N.: The Diagnostic Value of Smears From Purpuric Lesions ofthe Skin in Meningococcic Disease. J.A.M.A. 123: 31-32, 4 Sept. 1943.
40Bernhard, W. G., and Jordan, A. C.: Diagnosis of MeningococcicInfections, 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 withmeningitis, to difficulties in obtaining the drug, and to the inability of someinstallations to acquire the sodium salt of sulfadiazine. Early cases weretreated with sulfanilamide, sulfapyridine, sulfathiazole, or sulfadiazine aloneor in conjunction with antisera or antitoxin. Thomas,42 of the FourthService Command, reported a mortality of 20 percent in 40 cases treated duringthe first week of the epidemic (the week ending 1 January 1943) and 8.8 percentin 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 theresult of a decrease in virulence of the micro-organism. While 108 soldiers werebeing treated in one Army hospital in the Fourth Service Command with amortality of less than 3 percent, there were 4 deaths among 8 civilians in thesame county. The early high mortality was probably due to inexperience of themedical officers with the disease and delay in instituting treatment. Correctionof these conditions was prompt, with dramatic reduction in mortality.
Meningococcemia-The treatment of soldiers with simplemeningococcemia became relatively standardized in Army installations and washighly effective. Under clinical observation, it became obvious that those withuncomplicated meningococcemia who were treated early did not require largedoses 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 variedsomewhat at different Army hospitals. Massive dosage of sulfadiazine reachingmore than 20 gm. in the first 24 hours43 was used, with the achievement ofconcentrations in the blood of 18 to 24 mg. percent. Among 134 patients sotreated, complications of therapy (86 percent of which were renal) occurred in28 percent. At another hospital, a loading dose (of sodium sulfadiazine) of 0.1gm. per kilogram of body weight was given intravenously in 1,000 cc. of isotonicsodium chloride solution. Following this, one-half the initial dose was givenparenterally 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, grosshematuria occurred in 15 percent and anuria in 6.6 percent of the patients. Whendosage was reduced to 0.05 gm., followed by 0.025 gm. per kilogram of bodyweight 4 hours later, and the latter dose repeated every 8 hours thereafter, norenal complications were noted.44 With this dosage, the averageconcentrations of sulfadiazine in the blood and spinal fluid were 8.5 and 6.5mg. percent, respectively. In
42See footnote 14 (2), p. 244.
43(1) Ochs, L., Jr., and Peters, M.: Management ofMeningococcic Infections at the Station Hospital, Fort Benning, Ga. War Med. 4:599-605, December 1943. (2) Kaplan, G.: Massive-Dose Sulfadiazine Therapy inMeningococcus Meningitis. New York State J. Med. 43: 2210-2212, 15 Nov. 1943.
44See footnote 13, p. 244.
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this connection, it is of interest that Dowling and Lepper45 reported that no urinary calculi appeared in their patients with pneumoniawhen the concentration in the blood did not exceed 9.2 mg. percent.
Ochs and Peters,46 while treating patients with an initial intravenous dose of10 gm. of sodium sulfadiazine in 5 percent solution, encountered renalcomplications in 5 of 23 patients. Later, 2,000 cc. of 1/6 molarsodium lactate was given intravenously before administering the sulfadiazinewith the complete elimination of renal complications.
Drug of choice-Sulfanilamide, sulfathiazole, and sulfapyridine were usedearly in the epidemic because of the scarcity of sulfadiazine. The latter becamethe standard drug for treatment because of its efficiency and relatively lowtoxicity. Sulfanilamide retained an important place in therapy until penicillinbecame available. When gross hematuria, renal colic, oliguria, or anuriadeveloped during sulfadiazine therapy, sulfanilamide was an effectivesubstitute, since its use was not associated with the deposition of acetylatedmaterial in the urinary tract.
