Diagnosis and management of severe infections in infants and children: a review of experiences since the introduction of sulfonamide therapy

The Journal of Pediatrics JANUARY, 1945

VOL. 26

No. 1

Original Communications DIAGNOSIS AND MANAGEMENT OF S E V E R E I N F E C T I O N S IN INFANTS AND C H I L D R E N : A R E V I E W OF E X P E R I E N C E S SINCE T H E INTRODUCTION OF SULFONAMIDE THERAPY III.

MENINGOCOCCAL

INFECTIONS

A. EXPERIENCES AT THE ST. LouIs CHILDREN'S HOSPITAL DAVID GOLDRING, M,D., AND ALEXIS F. HARTMANN, M . D P B, EXPERIENCES AT THE ST. LOUIS ISOLATION HOSPITAL

DAVID GOLDRING,M.D., RICHARD MAXWELL, M.D., AND ALEXIS F. HARTMANN, M.D.t A. E X P E R I E N C E S AT T H E ST, LOUIS CHILDREN'S HOSPITAL HIS paper presents an analysis of our experiences in managing in 77 children at the St. Louis Children's Hospital since the advent of sulfonamide chemotherapy. The years 1937-1942 represent nonepidemie years during which time only a small number o~ cases with meningocoecal infections were admitted. The years 1943-1944 represent the greatest epidemic years in this country's history. 1 The majority of the cases in this series was seen during these last two years. The contagious pavilion at the St. Louis Children's Hospital can accommodate comparatively few patients, and so most of t h e patients with merdngococcal infections were sent ~to the St. Louis Isolation Hospital A review of these eases will appear in the second half of this paper.

T meningococeal infections

ANALYSIS OF DATA A.

DISTRIBUTION

OF

dence of meningococcal

PATIENTS BETWEEN 1937 AND 1944.--The inciinfections between the years 1937 and 1942 was

*From the Department of Pediatrics, Washington University School of Medicine, and the St. ~Louis Children's l:Iospital. tFrom the Departments of Pediatrics and lYiedicint~, "Washington University School of Medicine, and the St. Louis Isolation IIospital. 1

THE JOURNAL OF PEDIATRICS CHART 1 :DISTRIBUTIONOF :PATIENTS1937 TO 1944 DURINGMONTHS GP :EACHYEAR YEAR JAN.

1937 ]938 1939 1940 1941 1942 1943 1944

FEB.

MARCH

1

1

2 2. 1

APRIL MAY

2 1

JUNE

J U L Y AUG.

SEPT,

1

OCT. NOV. DEe.

1

1

7 7 2 2 3 7

2

1 1

2 9

Y E A R JAN.

3 7

3 8

FEB.

~ARC~

1 2 2 2

1

1

1

3

1

5

1

1 1

1

APRIL MAY J U N E

JULY

1

1

1

AUG. SEPT.

OCT. NOV. DEC.

I Chart

TOTAL PATIENTS

L--Monthly and yearly incidence of cases of meningococeal infections t h e St. L o u i s C h i l d r e n ' s H o s p i t a l o v e r t h e p e r i o d 1 9 3 7 - 1 9 4 4 ,

23 26 TOTAL PATIENTS

seen

at

s p o r a d i c a n d low, f r o m two to seven p e r y e a r ( C h a r t I ) . I f we exa m i n e the n u m b e r of cases, i n the y e a r of 1943, we see t h a t e v e r y m o n t h of the y e a r c o n t r i b u t e d at least one p a t i e n t . The first six m o n t h s a n d the last monti~ o; the y e a r c o n t r i b u t e d n_ost of the patic~nts. I n 1944, the first few m o n t h s of the y e a r also c o n t r i b u t e d most of the p a t i e n t s . This p r e d i l e c t i o n f o r the first six m o n t h s of the y e a r is even more definitely i l l u s t r a t e d b y the I s o l a t i o n H o s p i t a l m a t e r i a l . B. SEX DISTRIBUTION OF CAsES.--There was a definite p r e p o n d e r a n c e of males, 50 as c o m p a r e d to 27 females, a l t h o u g h this was n o t t r u e at the I s o l a t i o n Hospital.

SEX AND AGE DISTRIBUTION NO.OF PATIENTS 12

,,[ I0

91 al 71

i1i111ill I:LE ,Fll

0-1 I-I 2-3 AGE iN YEARS Chart

II.--Age

3-4

4-5

5-6

6-F

7-8

8-9

9-10" I0-11

I 1-12 1~-13

and sex distribution of cases of meningococcal infections St. L o u i s C h i l d r e n ' s H o s p i t a l o v e r t h e p e r i o d 1 9 3 7 - 1 9 4 4 .

seen at

the

G O L D R I N G ET A L . :

SEVERE I N F E C T I O N S

IN INFANTS

AND CHILDREN

3

C. AGE DISTRIBUTION.--The disease seems to have a g r e a t e r preference in both sexes f o r the first f e w years of life (Chart I I ) . D . D A Y OF D I S E A S E W H E N T H E R A P Y W A S INSTITUTED.---Probably the most i m p o r t a n t deciding factor in the favorable outcome of a meningococeal infection is the institution, of adequate sulfonamide chemotherapy very early in the disease. The following is a table which ilhlstrates the distribution of patients with relation to the a p p a r e n t day of the disease when t h e r a p y was instituted. DAY~ ELAPSII~G BEFOR]~ TREATMENT

0to1 ] 2 3 4 5 6 7 8 9 2 weeks 3 weeks

NU)~[BER OF PATIENTS

4 28 ]1 12 7 4 1 2 0 1 2 3

Thirty-two patients entered the hospital a f t e r three days of illness and five patients a f t e r two weeks. Only six patients received some sort of sulfonamide t h e r a p y before entry into the hospital, and in most instances this t h e r a p y was inadequate. E. CRITERION FOR DIAGN0S~S.--All cases included in this series are proved cases of meningocoecal infections in t h a t the meningococcus was cultured either f r o m the blood stream or spinal fluid of each patient. F. SYMPTOMS AND SmNs.--~The following symptoms were noted: SYmPTOmS

NU/~BER OF PATIENTS

Fever Headache Lethargy V~)miting Sore 'throat Malaise Convulsions

73 18 56 60 4 26 12

As we can see f r o m the foregoing table, fever, lethargy, and vomiting were the most frequent symptoms. The following signs were seen : SIGNS

Petechiae Stiff neck Positive Kernig and Brudzinski signs Collapse

NU~BEI~ OF PATIENTS

47 66 61 9

A petechial eruption was seen in approximately three-quarters of all the patients and was' a very i m p o r t a n t sign in helping to establish a diagnosis of meningococcal infection. I n a p p r o x i m a t e l y o n e - f o u r t h of the cases, however, it was absent. F r e q u e n t l y stained smears of serum

4

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OF P E D I A T R I C S

from the cut surface of a p u r p u r i e lesion revealed gram-negative diploeocei. G. VARIETIES OF MENINGOCOCCAL

INFECTIONS.---

1. Meningococcemia Without Meningitis.--Ten such cases were seen. In all, lumbar p~lnctures were performed, and the cell counts were within normal limits, and the cultures were sterile. Three of these cases (T-261, 0-2269, N-914) were what must be classified as fulminating ; that is, they were marked by an abrupt onset of symptoms, profound toxemia, and profuse p u r p u r i e rash, and all terminated in death in a few hours. The other 7 eases were mild in that the patients did not seem very ill and made uneventful recoveries after a course of sulfonamide chemotherapy. 2. Meningococcem~c~ and Meningitis.--This group was represented by 9 patients. All of these patients reeovered. 3. Meningitis Without Meningococcemia.--There were 58 patients in this g r o u p . In not atl eases was the spinal fluid purulent. In 4 eases the spinal fluid cell count ranged from 10 to 800 with polymorphonuclear ceils predominating. Most of these patients had a very mild course as illustrated by Chart I I I while a few had very hectic ones as illustrated by Chart IV. H. LABORATORY DATA.--Our laboratory employed two techniques in isolating the meningoeoeeus from spinal fluid and block. One was the usual laboratory method, employing tubes of blood agar* slants (for spinal fluid cultures) from which most of the air was exhausted by means of a water vacuum pump. The blood of the patients was cultured in tryptose b r o t h . f T h e other technique involved the use of the ehorioallantoie membrane of the chick embry o as described by Blattner, Heys, and HartmannY .This technique proved to be a valuable adjunct to the usual laboratory facilities for isolating organisms from body fluids of patients, especially after a patient was receiving sulfonamide chemotherapy. This point is emphasized in the foregoing' reference. In analyzing our results we were able to culture the meningoeoeeus from the spinal fluids of 66 patients in 8 of which positive cultures were obtained only by the chick embryo method. Organisms were seen in the stained smears of the spinal fluids of only 53 patients. As recounted previously, meningoeocei were cultured from the blood stream in ofily 19 patients. In 10 eases, however, no blood cultures were made. I. THERAPY.-1. Serum.---This therapy was used in 12 patients. It is difficult to make a statement about the efficacy of serum therapy, but our impression is that serum does not enhance the effectiveness of chemotherapy. This *Blood agar--composition: D i s t i l l e d w a t e r , b a c t o - t r y p t o s e 2 p e r c e n t , N a C 1 0.5 p e r c e n t , Na~I-IPO~ 0 . 3 : p e r c e n t , p a r a - a m i n o b e n z o i e a c i d 5 r a g . p e r ' c e n t , d e f i b r i n a t e d r a b b i t blood 5 per cent. t A b o v e eomlooSltion b u t l a c k i n g in a g a r a n d d e f i b r i n a t e d blood.