In analyzing the records of 300 of the patients who died of meningococcalinfection,47 only 3 instances of death as a result of sulfonamide medicationwere found. All of these were due to renal complications caused by therapy.Since it can be assumed that virtually all patients who received any specifictreatment were given sulfonamides, the case fatality ratio from complications oftherapy with sulfonamides in the 13,922 cases treated during the Second WorldWar was estimated to be about 0.04 percent (the total mortality from renalcomplications). This is astounding when one considers that massive dosage wasadministered to very ill, and often seriously dehydrated, patients. No deathfrom 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 ofmeningococcal infection.48 It has the virtue of greater solubilityand, in consequence, rarely causes renal complications. If extensive trialsjustify the promise of this drug, it may be preferred to sulfadiazine. Itsdosage is similar to that of sulfadiazine.
Fulminating infections-The treatment of soldiers with fulminatingbacteremia and with the Waterhouse-Friderichsen syndrome may be consideredtogether as, in general, their treatment was identical. Among the 300 deathsanalyzed, 156 patients died of fulminating meningococcal bacteremia, 126 withand 30 without adrenal hemorrhage (table 36). Of these, 30 had
45Dowling, H. F., and Lepper, M. H.: Toxic Reactions Following TherapyWith Sulfapyridine, Sulfathiazole and Sulfadiazine. J.A.M.A. 121: 1190-1194,10 Apr. 1943.
46See footnote 43 (1), p. 262.
47See 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 NewSulfonamide (Gantrisin). Arch. Int. Med. 85: 259-264, February 1950.
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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. Therecords concerning antiserum, antitoxin, and extracts of adrenal cortex were notadequate for analysis.
Thomas,49 early in the epidemic, stated that the three majorobjectives of treatment were to combat bacteremia, toxemia, and shock. Headvocated 3 to 5 gm. of sodium sulfadiazine intravenously with 1,000 cc. of 1/6molar sodium lactate and the maintenance of a concentration of sulfadiazine inthe blood of 10 to 15 mg. percent. Intravenous administration of 20,000 units ofmeningococcal antitoxin was advised as an initial dose, followed by the sameamount every 4 hours until 100,000 units had been given. Plasma, isotonic sodiumchloride, and aqueous extract of adrenal cortex in large doses (30 cc.) atfrequent intervals was advocated. In instances where pulmonary edema supervened,it was suggested that 500 cc. of 1.5 percent solution of sodium chloridecontaining 25 gm. of dextrose be given. A goodly number of patients were treatedby a regimen of this type with certain variations. Many received no antitoxinand others either insignificant amounts of adrenocortical extract or none. Inthe treatment of 13 recovered cases of the Waterhouse-Friderichsen syndrome, theonly constant and recurrent features of therapy were the administration ofsulfadiazine in adequate amounts, intravenous isotonic sodium chloride anddextrose, and oxygen. Penicillin, adrenocortical extract, desoxycorticosteroneacetate, plasma, adrenalin, adrenalin in oil, meningococcal antitoxin, orantimeningococcal serum were given in some. It would appear from the descriptionof treatment that recovery occurred in any case where early adequateantibacterial therapy and proper antishock measures were carefully carried out.The major objective was very early recognition of bacteremia with prompttreatment before the infection became fulminating.
Cortisone, which has become available since World War II,offers an additional potent agent in combating the adrenal insufficiencyincident to adrenal hemorrhage. Too few instances of its use have been recordedclearly to evaluate its place in therapy. However, its use in the Waterhouse-Friderichsen syndrome with adrenal hemorrhage is rational, in view ofits proved value in critical episodes occurring in Addison's disease withcomplicating infection. The number of circulating eosinophils should bedetermined to assist in differentiating this syndrome from fulminatingbacteremia without adrenal hemorrhage; the former may show more, and the latterless, than 50 cells per cubic millimeter. Therapy with cortisone should consistof an additional dose of 200 mg. divided into four 50 mg. doses injectedintramuscularly 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 AdrenalCortical Insufficiency. Veterans Admin. Tech. Bull. TB 10-62, pp. 1-23, 30 Mar.1950.
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dosage may be guided by following the level of circulatingeosinophils. These should be kept at 15 per cubic millimeter or below.51This will probably require 50 mg. or more every 6 hours for the first 2 days and25 mg. at thesame interval for the next 3 days. Thereafter, the dose should be graduallyreduced and discontinued over the period of 1 week.
Potent new pressor agents have become available since theSecond World War. Norepinephrine by continuous intravenous infusion has provedhelpful in maintaining blood pressure and combating shock in two instances ofthe Waterhouse-Friderichsen syndrome.52
Serum
In meningitis, antimeningococcal serum in conjunction withsulfadiazine was employed intravenously and occasionally intrathecally in somehospitals.53 Serum was often given to patients who had not shown anadequate response to therapy with sulfonamide 36 to 48 hours after theinitiation of treatment. It became rapidly apparent, however, that patientstreated with sulfonamides alone fared as well as those to whom serum was givenin addition.54
Antitoxin
Meningococcal antitoxin, originally advocated by Ferry55and used extensively by Hoyne,56 was given to a few patientswith meningitis, especially those with fulminating infections. In the earlyperiod of the epidemic, antitoxin was employed in some installations,particularly those in the Fourth Service Command, in patients ill withfulminating bacteremia. At 10 station hospitals, 134 patients were treated withthis material. It was thought by Thomas57 that benefit was observedin 56 of these patients. In retrospect, it appears that mortality in cases offulminating bacteremia treated with antitoxin is not lower than in cases treatedwith sulfadiazine alone. The excellent therapeutic results with sulfadiazinealone led the Council on Pharmacy and Chemistry of the American MedicalAssociation
51Faloon, W. W., Reynolds, R. W., and Beebe, R. T.: The Useof 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) Unpublishedobservations of the author.
53(1) See footnote 43 (1), p. 262. (2) Borden, W. B., andStrong, 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 StationHospital, 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 Testson Guinea Pigs. J. Immunol. 23: 315-324, October 1932.
56Hoyne, A. L.: Intravenous Treatment of Meningococcic Meningitis WithMeningococcus Antitoxin. J.A.M.A. 107: 478-481, 15 Aug. 1936.
57See footnote 19, p. 251.
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to remove antimeningococcal serum and meningococcal antitoxin from theaccepted preparations listed in "New and Nonofficial Remedies."58
Penicillin
During the early period of the war, penicillin was in itsexperimental stage and not in sufficient production for use in treatment ofmeningococcal infections. Beginning late in 1943, small amounts first becameavailable at some Army hospitals for the treatment of patients with thisinfection. TB MED (War Department Technical Bulletin) 9, dated 12 February 1944,first advocated the use of penicillin in conjunction with sulfadiazine inpatients with fulminating infection and in those who failed to respond to, orshould not receive, sulfadiazine. Therapy both intrathecally and by the usualparenteral routes was advised in meningitis.
There were relatively few published reports on the use ofpenicillin in meningococcal infections. Kolmer59 reported that in 96collected cases treated by intravenous, intramuscular, and intrathecalinjections, the mortality was about 8.5 percent. Of these 96 cases, 76 weredescribed by Drs. D. H. Rosenberg and P. A. Arling, who stated that 75recovered, a death rate of 1.3 percent. This is comparable to the mortality insimilar series of patients treated with sulfadiazine.60 Although thereports from the Army61 do not represent studies of the use of this antibioticin large numbers of patients, they quite clearly indicate its place in therapy.
Rammelkamp and Keefer62 found no penicillin inthe cerebrospinal fluid after constant intravenous administration over a 24-hourperiod, and as a result of their observations, the intrathecal together withother parenteral routes have been used in patients with meningitis. Rosenbergand Sylvester63 reported the finding of penicillin in the spinalfluid in patients with meningitis, and Price and Hodges reported the cure offour patients, following intramuscular and intravenous administrations alone.
58Status of Antimeningococcic Serum and MeningococcusAntitoxin; Report ofthe 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 ofSulfadiazine 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 ofPenicillin 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, 27Mar. 1945, subject: Transmittal of Report [Penicillin Studies]. (4) Rammelkamp,C. H., and Kirby, W. M. M.: Factors Determining the Dosage of Penicillin in theTreatment of Infections. Bull. New York Acad. Med. 21: 656-672, December 1945.(5) Dotterer, J. E.: A Fatal Case of Meningococcal Meningitis Treated WithSulfadiazine and Penicillin. ETO Med. Bull. 31: 36-38, May-June 145. (6) LoVetere, A. A.: Penicillin's Application to Meningitis, Meningococcemia andSepticemia. Kentucky M.J. 43: 24-27, January 1945. (7) Price, A. H., and Hodges,J. J.: Treatment of Meningitis With Penicillin Injected Intravenously andIntramuscularly. New York State J. Med. 44: 2012-2014, 15 Sept. 1944.