GOLDRING E T A t . :

SEVERE I N F E C T I O N S I N I N F A N T S AND C H I L D R E N

i SPINAL FLU|Dr GZLL COURT BUR (O~SUliMll) eJLTURt[ ~ I I ~ A R BLOOD: 9 W.S.G.{IO00)

*** ~******

ISr --

')***

--

B7 --

BOAI

5

R I C H A R D D, AGE EY ~ , II g~l, ESTIMATED WT, WT'<~I2*S K2. ACTUAl. WT. HISTORY: ~NSET IO A.M. 3-24"44 F E U d , ANOREXIA* VOMITIN2, IRRITABILITY PURPURIG 2FAIPTIOR 12 HR. LATER NO OHEMOTHERAPY

CLSiOI

1" *D 9 41

I~

FINDINGS: STIFF NECK AND RACK MOOERATE DEGREE OF TOXIGITY SENSRAt.IZED pURPUR[C ERUPTION

H i , 014.1100 I~.G. URINE; AppROXiMATE pR . I gROSS

I~.i

THERAPY: IO'& DEXTROSE I~ r 0.S% Na-$ULFADIAZINE iN F.L'flqS

S|(~ ISQ E~OR40

.

RLOOO'~.mCROSOC~, m m

ill ?* T* T* ?* T* T~ T* T~ . . . . . . -

__

,

. . . . . .

S~ u ~ ~

BULFAO,AZINSORALLy-SOS.

co~ ~L~:)

MOt.AR N&" LACTATE ORALL~r* 9 64 ~4 64 6 4 (S GG./I~.124 NR.I ASOORBIG ACID I00 MS./E4 HR. OiL R4.SO* ~LS (.~ 6M,/K~) SUI~UT. LI liL,IO,I/RS)(Y[AY B M ,

SULFAOIAZIN( Ual; ~o

!

I llIl;;

MENINGOGOGGIG

MENINGITIS

9

SO (3

AVERAGE

SEVERITY

SPINAL ~rLUI~ IO

| 2 34

DAY OF T R E A T M E N T

5 6 7

C h a r t I I I . - - C l i n i c a l c o u r s e of a e a s e of m e n i n g o e o c c a l m e n i n g i t i s of " a v e r a g e " s e v e r i t y .

~94t APRIl.

|0,||

i2,13,i4~|51i6,;7~18,19,20,21

222324252627282930

' i ~ " Div o4=.EHI.GITm mENI.aO~O~C~) . SPINAL FLUID: SELL (;OUlIT SlIS*~ (OSSJlItSMSI

GUL~USr

.

.

.

.

U', *Die

',t')

'ZOO . . . . . . . .

'iS. . . . . . . --

~":'"

".'t~;.~_--- -- -

BLOOP GUL'I"USE

-T ~ 42

S. . . . . . .

' S.

.

.

.

.

.

.

.

ROBERT F. AlE IGMO.WT.IIKG. HISTORY; 4-4-41 RUBELLA

.

.1, IRmTOlUTV."~F(VSR,~UPOR. RASH In REGULAR.SREakTHING VOklITIRS

- - ~"FREGUEmTGONYULI4CCCSANDIEXTII(M[ RIE|Tt.ESSNESS ~ "CGFF['[" GROUN40"VOMITUS GGN"~O Uir JINSI I m UItUlPJALLYM&ItKLD MUSGUL&RRIGIDITY

FINDINGS: TYPIGAL SIGNS OF MENINGITIS

l' I,S,~,

I000

Ilsl

RI.G. IO00OOO H I . G i . I IOOC G. tiE'tEl" WHOLE BLOOB I.V. r DEXTROSE. L.RS D.C. NA-SULFAPYRIOINE I.V. SULFANILAMIOE t,S, " SOB.GUT. " ORALLY SULFAPYRIOINE " ANTITOXIN I.V UNITS ANTISERUM I.S. C,G,

r162 :p u; i ,oor c

I0,I

,.e4 10.8

].~e [5 I.i ZOO

,s

lt,O

?.I

3~* i.i US

IZO.e*O ZOo I.Y .~S .14 2.z ,.s I.o IJb I.O.I.O.s~

~IENINGOGOGGIG MENINGITIS lifO0 :z

.. -..

. . . . . . . . .

TO

tO.e

""-.,

SEVERE

I0 mS~rL

9DAY OF TREATMENT 2 5 , 4 .

.

.

TYPE

. . . . .. . . . . It . .12.15,14,15,

C h a r t I V . - - C l i n i e a l c o u r s e of a v e r y s e v e r e ~ t y p e of m e n i n g o e o e e a l M e n i n g i t i s .

6

THE JOURNAL OF PEDIATRICS

was also our impression after we studied our larger series of cases from the St. Louis Isolation Hospital. In what appeared to be overwhelming infections, we hesitated, however, to withhold serum therapy. 2. Sulfonamide Chemother~py.--Six sulfonamide drugs were used: prontysil (4' sulfonamido-2, 4-diaminobenzene), sulfanilamide (p-aminobenzene sulfonamide), sulfapyridine (2-p-sulfanilamidopyridine), su]fadiazine (2-p-amiuobenzene sulfonamidopyrimidine), sulfapyrazine (2sulfanilamidopyrazine), and sulfamerazine (2-sulfanilamido-4-methy!pyrimidine). The number of patients treated with each drug was: Prontysil Sulfanilamide Sulfapyridine Su]fadiazine Su]fapyrazine Sulfamerazine

1 5 5 33 9 14

l~atient patients patients patients patients patients

There were a few patients who were treated with two drugs because they developed urinary complications and had to be placed upon sulfanilamide. There was some variation in the therapy of these 77 patients. Three routes of drug administration were employed; that is, intrathecal, intravenous, and oral. It was not until 1942 that our present therapy for meningococcal infections became more or less routine and we formulated certain principles. These were: (a) It was definitely decided that intensive sulfonamide chemotherapy was the treatment of choice. For the first twenty-four to fortyeight hours the patients received 0.6 Gin. per kilogram of body weight per day of sulfonamide. The reason for this was that many times the responsible organism was not isolated for from twenty-four to forty-eight hours, so that we were in doubt during that interval as to the kind of purulent meningitis with which we were dealing. It was because of such a possibility that we felt that the patients should be treated at the outset in a way that would be adequate for such more serious infections as pneumocoecal or influenzal meningitis. By employing this type of therapy, valuable time was not lost in a ease which was thought at first to be a meningoeoecus meningitis and after from two to three days was found to be a more serious type. The drug was administered parenterally for the first twenty-four to forty-eight hours (0.6 Gm. per kilogram of body weight per day), and as soon as tile meningoeoceus was isolated either from the spinal fluid or blood of a.patient, the dose of the sulfonamide drug was reduced to 0.3 Gin. per kilogram of body weight per day, provided that reduetion of dosage also seemed justified by clinical improvement of the patient. This latter dosage was continued until the temperature remained normal for two days. It was then reduced to 0.2 Gin. per kilogram of body weight per day. After two more days of normal temperature, the dose was cut to 0.1 Gin. per kilogram of body weight per day, and after two

(~OLDt~ING E T AL. :