62Rammelkamp, C. H., and Keefer, C. S.: The Absorption, Excretion, andDistribution of Penicillin. J. Clin. Investigation 22: 425-437, May 1943.
63Rosenberg, D. H., and Sylvester, J. C.: The Excretion ofPenicillin in the Spinal Fluid in Meningitis. Science 100: 132-133,11 Aug. 1944.
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Studies were undertaken at the Regional Hospital at Fort Bragg, N.C., toobtain further information on the most efficient mode of therapy. In 20 patientswith primary or secondary syphilis given 20,000 to 40,000 units of penicillinevery 3 hours from 1 to 8 days, no penicillin appeared in the spinal fluid. Insix patients with meningococcemia uncomplicated by meningitis, 25,000 to 40,000units of penicillin were given at the same interval. Twelve specimens of spinalfluid obtained 8 and 24 hours after institution of therapy and on the fifth andninth days of treatment showed no penicillin. One patient with tuberculousmeningitis showed a trace of penicillin at the 11th hour after 200,000 units ofpenicillin, and none at the 23d hour. Another patient with the same disease wasgiven comparable amounts and showed no penicillin in the spinal fluid at 18hours, and only a trace at 23 hours when the blood level was 0.4 units per cubiccentimeter. Two patients with meningococcal meningitis were treatedintramuscularly only. One showed a measurable amount of penicillin in the spinalfluid only at 24 hours, and in the other assays revealed none at 1?, 2?, 10, and 16 hours after treatment was begun. Both patientsshowed initial improvement but relapsed after 24 hours. In one, culture of thespinal fluid remained positive for meningococci. Both patients recoveredpromptly when sulfadiazine was administered. In seven other patients withmeningococcal meningitis, penicillin was administered (intramuscularly) in largedoses in the early part of their illness prior to beginning the usual therapywith sulfadiazine. The range of penicillin in the spinal fluid was from 0 to 0.5units per cubic centimeter, 1? to 27 hours after treatment wasstarted. It is clear that, without intrathecal administration, penicillin maypenetrate into the spinal fluid, but irregularly and in low concentrations. Thiswork did not invalidate reported recoveries, but it indicated the hazards ofmodes of therapy that exclude the intrathecal route.
It was demonstrated64 that, following the administration of10,000 units of penicillin intrathecally, from 4 to 20 units per cubiccentimeter were still present in the spinal fluid 8 hours later and from 0.08 to0.31 units after 24 hours.
In a study65 of comparable cases ofuncomplicatedmeningococcal bacteremia, 18 were treated with penicillin and 12 withsulfadiazine. All patients recovered and were free of symptoms within 24 hours.Those treated with penicillin had normal temperatures at 12 hours while, in thesulfadiazine group, the temperatures remained elevated for 24 hours. The rashfaded in both groups in 2 days. Penicillin was apparently more effective thansulfadiazine in rapidly controlling symptoms in this group. However, itsinconstant appearance in the spinal fluid after intramuscular injection made ita less desirable mode of therapy, since bacteriostatic levels of penicillin in
64See footnote 61 (2), p. 266.
65See footnote 61 (1), p. 266.
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the spinal fluid could not be depended upon to prevent meningitis, or tocontrol early meningitis if it occurred in these cases.
In eight patients with meningococcal meningitis, alternatecases were treated either with sulfadiazine in the usual dosage, or with 25,000to 40,000 units of penicillin every 3 hours intramuscularly and 10,000 unitsintrathecally daily for 3 days.66 All patients recovered. Those treated withsulfadiazine developed normal temperatures more rapidly, became free of headacheand meningeal manifestations sooner, and were out of bed earlier than those whoreceived penicillin. One patient who received intrathecally 10,000 units of adark-colored penicillin in 10 cc. of normal saline promptly developed extremeheadache, stiffness of the neck, opisthotonos, and increasing fever associatedwith a rise of leukocytes in the spinal fluid from a few hundred to 50,000within a few hours. It became necessary to stop the intrathecal penicillin andresort to sulfadiazine therapy. One other patient given the same dark-coloredpenicillin 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 penicillinintrathecally were noted. In one, following a large cisternal dose, hemorrhagein the medulla was found at necropsy.67 Several instances of pleocytosis andactual hemorrhage have attended doses in excess of 10,000 units.68
Meningitis developed in two patients69 while on intramuscular penicillin. Onewas being treated for meningococcemia and one for abdominal wounds. From thehistory of the first patient it is possible that meningitis already existed inspite of a normal spinal fluid.
In rare instances, penicillin was effective when sulfadiazinefailed. A native of New Guinea (at Aitape) was seen at the 30th EvacuationHospital by the author and Col. Vernon J. Erkenbeck, MC, in a moribund conditionwith meningococcal meningitis. He had been under treatment with massive dosesof sulfadiazine for 5 days, and concentrations of sulfadiazine in blood andspinal fluid were high. In spite of this, there was extreme opisthotonos andhyperpnea, and death seemed imminent. Penicillin intrathecally and intravenouslyproduced rapid improvement and ultimate recovery.
Since World War II, it has been shown that satisfactory cerebrospinal fluidlevels of penicillin can be attained by the intramuscular route alone if enoughpenicillin is given. Dowling and his coworkers70 found that 1 million units ofaqueous penicillin intramuscularly every 2 hours resulted in adequateconcentrations in the cerebrospinal fluid.
66See footnote 52, (2), p. 265.
67See footnote 18, p. 251.
68Annual Report, Professional Service Division, Medical ConsultationService, Office of the Chief Surgeon, Headquarters, European Theater ofOperations, 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.: SpecificTherapy of Bacterial Infections of the Central Nervous System. J.A.M.A. 139:755-758, 19 Mar. 1949.
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It becomes clear that sulfadiazine has proved to be the drugof choice in the mild or average instance of meningococcal infection. Penicillinshould not be used as a routine measure. It should be given in massive dosagein conjunction with sulfadiazine in fulminating bacteremia or meningitis, and toreplace 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 discontinuingsulfadiazine.
Therapy With Other Drugs
Certain new antibiotics that have becomeavailable since World War II are highly effective in the treatment of bothbacteremia and meningitis. Aureomycin (chlortetracycline),71 chloramphenicol,72 andTerramycin (oxytetracycline)73 have been used successfully in thetreatment of small groups of patients. Should a patient demonstrate clear-cutevidence of sensitivity to the sulfonamides and penicillin, one of these otherdrugs can be used with confidence.
Adjuvant Therapy
Fluid balance-Patients admitted with meningitis, orseverely ill with bacteremia, are almost invariably dehydrated, so that carefulattention to fluid balance is necessary for its own sake as well as to preventthe renal complications of sulfonamide therapy. Urine flow should not be lessthan 1,200 cc. per day. Attention to this detail of therapy was often painfullylearned by medical officers when gross hematuria or oliguria developed duringadministration of sulfadiazine. It was soon found that the use of sodiumsulfadiazine in 5 percent solution, as suggested in Circular Letter No. 170, wasfraught with danger unless a large amount of fluid had preceded treatment. Whenthe patient's condition permits slight delay, Ochs' recommendation74 of 2,000cc. of 1/6 molar sodium lactate prior to sulfadiazine may be wise. He alsoadvocated using the same quantity of this solution following the drug and themaintenance of an alkaline urine. However, renal complications were rare whenthe initial dose of sodium sulfadiazine was administered in 1,000 cc. ofisotonic sodium chloride or the same volume of 1/6 molar sodiumlactate. In some hospitals, the major portion of the intake of fluid was administered to comatose patients by Levin tube and in others by aparenteral 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 theTreatment of MeningococcalMeningitis. 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.
74Seefootnote 43 (1), p. 262.