SEVERE I N F E C T I O N S

IN INFANTS

AND C H I L D R E N

7

days more of normal temperature chemotherapy was discontinued. If the patients remained afebrile for from two to three days after the discontinuation of chemotherapy, they were discharged. The average duration of chemotherapy was 10.6 days; the average hospital stay was 14.1 days. (b) Parenteral chemotherapy for the first day or two was selected because most of our patients were comatose, irrational, uncooperative, or vomiting upon admission, so that oral administration of the sulfonamide drug was either impossible or unreliable. (e) In January, 1943, the subcutaneous route of drug administration was adopted as the route of choice. This decision was primarily the result of the work of Barnett and associates, 3 who noted that the speed in attaining a desired sustained drug ]eve] in the Mood was almost as rapid by the subcutaneous as by the intravenous route, the plateau being reached from below upward. Theoretically the risk of precipitation in the urinary tract would be less in this way than by the intravenous route. (d) About the sanle time, it was appreciated that the a]kalinization of the urine was of great value in reducing' the degree of erysta]luria in the case of certain of the drugs. It was found by giving 12 adults and a group of more than 50 children 5 c.e. per kilogram of body weight per day of molar sodimn ]aerate in four divided doses the urine wou/d be rendered alkaline (pit 7 to 8). The sulfonamide drugs in 0.5 per cent solution were, therefore, incorporated in a mixture of one-half "fortified lactate R i n g e r ' s . ''~',' The following dosage regimes have been adapted for sulfadiazine and sulfamerazine for the first twenty-four to fortyeight hours. Sulfadiazine: 60 c.c. per kilogram of body weight of a 0.5 per~cent solution of sodium sulfadiazine (0.3 Gin. per kilogram) made up in onehalf "fortified lactate Ringer's" solution for the initial dose and 30 c.e. per kilogram of body weight of the above solution (0.15 Gin. per kilogram) every eight hours for the first twenty-four to forty-eight hours. Su]famerazine: After an initial dose similar to that of sulfadiazine, 20 e.e. per kilogram of body weight (0.1 Gin. per kilogram) of the solution were given every eight hours for the first twenty-four to forty-eight hours. When the patient was able to take drug by mouth, the lactate was given in fruit jfiiee or milk formula. The amount given was 5 e.c. per kilogram of body weight of a molar solution in four divided doses during the twenty-four hours. This form 0f drug administration accomplishes the following: (1) The subcutaneous route of drug administration is extremely easy from a technical viewpoint and is especially valuable i n pediatrics. *Half fortified lactate Ringer's: solution.

Sodium lactate.made

u p to 1~o m o l a r in R i n g e r ' s

8

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OF

PEDIATRICS

(2) An adequate sulfonamide blood level is rapidly attained in from one to three hours2 It is often difficult to obtain the desired high levels of drug by oral dosage. (3) Hydration is necessarily accomplished by the large amount of fluid in which the 0.5 per cent drug is given, and it becomes automatically impossible to create dangerously high drug levels because of unrelieved dehydration. (4) Any chloride deficit caused by vomiting is replaced by the Ringer's salts and renders more certain the prompt secretion of an alkaline urine, which is made possible because of the added sodium lactate. In addition to the alkalinizing effect of the sodium lactate, the glucogenic effect of this substance was also desirable. Another advantage to the use of sodium lactate is that it is very easily adaptable to oral as well as parenteral use and when given orally does not have the undesirable effect of sodium bicarbonate in causing belching, vomiting, and in reducing too much the acidity of the gastric juice. J . OTHER ADJUNCTS OF THERAPY.---

(1) Adequate hydration was keenly stressed, and all patients were given in a minimum of 10 per cent of their body weight in fluids per day. (2) Careful charts were kept of each patient's daily intake and output. (3) Urine examinations were made daily. The p t I of the urine was determined with nitrazine paper, and the urine was tested for albumin, and the microscopic sediment was examined for cellular elements. (4) A white blood cell count was made every other day. (5) Blood cultures" were obtained upon admission and at any time when there occurred a sudden spike in temperature to 39 ~ C. or over.

(6) A lumbar puncture was performed upon all patients on admission and was usually repeated every three to four days if fever persisted and again shortly before each patient was discharged from the hospital. All spinal fluids were examined for eellular elements and cultured either on blood agar or upon the chorioallantoic membrane of the chick embryo. (7) Sulfonamide drug levels were obtained every day for the first three hospital days and usually every other day thereafter. l~. COMPLICATIONS FROM D R U G . - COMPLICATIONS IIematuria Gross Microscopic Fever Rash Cyanosls

NUMBER OF PATIENTS 9 5 2 1 ]4

11.6% 6.4% 2.3% 1.2% 18.1%

GOLDRING ET AL. :

SEVERE INFECTIONS IN INFANTS AND CHILDREN

9

The most frequent complication we saw was cyanosis. This was due to methemoglobin formation--all in patients who were, treated with sulfanilamide. Whenever thought necessary, methemoglobinemia was controlled by appropriate dosage of methylene blue. ~ The 9 cases of gross hematuria were made up of 8 patients who received sulfadiazine and 1 who received sulfapyrazine. The other toxic complications were of little importance. It must be remembered that the patients in this series received intensive sulfonamide chemotherapy (see range of drug levels in Table I), and the 9 cases of gross hematuria must be interpreted with that in mind. I n all instances the hematuria subsided promptly as soon as the intensive chemotherapy was relaxed or the offending drug discontinued entirely. L. COMPLICATIONS FROM THE D I S E A S E . u CO~PT,ICATIONS Arthritis Deafness Encephalitis Paralysis

ZCU~B~ROF rAa~m~TS 8 10.3% 5 6.4% 2 2.3 % 6 7.7%

Arthritis was the most frequent complication seen and usually involved multiple joints of the body. It usually appeared during convalescence and was never very severe, the joints being tender for a few days, showing fusiform swelling, and usually subsiding spontaneously. Paralysis was the next most frequent complication and usually involved the extraoeular muscles. ' Strabismus so produced appeared both early and late i n the disease and subsided spontaneously in all cases. Only one case of hemiparesis was seen, and this cleared up by the time of the patient's discharge from the hospital. Deafness was encountered in o n l y 6.4 per cent of the cases. This was usually noted during convalescence and was of the nerve type, usually involving both ears, and seemed permanent. The last and rather infrequent complication was a postinfectious type of encaphalitis which was characterized by behavior changes and emotional instability. In both cases which have been followed since dismissal from the hospital there has been a definite but slow recovery. M. ~V~ORTALITYRATE.--Eleven of the 77 patients (14.2 per cent) expired. If we analyze these deaths (Table II), We see that the patient, S-3067, died as a result of bronehiolitis well after the meningitic process had subsided. Three patients expired before any form of therapy could be instituted, and 7 patients died during the first twenty hours in the hospital, and only 3 patients expired who received the full dosage of chemotherapy, 3.8 per cent Of the total number. Not one received any sulfonamide drug befor~e admission to the hospital. N. AUTOPSY REPORTS. ~Te were able to perform post-mortem examinations on 7 out of the 11 patients who'expired. We see (Table II)

10

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OF P E D I A T R I C S TABL~ S ULFONAM~

APPARENT D2LTE O F CASI

ADI~I I S-

SIGN

AGE

SEX

NO.

(KG.)

DAY OF MENINGITIS

WHEN

THER~PY W A S BEGUN

USED

OEA

4.6

1.0

18.0

0

13.9

1.3

6.4

27.7 5 96.9 11.1

0 0 0 0

17.0 5 22.0 10.0

1.03 0 1.54 1.1

9.7 0 73..4 O

SA

25.1

0

6

1.1

18.0

SA

11.4

0

4.5

1.7

6.2

3 days 1 day 4 days

SA SA SP

49.4 2.0 5.5

0 0 0

30.5 2.0 0

.73 0 0

18.2 0 5.5

3.3

1 wk.

15.9

1 day

SA SP SP

8.1 .9 1.5

SP SA SP SA SP

I~

5

6 / 3/37

N-906

M

3~ yr.

Ii.I

9 10

10/24/37 12/30/37 1/18/o8 1/18/38 2/19/38

N-1943 N-2289 N-914 N-111 O-413

M M M F F

5 8 6 5 l~

11.0 22.3 22.2 19.5 9.6

2 1 1 4 2

days wk. day days wk.

SA PR 0 SA SA SA SA

15.2 6.4

6 7

11

3 / 8/38

O-507

M

1I/2 y r .

ll.O

3 days

12

5/ 1/38

0-869

M

2 wk.

13 14 15

1 1 / 1/38 i i / 5/38 1/19/39

0-2240 O-2269 P-210

:M:

F

20.0 18.0 11.5

P-783

M

1 mo.