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Sedation.-Restlessness is common and when mild can be disregarded or allayedby simple sedatives, such as the barbiturates. Great restlessness and almostmaniacal delirium occur frequently with meningitis, often making lumbar punctureor intravenous treatments difficult or impossible. Paraldehyde, 16 cc., provedthe most effective sedative. Intravenous barbiturates are occasionallynecessary, though undesirable. Morphine, though considered hazardous by somebecause of its depressant effect on respiration, is at times essential. Extremerestlessness and even delirium can often be relieved by lumbar puncture with thereduction of pressure of the spinal fluid. Catheterization with relief ofbladder distention often quiets a restless, thrashing patient who is hard tokeep 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 ofdelirium. Freedom to thrash about in bed for a few minutes without restraint isoften followed by quiet and relaxation. In fulminating bacteremia, morphineappears to be the most effective drug for restlessness and is indicated if shocksupervenes.
Lumbar puncture-Initial diagnosis may be the only occasion for the useof this procedure in patients who show prompt and continued improvementfollowing treatment. As a therapeutic procedure for reduction of intracranialpressure, lumbar puncture is of great importance when headache is excessive,restlessness intractable, coma deepening, and hyperpnea, Biot's breathing, orother respiratory abnormalities are marked. Striking improvement has been notedin patients following reduction in intracranial pressure.
Complete recovery with return to full duty after an average hospitalizationfor 1 month and a similar period on sick furlough or reconditioning has beenusual. Data as to actual days lost are not available. In mild and uncomplicatedbacteremia, many soldiers have been returned to full duty within 2 weeks fromonset.
Preliminary tabulations of individual medical records, during1942-45, indicate that 105 U.S. Army personnel were separated for disability dueto meningococcal infection.
PATHOLOGICAL FINDINGS
The vast amount of pathological material available at the Armed ForcesInstitute of Pathology is being carefully studied by the medical officersassigned there. The major lesions disclosed at autopsy in those patients whodied of meningitis were inflammatory changes in the leptomeninges of the brainand cord, usually without evidence of organization of exudate. True encephalitiswas present in relatively few cases (p. 257). The pathological findings inpatients with meningitis who died early were comparable with those who died ofbacteremia.
Of the 156 patients who died from fulminating bacteremia (table 36), 126showed hemorrhage in the adrenal glands ranging from mild extravasa-
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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 othersthe meningeal inflammation was minimal. Pulmonary edema was striking in almostall and gross hemorrhage into the lung was not unusual. There were smalleffusions into one or both pleural cavities in about half of the patients.Widespread focal hemorrhages were scattered over the serous surfaces in mostcases and sometimes involved the myocardium. Interstitial myocarditis,occasionally severe but usually of mild focal character, occurred in 28 of the126 patients with adrenal hemorrhage. Renal changes indicative of shock wereobserved 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 wasdeath the result of renal lesions due to sulfonamides.
TREATMENT OF MENINGOCOCCAL INFECTIONS
It seems worthwhile to outline briefly recommendations for treatment based onthe published reports and the experience of many medical officers with about14,000 patients ill with meningococcal infection during World War II, and onadvances in therapy since the war ended.
Acute or chronic bacteremia-Sulfadiazine, 4.0 gm., should be given bymouth and be followed by 1 gm. every 4 hours until fever, symptoms, and othermanifestations of infection have been absent for at least 48 hours. When thereis vomiting, comparable amounts of sodium sulfadiazine dissolved in a liter ofnormal saline solution should be administered intravenously. These dosages areusually sufficient to maintain a concentration in blood from 5 to 11 mg. per 100cc. of plasma, and as a rule prevent the development of fulminating bacteremiaor meningitis.
Fulminating bacteremia with peripheral circulatory failure-Thisis amajor medical emergency requiring immediate action and continued, constantobservation by resourceful physicians and nurses. Even though meningitis ispresent or suspected, it is of quite secondary importance, and the patientshould not be subjected to the strain of lumbar puncture.
An hourly chart of pulse, respiration, temperature, and bloodpressure is begun. The patient is placed in the shock position. Oxygen isadministered continuously to combat cyanosis. External warmth is applied. Aninfusion of sodium sulfadiazine, 0.1 gm. per kilogram of body weight dissolvedin 1,000 cc. of normal saline solution, is begun in an antecubital vein of onearm; in the other arm, an infusion of 500 cc. of 10 percent dextrose in water isbegun; 500,000 units of penicillin dissolved in 20 cc. of normal saline solutionare 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, 200mg. divided into four 50 mg. doses injected into
75See footnote 14 (2), p. 244.
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four separate sites, and (2) penicillin, 1 million unitsdivided into two 500,000-unit doses injected into two separate sites. If thesystolic 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 necessaryto maintain adequate blood pressure. This is usually about 2 to 4 μg. perminute.
Further therapy may include: (1) Plasma, or 25 gm. of concentrated humanalbumin administered in 5 percent solution, if indicated for shock; (2) sodiumsulfadiazine, 0.05 gm. per kilogram of body weight every 4 hours intravenouslyuntil the drug (approximately 1 to 1.5 gm. every 4 hours) is tolerated by theoral 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 graduallydiscontinued over the course of a week; and (5) small quantities of ginger aleor sweetened fruit juice, orally, as soon as possible amounting to 3,000 cc. offluids or more daily.
The dosage of sulfadiazine should be guided by frequent determinations ofdrug level in the blood, 15 to 20 mg. per 100 cc. being the optimum range. Fullchemotherapy should be continued for at least 4 days after the patient hasrecovered from the acute phase of his disease, counted from the first day ofnormal temperature.
After the first day, no more than 1,000 cc. of normal saline need be givendaily intravenously. Should pulmonary, sacral, or peripheral edema appear,however, the quantity of normal saline solution should be markedly reduced. Ifmarked pulmonary edema develops, 1 to 3 units of plasma or 25 to 50 gm. ofconcentrated human albumin may be administered slowly. Positive pressure oxygenmay be helpful.
If the patient is failing, hypoglycemia and hypopotassemia should beconsidered. The appropriate blood determinations should be made, and theirabnormalities corrected. An electrocardiogram might show evidence of potassiumdeficiency.
In those patients with fulminating bacteremia whose manifestations are notthose of shock, the use of plasma, norepinephrine, oxygen, and adrenocorticalcompounds should be omitted.
A count of circulating eosinophils should be performed to assist indifferentiation of the Waterhouse-Friderichsen syndrome from fulminating sepsiswithout adrenal insufficiency; the former may show more, and the latter less,than 50 cells per cubic millimeter. Cortisone dosage should be adequate tomaintain the number of eosinophils at 15 per cubic millimeter or less.
Meningitis-The potential seriousness of this conditionis such that, regardless of its severity, all patients should receive a liter ofsaline containing sodium sulfadiazine intravenously-6 gm. for a heavyweight, 5gm. for
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a mediumweight, and 4 gm. for a lightweight adult. It iswise to administer half the original dose parenterally 4 hours later, but, inconscious and cooperative patients who are not vomiting, the oral route may beused at this time. If, following this, continued parenteral therapy is needed, 2gm. of sulfadiazine dissolved in saline should be injected intravenously orsubcutaneously every 8 hours. In comatose patients, the drug may be administeredby 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 concentrationin the spinal fluid around 6 mg. per 100 cc. A concentration in blood of 6 to 10mg. is adequate.In fulminating cases, the dosage should be adjusted to maintain theconcentration in the blood between 15 and 20 mg. per 100 milliliter. In thegravely 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 2hours) should replace it. If sensitivity to both of these agents should bepresent, chloramphenicol, Aureomycin, and Terramycin are effective drugs.
DISCUSSION
The experiences of medical officers who have treatedmeningococcal infection during the Second World War have clarified and extendedknowledge of the various forms which this infection may assume. Theseobservations amply confirmed the opinion of Herrick and others in the World WarI epidemic that the disease begins as a bacteremia and, if not prevented byspontaneous resistance or therapy, involves the meninges, skin, and otherorgans, or it may be fatal in the bacteremic form.
The major contribution has been the development of a triedtherapeutic plan, which has reduced the case fatality to 4 percent in contrastto about 31 percent in World War I (table 34). In the Zone of Interior, where noproblem of evacuation existed, the case fatality was 3.9 percent compared to 4.5percent for oversea areas. The ratios for the continental United States in 1944and 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 befurther significantly reduced, unless some means can be found which will enablethe physician to recognize incipient meningococcal bacteremia during the phaseof prodromal respiratory symptoms.