Q-2485

M

4 yr.

16

4/14/39

17

11/21/40

6 raG. 4 yr. 2I/z yr. 6 mo.

4 days 2 days 5 days

?

26 days

7.2

I~

days

0 Prontylin

24.6

0 0 0

.1 0 0

27.4 :42 8.9 5.1 10.1

.4 .42 2.2 0 1.6

0 0 0 2.2 0

.15 0 0 .26 O

26.8 0 6.7 2.6 8.5

SA SP SD SD SD SD SD SD SD SD 0 SD SD SA

19.0 2.1 61.9 79 8 87 5.0 29.2 40.5 38.5

0 1.1 3.9 5 0 9.7 4.8 5 6.25 5.0

0 0 0 0 0 .4 .2 .26 0 0

0 0 0 0 0 0 0 0 0 0

19.0 0 58.0 74 8 77 0 24 34.3 33.5

35.9 4.6 75.0

0 O

0 0

2.85 2.6 3,0

33 2 72

0

0 0 0

0 0 9.0 0

8.8 15.5 0 13

58.8 32.0 26 66

0 0

8.5 17,7

58.0 0

0

6.8

18

12/15/40

Q-2296

M:

3 mo.

4.2

2/:5/41

4/10/41

R-301 R-703

M M

3 yr. 16 m o .

15.0 II.I

21

7/20/41

R-1511

M

6 wk.

5.2

M ~/I M M F M M F iYl M M

9 mo. I0 yr. 4 yr. 2 yr. I I mo. 17 mo. 2 yr. 10 m o . 4 mo. 3 yr. 7 yr.

9.0 25.0 30.0 11.0 7.9 9.5 12.7 7.2 ? 15.4 26.3

21.3 50.0 9.2 26.0

2 days 2 days 1 day ?

SO SPZ SPZ SPZ

67.6 37.5 35 79.0

9.1 11.3 21.8

2 days 2 days 1 day

SD SPZ SD SA SPZ SD SD SD SPZ SPZ SPZ

66.5 17.7 6.8 10.4 38.2 40.5 24.75 58.0 54.0 109.5 45.9

0 0 0 0 0 0 0 0 0

SPZ SD

14.3 40.75

SD SNf SM SD SD SM

21.0 24.0 23.7 55.7 33.6 27.5

38 34 35 36

2/26/43 3 / 6/43 3/10/43 3/21/43

T-530 T-581 T-611 T-695

F F F F

6 11 15 9

yr. yr. mo. yr,

97 38 39

4 / 2/43 4/16/43 5/31/43

T-799 T-927 T-987

F t'J F

2 yr. 2V2yr. 5 yr.

1 day 1 day 5 days

I~ day 6 2 5 2 3 4 1 5 1 1 36

40 41 42 43 44 45

6/16/43 6/22/43 7/ 2/43 8/15/43 9/23/43 10/10/43

T-1477 T-1528 T-1650 T-2053 T-2400 R-1578

lY[ F M F M M

11 mo. 2 yr. 10 y r . 5 yr. 7 yr. 289 yr.

8.6 7.7 40.0 14.5 28.1 11.3

46 47

T-2836 T-2949

F M

6 mo. 15 mo.

7.4 12.9

48 49 50 51

11/18/43 1 2 / 6/43 i I 1 2 / 5/43 12/18/43 12/18/43 12/31/43

]VI

3 yr. 6 yr. 11 y r . 2V2 y r .

15.0 27.2 31.3 12.2

3 4 1 2

53

1 / 5/44

20.0

3 days

52

T-2994 T-8000

I~

T-3003 T-3058

F 1Vi

1/2/44 u-106

~

U-121

*SA =Sulfanilamide Sulfamerazine; SD Spinal ~luid.

:

2~yr

yr.

i 120

2 3 3 3 1 1

days days days days wk. days day days day day hr.

days days days days day ,day

12 hr. 36 h r . days days day

days

90ays

SC

0 0 1.5

19 20

4/ 6/42 S-748 4/22/42 S-878 5/29/42 S-1173 11/27/42 S-2914 12/ 4/42 S-2951 12/14/42 S-3018 1 2 / 2 2 / 4 2 S-3067 1 / 4/43 T - 1 2 0 1 / 2 4 / 4 3 T-261 2/17/43 T-454 2/24/43 T-191

ADMINISTERED

IT

? ? 12.2

, IV

5/ 9/37 N-748

raG. yr. yr. yr. yr.

"!

G/VL

4

6 mo.

ROUTE

DRUG TOTAL

r F M

M

~;Y4 y r . 5 yr. 1~ yr.

i

J 1 / 2 8 / 3 7 N-231 1/28/37 K-2664 3 5/ 2/37 N-711

22 23 24 25 26 27 28 29 30 31 32

= =

HISTORY

BODY WT.

7.9 .9 0

0

4.4 2.2

6 36

0

10.5

30

0 0 0 0 0

4.75 18.0 16.5 122.5 13.5

20 40 37.5 87.0 32.4

0 0

5.3 0

0 13.25

9.0 27.5

0 0 0 0 0 0

0 0 0 0 0 0

3.0 4.5 9.4 7.7 33.0 14.0

18.0 19.5 14.2{ 4,8.0 0 12.0

S T = S u l f a t h i a z o l e ; S P ~--- S u ] f a p y r i d i n e ; S P Z = S u l f a P y r a z i n e ; SM S u l f a d i a z i n e ; P R = P r o n t o s i l ; A T = A n t i t o x i n ; S = S e r u m ; S.F.

GOLDRING

ET

AL. :

SEVERE

INFECTIONS

IN

INFANTS

AND

11

CHILDREN

i ,rOTAI~ No. o F ON

CONCENTRATION M~./100 c.c. DA~

DAY

BAOTE~IOL0~ICAILDATA SP. FLUID SMEAR CULTUR~ BLOOD

Sg~ 'HE! tAPY

CELL1

DAY

14

8 24 5

~

S.F.

S.i~

14.9

9.1

8

(

1~.i

8

8.2

20

9.7

15.7

7 8

4,0 SP 33.2

4.6 S~ 23.1

0

SP 14.7

SA

SP

SA

22.8

38.4 19.3

10.~ 21.3 18.9

22

]

~12,ooo / 1,596

+

I

+

]

/

o

I

+

1

/

0 0 + + 0

+

I

+

+ 0 0

+ -b 0 + +

j810 +] 17'680 1 6,000

I

:R.

R

11 ] 28 |

D R

21~r

D 1~ D

t21hr.

l:t

12

0

8

0

0

+

D

+

0

1%

+

R

0

l:t

0

i:~

4,100

q-

720

14.5 38 26.9 22.2 29.7

42

47

52.5 48.0 20.2

44,7

5,250 :4,000 3,600

12.7

3,800

10 44

24.2 SD 21.6

18 5 13 9

22.8 26.4

25.2 SD 22,6 SA 17.9 45.3 24

30.0

43,7

15 7 11

31.4 36.2 SD 44.4

~5.6 SA 23.6

~4.4 58.0 SA [7.9

9 5 10 12 9 11

22.8 19.4 30.4 30.7 2%9 30.7

13.5 14.9

20.0 10.~

48.8

~0.4 4.7

7 8

52.4 34.7

6 10 8 16 13 12

28.3 22.4 28.8

21.1 20.5 t6,3

11.4

[8.4 t7.8

§

+

ii

+ + + +

0 .2,600 ~4,250

21.7 16.3

'

S.F.

+

[

tO.2

! [

7D l~ l:t

R R R R -p. R

"7

[

14hr"

D

L8,550 9,000 ),1,500 ~2,000 9.800 270

~5.0

i

IP.~L

,9,800 5;775 7,250 I 8,900 I 7,200 9.000

+

+ 0 + + + +

0 0 0 0 0 0 0 0 0 0 0

R R R D 1~

l:t 1~ lCL i%

+ O + + ? +

0

o

0 12 G i n . S T

0 0

)

o 0

+ + +

+

0

25 12

+

23 24 15

o

+ +

0 0 0

I:~

+ o o 0,640 ? + 4,300 + 5,630 1,600 0 ~p. FI. v ~ l t n r e p o s i t i v ~ i~ hosp. at A l t o n , I l l i n o i s L0,750 ] 0 § 7,500 [ + + 2.000 + + ] { ] ~

]

XR. +

.4,800

4,900

0 0

+

0

+ +

0

0

0

D

+

1,060

+ 0

O

lood~ 200 .0,0O0

0

0 0

+

L2,8OC

0 A'

'

R

O

C

~NTRY

t7 h r . 27 12

+

35.7 37

t4.7 L8.8 L9.5 6.5 8.7 9.7

/

0

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24.0 34.5

24.0

J--I~/

+ Vent. +

+

0

+

+

0

18

-

0

800

15 12 3 14 2 9 14 10

48.8. 18.7

-

i + R 19 0 ' D + 51~r. 0 0 D } " ~ o 1 d a y s l a t e r M~owed 51,600 v e i l s ; g r a m | n negr e g a t i$v v e diplovoeci c r e t e s e e n , a ~ g menCnI goeoeei c r e t e cultured, f r o m t h i s ~uic~

19

18

2,250

BL.

I AaAR

DAYS THERAPYr

ouweUL- [COME l HOSP. TURE [

]

~

+

+S ~13,900 S ]3

_

ORQ. 0 +

| 1 500

S~.~

_

12,000

/ (

II.~

_

-~,~

+s

1O

_ ,

)r

gg

12

THE

JOURNAL

OF PEDIATRICS

TABLE SULFONAMI~ SULFONA1V

APPARENTDA_y OF I D~TE OF CASE

-4.DMIS-

SION

BODY HISTORY

SEX

AGE

NO.

W~.

( K(~. )

MENINGITIS

WHEN

THERAPY

WAS 1 3 10 3 1

BEGUN day wk. hr. days day

DR~G

~OTAL

USED

GIV~.

SM SD SM SD SM

13.0 35.5 30.8 29.4 40.8

ROUTE

IV

SC 0 0 0 6.4 0

IT 4.0 9.5 0 0 7.0

, OF ORAL 9.0-26.0 30.8 23.0 33.8

75.5 36.0

0 0

67.5 3.0

6.0 33.0

SD SM SM SD

21.7 29.0 I7.5 20.5

10.7 9/0 5.0 6.5

0 0 0 0

11.0 20.0 12.5 14.0

11/2 d a y s 4 d~ys 3 d~ys 3 days

SM SD SM SM

31.0 18.3 58.5 24.8

13.6 7.3 6.0 7.8

I 0 I 0 I 0 0

17.4 11.0 52.5 17.0

1 day 11 h r . I day

SM SD SD

14.8 23.4 21.0

7:5 1.4 9.0

0 0 0

i2.0

1 day 4 days 1 day

S!VI SD SD

95.4 -42.3 24.3

0 0 0

22.0 16:0 9.9

i 0 0 0

11.8

1 day

5.0 31.5 5:0 7.4

0

0

2 days 1 day

5.0 31i5 5.0 , 15.4

0

? 11.3

SD SA SM SD

0 0

0 8.0

,

54 55 56 57 58

1/ 7/44 1/16/44 1/17/44 1/19/44 1/21/44

U-128 U-162 U-172 U-181 U-199

NI F M F F

21/2 y r . 4 yr. 8 yr. 11 m o . 5 yr.

10.0 15.0 24.0 9.0 16.8

59 60

1/26/44 1/28/44

U-224 U-236

M F

8 yr. 14 m o .

25.4 8.6

1 day 1 day

SD SD

61 62 63 64

2 / 1/44 2/12/44 2/14/44 2/19/44

U-261 U-318 U-332 U-366

F F M F

l~j~ 4 9 2

yr. yr. too. yr.

11.1 12.0 9~1 10.0

1 day 21/2 d a y s 3 days 3 days

65 66 67 68

2/22/44 2/25/44 2/28/44 3/ 3/44

U~388 U-411 U'432 U-455

1VI M M F

3 yr. 9 too. 4~/2 y r . 3 yr.

16.8 9.2 15.4 13.6

69 70 71

3/ 6/44 3/10/44 3/ 2/44

U-469 U-500

F F F

6 too. 4 yr. 3 yr.

8.2 14.0 13.4

72 73 74

3/16/44 3/20/44 3/25/44

U-548 U-580 U-611

M M M

9 yr. 5 yr. 2 yr.

34.0 15.5 11.0

75

3/31/44

U-645

M

22

too.

76 77

4_/13/4~ 4/16/44

M M

13 22

yr. too.

0

O 0

~

ADMINISTERED

that 3 patients showed bilateral adrenal hemorrhage (WaterhouseFriderichsen syndrome). One patient 'had meningococcal pericarditis. The other findings at autopsy for this group were not especially noteworthy. SUMMARY AND CONCLUSIONS We have analyzed 77 patients with_ meningococcal infections seen at the St. Louis Children's Hospital between the years 1937-1944. The years 1937-1942 represent nonepidemic years, and i943-1944 represent epidemic years. As we gained more and more experience with the use of sulfonamide drugs in meningitis, we have come to certain fundamental conclusions. We believe that intensive parenteral chemotherapy by the subcutaneous route is the treatment of choice of purulent meningitis for the first twenty-four to forty-eight hours or until the etiological organism is proved to be a meningococcus and that blood levels for the first few days of treatment should range between 20 and 40 rag. per cent. This level of drug, we feel, is adequate to cope even with the most serious meningidities; that is, pneumococcal or influenzal. Although such intensive chemotherapy probably enhances somewhat the possibility for kidney complications, when such precautions as adequate hydration, alkalization of the urine, careful records of daily intake and output, and daily urine examinations are taken, serious difficulties are rare. As soon as the etiological organism is definitely established as tile meningocoeeus

7.25 22.0

73.4 26.25 14.9

GOLDRING ET

AL. :

SEVERE

INFECTIONS

IN

INFANTS

AND

13

CHILDREN

[ - - C O N T 'D TflERAPY TOTAL N0, O F DAYS ON DRUG

13 11 6 9

BAOTERIOLOGICAL DATA CONCENTRATION

~ o . / 1 0 0 c.c. 2NI__[ 3RD 4TH DA~ DAY DAY 21.9 7,2 11.4 26.2 44.5 10.7 5.8 12.1

13 11

27.7

17.4

7 10 14 10

24.6 26.5 20.6

12.5 16.2

13 8 15 8

25.9

16.2 13.9

28.6 26.5

SMEAR

cELLS 1,800 4,200 4 7,050 8,800

22.9 , 4.8 10.5

oRG. + 0 0 + + + +

5,600 25,000

0 + + +

1,100

17 12 12 14 18 17

+ 8th day +

0 0 0

17 10 17 10

0 0 0 0 0 O .5 G i n . sulfonamide 0 0 0

§

0

4 0 0

9 8 14

3,200 3,770

+ +

+ +

op&que

+

0 0 0

24 16 16

90

16,8

14 13 7

34.0 13.2 28.3

33.0 22.6 17.3

12

25.4

4,000

+

28.2

4,104 11,350

+ ?

+

0

0 0

18 9 hr.

0

0

0 0 0 1 G-m, sulfonamide 0 0

10 12 18 11

0

24.8

6

+ 0 +

THERAPY BEFORE ENTRY

_:E + 0 0 0 +

+ + + 0

27,2

23.9 8.0 9.9

Er~

DAYS

[

CULTURE

4,200 12,000 6,000 opMescent 3 7,400 10

33.2

9 hr.

11.1

-I ,[ I [

315 4,200

5,500

8.2 40.4

SERUM THERAPY

SP. FLUID

0

2.5 G i n . SD 0 0

and the clinical course has exhibited a favorable trend, ihen the patient may be safely maintained on 0.3 Gin. per kilogram o f body weight of a sulfonamide. We do not believe that serum therapy sufficiently enhances t h e effectiveness of sulfonamide t h e r a p y to justify its use routinely. Adequate hydration is of utmost importance, and we strive for a minimum of 10 per cent of the body weight in fluids per day. Alkalinization 'of the urine is important, and we believe that the easiest and most effective means is by the administration of sodium lactate either parenteralty or enterally. Accurate daily records of the patient's intake and output are important as well as daily examinations of the urine a n d regular white blood cell counts, especially during the second week of chemotherapy. There were comparatively few :.complications. The one most frequently encountered was a generalized arthritis which cleared spontaneously. The m~ost serious complication which remained as a permanent residual was bilateral nerve deafness. We encountered 2 cases of postinfectious encephalitis. The uncorrected mortality rate was 14.2 per cent. I f the One patient who died of another disease a n d the 7 patients who expired a f t e r being in the hospital less than twenty-four hours are excluded (3 receiving no treatment), the mortality rate f o r the seven-year-period is 3.8 per cent.

1~

THE JOURNAL OF PEDIATRICS

-~

~

'~

/ -i1

~

l~///~

~

~,~1 ~

~

'~176

///1~ -0~

~:

~

~

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~

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GOLDI~ING E T AL. :

SEVERE I N F E C T I O N S

IN

INFANTS

AND CHILDREN

15

B. E X P E R I E N C E S AT THE ST. LOUIS ISOLATION HOSPITAL This is a report on 209 cases (Table III) of meningoeoecal infection at the Isolation Hospital of St. Louis, Mo., admitted between January of 1942 and August of 1943: The patients were drawn from an area which includes the City and County of St. Louis and neighboring communities in the states of Missouri and Illinois. Since the Isolation Hospital is the center :for the treatment of contagious diseases in this area, this number represents the majority of hospital treated cases. For several years prior to 1942, cases of meningococcal infection seen at Isolation Hospital were few and averaged _12 per year for the fiveyear period dating back to 1937. In 1942, 26 cases were reported to tl~e St. Louis Health Departnlent, and 13 patients were treated in this hospital and were-included in this report. In 1943, 342 local cases were reported, 245 occurring in the seven-month period from January to August. In this same seven-month period, 196 patients (resident and nonresident) were admitted to the Isolation Hospital and are included in \ this report. The 1943 epidemic of meningoeoccie meningitis is thought to be the most extensive epidemic of disease recorded in this country; it was estimated~ that approximately 17,000 cases were recognized. Upon examining the distribution of cases in metropolitan St. Louis (see map, Chart V) it is apparent that the majority of patients came from the east-central section of the city bordering on the Mississippi River. In this section living conditions are very poor, and the houses are old and overcrowded. In view of this fact it is interesting that we found but few instances where more than one person in the family developed the disease. The following are the only instances recorded of more than one infection within a family : (1) G. S. (1183-42) developed meningoeoccic meningitis nine days after her mother developed the disease. (The patient's mother was treated in another St. Louis hospital.) (2) :~r R. (1326-42) had meningococcic merringitis, and her sister, L. R. (1351-42), entered the hospital a few days later with meningoeoccemia. (3) W. L. (223-43) was found to have a meningococeemia upon admission. The sister of this patient, J. L. (224-43), was admitted the following day with meningococcus meningitis a n d meningococcemia. (4) The following group of children, B. D. (i80-43), B. W. (193-43), and B. G. (171-43), represents three families. They all slept in one room and were admitted during the period of ~one week. B. G. was found to have meningococcus meningitis, and B: D. and B. W. were found to have fever, petechial rashes, and elevated cell counts in the spinal i~uid without meningeal symptoms.

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22

THE

JOURNAL

OF P E D I A T R I C S

The blood cultures on the latter two were sterile, but there is enough presumptive evidence to classify these as meningococcal infections. The distribution of the number of cases among the several months covered by this report is shown in Chart VI. There is a definite predominance of cases in the early months of 1943, and a decided decline later in the year. This is the distribution that was observed in previous epidemics according to Brinton2 There was no significant difference in the incidence of the disease in males as compared with females. In this series there were 113 females and 96 males.

DISTRIBUTION

OF GASES IN ST. LOUIS

METROPOLITAN

o

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ROVF.R

of t h e C i t y o f St. L o u i s , :~o., s h o w i n g t h e d i s t r i b u t i o n meningococcal meningitis in the 1943-1944 epidemic.

of c a s e s of

The age distribution graph (see Chart V I I ) is significant in that it emphasizes that the meningoeoeeus selects principally children and young adults for its victims. The definitely greater prevalence of the disease among children (from birth to 14 years of age), as compared with adults (14 to 75 years of age) is brought out by the following figures. According to the last national census, 69 per cent of our living population was between the ages of 14 and 75, and 29.5 per cent was between the ages 0 to 14. With equal age distribution the expected number of victims between the ages of 0 to 14 should have been 64, and the expected m o r b i d i t y between the ages of 14 and 75 should have been 151.8. The actual number of patients between the ages of 0 to 14 was 90, and between the ages of 14 to 75 the actual n u m b e r of victims was 119.

GOLDRING E T

AL. :

23

SEVERE I N F E C T I O N S I N INFAINTS A N D C H I L D R E N

One more observation might be pointed out. Chart VII also shows that in the age group 0 to 14, 22 patients were Negro and 69 were white. Thus 58 per cent of all infections in Negroes and 40 per cent of all infections in white people occurred in children under 14 years of age. There seems also to be some predilection for the Negro, although there was a definite preponderance of white patients affected, 171 as compared to 38 Negro. The percentage of Negro people in St. Louis is approximately 12, and the expected morbidity for the Negro race should have been 25 in this epidemic. This figure, however, was increased by 50 per cent in the observed cases.

PATIENTS 50

DISTRIBUTION OF IN

45

,/~

40 35

30 25 e~ 15 tO

i 5: ,'~ J/U~l, FEB. MAR. Nard. MAy ~tJ~ JULY AUG. SF,.PT.OGT. NOV, 0~;. "JAN. ~ 1949'

9

|

r

s

MiiR. APRIL MAY JUNE JULY JlOl.

1943

C h a r t Y I , - - ~ c I o n t h l y i n c i d e n c e of c a s e s of m e n i n g o e o e c a t i n f e c t i o n f o r t h e y e a r s 19421943, TOTAL NUMBER OF PATI E BTI,$ FOR EAGR AGE GROUP

DISTRIBUTION OF PATIENTS AGGORDING TO AGE AND RAGE

-40-

-35- - rl 9

WHITE NEGRO

n n_n H.FLn. Chart u

and

r a c e d i s t r i b u t i o n of cases of m e n i n g o c o e c a l i n f e c t i o n .

2~

THE JOURNAL OF PEDIATRICS

It is of interest to note that 137 patients (65 per cent) in this series entered the hospital after forty-eight hours of illness. Sixty-seven patients (32 per cent) entered the hospital after three days or more of illness. Recent reports %~ of meningococeic infections in certain army camps indicate a much shorter time interval between onset of symptoms and the beginning of treatment, and the case fatality rate is correspondingly lower. Although a great number of our patients was first seen by physicians at home or at hospitals, yet very few, only 41 p a t i e n t s (19 per cent), received some form of sulfonamide therapy before admission to the Isolation Hospital. The presenting symptoms in order of frequency were: SYMPTOM:S Fever Lethargy Headache Vomiting Malaise Chills Sore t h r o a t Convulsions

NUI~IBEIg OF PATIENTS I96 173 154 145 99 66 30 23

The most common signs which the patients presented were in order of frequency : SIGNS Stiff neck Positive K e r n i g or Brudzinski signs Peteehiae

NU3s

OF PATIENTS 200 184 155

The diagnosis of meningocoecie meningitis was made in all cases of demonstrated purulent meningitis in which tiny one of the four positive findings listed below was present. (1) Typical petechiae (2) Gram-negative diploeoeei in a stained smear of the spinal fluid (3) Positive blood culture for Neisseria meningococcus (4) Positive spinal fluid culture for N. ,meningococcus. It ]night be pointed out at this time that we encountered only 6 cases of meningococcemia without meningitis. In each of these patients the typical skin rash was profuse, and the meningococeus was cultured from the patient's blood in all but two instances. These patients, B. D. (180-43) and B. W. (193-43), were admitted from a one-room dwelling in which another proved meningoeoceic infection originated within a week, and we felt justified in making a diagnosis on the basis of a typical rash without positive blood culture. The length of hospital stay ranged from six to forty-two days for those patients who recovered. The average duration of hospitalization was 12.8 days. There were no definite criteria for discharge, the patient being signed out after he had been off ehemotherapy for several days and appeared to be well clinically. There have been no known relapses among the diseharged patients.

GOLDR1NG E T AL. :

SEVERE I N F E C T I O N S I N I N F A N T S

AND C H I L D R E N

25

MANA@EMENT A N D TI-1ERAPu OF P A T I E N T S

Although there were slight variations in the management and tilerapy of patients at the inception of the epidemic, the. plan of treatment had assumed a uniform pattern when the disease had reached epidemie proportions, and the following is a r~sum~ of the routine employed. In addition to the usual information obtained in the medical history of each patient, specific questions were asked about the duration of illness before entry to the hospital, whether any chemotherapy was given before admission, and about the following symptoms: fever, headache, vomiting, chills, lethargy, sore throat, muscular aches and pains, and convulsions. During the physical examination special attention was paid to the following signs : peteehiae, stiff neck, Kernig and Brudzinski signs, and evidence of collapse. Certain laboratory procedures and diagnostic tests were used routinely. Most patients included in this series had a lumbar puncture upon admission to this hospital. The only exceptions were the few patients who had lumbar punctures performed in the hospitals from which they were transferred. In these eases the information gained from a spinal fluid examination was obtained from the private physician or the referring hospital. Additional lumbar punctures during the patient's stay in the hospital were performed only when the response to treatment was not satisfactory; that is, when fever persisted for more than a few days after ad~ mission, when there occurred a sudden temperature elevation, or when the signs of meningeal irritation persisted past the third day os treatment. The spinal fluid was examined at once for cellular content, for organisms by stained smear, and was cultured'* using the candle method for obtaining miero-aerophilie conditions. Blood cultures were secured on all p~tients upon admission and thereafter in most instances when the temperature rose suddenly to more than 103 ~ P. Adequate hydration of the patients during active chemotherapy was stressed; all adults received from 3,000 e.e. to 5,000 c.c. of fluids daily, and children received at least 10 per cent of the body weight in fluids per day. The parenteral route was relied upon for the administration of fluids during the first two or three hospital days until the patient could take and retain liquids easily by mouth. The parenteral fluids used were 10 per cent glucose for intravenous administration and some type of lactate--Ringer's solution for subcutaneous use. An effort was made to keep an accurate record of each patient's fluid intake and output. Six sulfonamide drugs were used in the treatment of t h e patients in this series. These were sulfadiazinet (2-p-aminobenzene sulf0namidopyrimidine), sulfamerazine (2-sulfanilmnido-4-methylpyrimidine), sulfa*The culture m e d i u m , used w a s horse m e a t broth agar, containing baeto-peptone, h u m a n b l o o d (8 to 10 p e r c e n t ) , p a r a ~ a m i n o b e n z o i c a c i d (5 rag- p e r 100 e , c , ) . T h i s w a s p r e p a r e d a c c o r d i n g to t h e m e t h o d of H. D. W r i g h t (J. P a t h . & B e e t . ST: 257, 1933). t S u l f a d i a z i n e f o r t h i s s t u d y w a s s u p p l i e d t h r o u g h t h e c o u r t e s y of lY[~]or J o s e p h C. E d w a r d s , M e d i c a l Corps, A r m y of t h e U n i t e d S t a t e s , ~ n d L e d e r l e L a b o r a t o r i e s , Inc.

26

T H E J O U R N A L OF PEDIATRICS

pyrazine (2-sulfanilamidopyrazine), sulfapyridine (2-p-sulfanilamidopyridine), sulfathiazole (2-p-aminobenzene sulfonamidothiazole), and sulfanilamide (p-aminobenzene sulfonamide). A number of patients received sulfonamide chemotherapy before admission, and we continued therapy with the same drug whenever this seemed practical and for the patient's best interest. Sulfadiazine was the principal drug used in the management of 110 patients. Thirtysix patients were treated with sulfamerazine and represented part o f a study of this new drug undertaken by members of the Washington University Department of Internal Medicine.s Twenty-three patients treated with sulfapyrazine were all children and were part of a study of sulfapyrazine undertaken by members of the Department of Pediatrics 3 of Washington University. Only 9 patients were treated with sulfapyridine. The 15 individuals who received su]fathiazole were carefully selected and included only those patients who presented typical clinical and laboratory findings of meningococcic meningitis and who were not desperately ill. Patients treated with sulfanilamide usually represented those who had developed urinary tract complications during the course of therapy with one of the other sulfonamide drugs. The plan of chemotherapy was essentially as follows: Every patient with meningitis that was admitted to this hospital was treated as though he had one of the most serious forms of meningitis; that is, pneumococcal or influenzal. During the first twenty-four or forty-eight hours all patients received sulfonamide drug in quantities adequate to cope with such serious infections. It was not until the causative organism was grown out in culture and shown to be a meningococeus or until the clinical course clearly pointed to a meningococcic infection that the intensive chemotherapy was reduced. The following is the pattern of drug administration that was followed in most cases. For adults 15 Gin. of the sodium salt of a sulfonamide were given subcutaneously in the first twenty-four hours, and for children the initial twenty-four-hour dose was calculated on the basis of from 0.4 to 0.5 Gm. per kilogram of body weight. This calculated dose was usually divided into three equal parts, one-third being administered immediately, and the remaining two-thirds given in two equal doses at eight-hour intervals. The sodium salts were given in 1/2 per cent concentration in a "fortified lactate-Ringer's" solution. Most patients received an additional intravenous injection of 10 per cent glucose, 750 c.c. for adults and a proportionate amount for children. By such a regimen adequate fluid intake, adequate and accurate administration of sulfonamide, and a dilute alkaline urine were assured. The second and third twenty-four-hour period of therapy were usually much less standardized and consisted simply of maintaining the 20 to 40 mg. per cent level of drug in the blood with sufficient fluids and alkali to maintain a large volume of alkaline urine. As soon as the

GOLDRING ET A L . :

SEVERE I N F E C T I O N S

IN

INFANTS

AND CHILDREN

27

patient became sufficiently rational and cooperative, usually within the second period of twenty-four hours, drug and fluids were begun orally. The initial intensive chemotherapy was relaxed as soon as definite clinical improvement was apparent. Adults were usually dropped from 15 Gin. per twenty-four hours to 12 Gin., then to 8 Gm., and maintained on 8 Gin. daffy for about five days. In children when the temperature was normal for two days, the drug dosage was reduced to 0.2 Gin. for ] or 2 days, then to 0.1 Gin. per kilogram per twenty-four hours, and after two more days of normal temperature, drug administration was discontinued. The average number of days that all patients in this series were treated with sulfonamides was 8.9 days. Sulfonamide levels of the blood and spinal fluid were obtained every day on those patients who were treated with sulfamerazine and sulfapyrazine, and the findings have beeen published elsewhere,s, a In those patients receiving the other sulfonamides, drug levels of the blood were secured every other day, and spinal fluid levels were obtained whenever lumbar puncture was done. Thirty-six patients in this series received antimeningococcal serum2 The antiserum was given only to those patients who were in shock or were moribund in the admitting room, usually from fulminating meningococcemia. Adults were given from 40,000 to 60,000 units and children from 20,000 to 30,000 units, one-half intravenously and the remainder, intramuscularly. Such patients were given, in addition to chemotherapy and antiserum, adrenal cortex hormone, intravenous glucose, oxygen, adrenalin, and other stimulants. COMPLICATIONS Fortunately there were few serious complications observed during this epidemic. Arthritis was one of the most common and was noted in 20 cases (9.5 per cent). Only the joints of the extremities were involved, and in each instance more than one joint was affected. Arthritis was noted both early and late in the course of the disease, and it was not unusual to have the disability develop while the patient was receiving sulfonamide treatment. Most of the affected joints showed tenderness, swelling, increased heat, redness, and limitation of motion. Very few patients developed a frankly purulent arthritis, and when pus was aspirated it was always found to be sterile. Nopermanent residual disability was seen in any of the patients. There were 6 cases (2.9 per cent) of bilateral deafness. All of these patients were unconscious and gravely ill for the first few hospital days, so that the deafness was not apparent until convalescence had begun. It was our impression that the deafness was total, although no accurate analysis of the degree of deafness was made. In no instance had the hearing improved at the time of discharge, and these patients have not been followed since leaving the hospital *Lederle Laboratories,

Inc.

28

TIlE

JOURNAL

OF PEDIATRICS

There was noted in one patient a peripheral facial palsy and foot drop. Both palsies had disappeared before the patient's discharge from the hospital. In another patient a gross tremor appeared that was Iimited to the upper extremities, and the tremor was still present at the end of the hospital stay. Four patients had one or more generalized convulsions late in t h e i r convalescence. These were the first convulsive episodes known to the patients or ttieir relatives. There was a family history of epilepsy in only one of these individuals. It was impossible to follow these patients after discharge, but at the last examination they presented no abnormal findings. One individual was admitted with a bilateral metastatic panophthalmitis and was partially blind. At the time of discharge vision had returned, and the eyes appeared quite normal. CO]~PLICATIONS OF SULFONAMII)E THERAPY

Twenty-seven unfavorable reactions to su]fonamide drugs were recorded, an incidence of 13.3 per cent in the 202 patients receiving chemotherapy. Only two of these reactions occurred in patients who died, and in bnly one instance was the sulfonamide a possible factor in the fatal outeome. This was the case of a 52-year-old white male who responded very poorly to sulfamerazine and finally developed pneumonia after two weeks of sulfamerazine therapy with blood levels varying between 12 and 25 mg. per cent. Because he developed pneumonia while on sulfamerazine, it was decided to change to sulfapyridine, and the patient died after four days on this latter drug. At autopsy there were concretions in the kidneys and ureters with evidence of obstruction of the urina~w tract. The concretions obtained at autopsy were analyzed* and were found to be composed of acetylsulfamerazine. Another serious complication was seen in the series, but the patient recovered. This was an instance of agranuloeytosis that developed in a patient receiving sulfadiazine. A single instance of mental confusion due to sulfapyridine was noted. Four patients developed uncomplicated morbilliform rashes that were not of serious consequence. Five instances of drug fever were recorded. The most common complication of sulfonamide therapy was gross hematuria, which occurred 15 times, an incidence of 7.4 per cent. Microscopie hematuria was noted in an additional 15 instances. There were 2 patients with hematuria who had associated abdominal pain that was interpreted as being due to ureteral obstruction and spasm. The following table indicates the percentage of hematuria occurring with the various sulfonamides. DRUG Sulfadiazine Sutfamerazine Sulfapyrazine Sulfathiazole Sulfapyridine

NUIv~BER OP PATIENTS 110 36 23 15 9

GROSS I-IEMATURIzk 10 3 2 0 0

I~[ICROSCOPIe PERCENTAGE OF ttE-~[~kTURIA. GROSS Hlgh~ATURIA 9 9.0 I 8.3 0 8.7 0 0.0 5 0.0

*The chemical analyses were carried out in the laboratories Inc., ~ l e n o l d e n , Pennsylvania.

of Sharp & Dohme,

GOLDRING E T AL. :

SEVERE I N F E C T I O N S

IN INFANTS

AND CHILDREN

29

Too much weight should not be given these figures, because as has already been pointed out, the eases were selected for the different drugs. Therapy with sulfathiazole, for example, was never Very intensive because the less seriously ill patients were given this sulfonamide. The early eases given sulfamerazine were carefully chosen also because for a time the sodium salt was not available for parenteral use. FATALITIES

Before a statement is made about the case fatality rate in this series, certain factors which directly influenced it should be stressed. (1) Both extremes in age were represented. The youngest patient was 3 months of age and the oldest, 80 years of age. Nineteen Patients seen in this epidemic were under 2 years of age, and 6 were u n d e r 1 y e a r of age. Thirty-seven patients were 40 years of age or over. Twenty-four patients were 50 years or over, and 7 persons were over 60 years of age. (2) Although 78 of the patients in this series entered the hospital during the first twenty-four hours of illness, 98 patients entered for treatment after two days of illness. Thirty-one patients entered the hospital a f t e r f o u r or more days of illness. (3) V e r y few patients (41) in this series received sulfonamide thera p y before e n t r y into the hospital, and in most of these cases the t h e r a p y was inadequate. The total number of deaths in this series was 19, whicl~ represents a 9.1 per cent case fatality rate. Ten patients died within twenty-four hours after admission. These patients died either before any t h e r a p y was given or received only a minimal amount of sulfonamide drug. I f we deduct this number from the total of 19, we then have a corrected mortality rate of 4.5 per cent. Among the 9 patients who survived for more than twenty-four hours but eventually died, 5 were 60 years of age or over, and 3 were 45 years or over. As already noted, one of these patients probably died from the toxic c0mplieations of sulfonamide chemotherapy one week after the meningitic process was cured and while he was being treated for a bronchopneumonia which developed in the wake of his initial illness. AUTOPSY FINDINGS Post-mortem examinations were allowed on 10 patients. The findings were not unusual. There were 2 patients , II. H. (56-43) and R. T. (i418-42), who showed extensive hemorrhage ~into the adrenal glands. Both of these patients had a fulminating type of meningococeemim Two patients showed acute i~ulmonary edema, J. S. (2-43) and J. M, (30943). The other autopsies revealed only the evidence of p u r u l e n t meningitis.

30

THE JOURNAL OF PEDIATRICS COMMENT

In reviewing our experiences during this epidemic, we were impressed with the importance of instituting immediate, intensive parenteral chemotherapy as soon as a definite diagnosis of purulent meningitis was made. Earliest possible therapy is important because of the rapid fulminating course taken by some forms of this disease. We have seen a number of patients die within from twelve to twenty-four hours after the onset of symptoms. Initial intensive therapy is of importance because at first inspection of a patient with meniugococcal infection it is impossible to predict how severe the illness will be. Since the optimum in vivo bacteriostatic sulfonamide drug level effective against the meningoeoccus has not been established definitely, we believe it is best to obtain levels which are certain to be effective against this organism. We consider this level to be between 20 to 40 rag. per cent. A second point in favor of intensive chemotherapy i n t h e treatment of meningococca] meningitis is that frequently the recovery of the meningocoecus is delayed for one or more days, and a patient thought to be infected with the meningococcus is later found to have a purulent meningitis due to the pneumoeoccus or influenzal organisms. The levels of drug we strived to attain; that is, 20 to 40 rag. per cent would, therefore, be considered adequate to cope with any of these infections. The parenteral route of administration of the drugs was depended upon since we could place little reliance on drugs given by mouth to be retained, as many of the patients were vomiting during the first one to two days of their illness. The intravenous route of sulfonamide administration was abandoned in favor of the subcutaneous method of a,dministration, although the former method is quite good if the patient is not dehydrated. It seemed most satisfactory to us to give the sulfonamide drugs subcutaneously in 1/2 per cent solution. The sodium salt thus diluted was found to be nonirritating to the tissues, and hydration of the patient was accomplished concurrently, and adequate blood levels usually were attained in from two to three hours. SUMMARY AND CONCLUSIONS

1. Two hundred and nine patients with meningococcic infections were admitted to the St. Louis Isolation Hospital between January of 1942 and August of 1943. The majority of cases was seen in the first six months of 1943: 2. A predilection of the disease for younger individuals and for Negroes was noted, There was a fairly equal distribution between the sexes.

GOLI)R!NG ET AL. :

SEVERE INFECTIONS IN INFANTS AND CHILDREN

31

3. Classical signs of meningitis or meningococcemia were present in the majority of patients. Petechiae were noted in 155 instances. 4. The diagnosis of meningococcal infection was based on the recovery of the meningococcus from blood or spinal fluid or on the discovery of typical petechiae in patients with purulent but sterile spinal fluid. 5. A regimen of rather intensive sulfonamide chemotherapy was used with satisfactory results. It is felt that the optimum blood sulfonamide level is between 20 and 40 rag. per cent until the patient shows definite clinical improvement. No unusual evidence of harm to patients from these blood' levels was noted. A large volume of dilute alkaline urine is thought to be important in preventing hematuria. Sulfanilamide may be used to replace other sulfonamides in the treatment of meningococcic infections if gross hematuria or suppression of urine occurs. 6. The newer sulfonamides, sulfamerazine and sulfapyrazine, appear to be as effective as sulfadiazine in cont"oiling meningococcic infections. For careful clinical studies of these drugs, the reader is referred to earlier reports in the medical literature. 7. The case fatality rate in this group of patients was 9.1 per cent. One-half o f the deaths occurred in patients who were moribund on admission. If these deaths are excluded, the case fatality rate is 4.5 per cent. The majority of deaths in patients who survived over twentyfour hours after admission to the hospital occurred in elderly individuals. I~EFEI~ENCES 1. Statistical ]~ulletin, Metropolitan Life Insurance Co., Vol. 24, No. 8, Aug., 1943. 2. Blattner, R. J., Heys, F. M., and I-Iartmann, A. F.: Arch. Path. 36: 262, 1943. 3. Barnett, H. L., Perley, A. M., Forbes, G. B., and Goldring, D.: Am. J. M. Sc. 206: 599, 1943. 4. Hartmann, A. F., Perley, A. M., and Barnett, H . L . : J. Clin. Investigation 17: 699, 1938. 5. Brinton, D.: Cerebral Spinal Fever, Baltimore, 1941, Williams and Wilkins Company, p. 16. 6. Hill, L. W., and Lever, H. S.: J . A . M . A . 123: 9, 1943. 7. Thomas~ H. M., Jr.: J . A . M . A . 123: 264, 1943. 8. Hageman, P. O., Itarford, C. G., Sobin, S. S.~ and Ahrens, R . E . : J . A . M . A . 123: 335, 1943.