Intra-articular penicillin treatment of suppurativearthritis in infants and children

INTRA-ARTICULAR PENICILLIN TREATMENT OF SUPPURATIVE ARTHRITIS IN INFANTS AND CHILDREN JAMES L . TUCKER,

M.D., AND WARRE:N R. TEPPER, M . D . NEW YO~K, N. Y.

LTHOUGH local treatment of suppurative arthritis with penicillin has been advocated,!-~ we have been unable to find any detailed reports of such therapy in infants and children; three cases thus treated were briefly mentioned by Herre]l and Kennedy ~ in a report on the use of penicillin in pediatrics. The paucity of data prompted this report of four cases of pyarthrosis treated by intra-articular penicillin on the Pediatric service of the New York Hospital between November, 1944, and January, 1946. CASE REPORTS CASE 1.--M~ P., a newborn, white female infant, was admitted on Oct. 22, 1944, because of an imperforate anus. Multiple gastrointestinal and genitourinary anomalies were found at operation. On the t e n t h postoperative day the t e m p e r a t u r e rose to 38.2 ~ C. and the white cell count was 55,000 with 92 per cent polymorphonuclear cells. E x a m i n a t i o n disclosed moderate purulent drainage irom a cut-down site in the ankle. Blood, nose, throat, and ankle cultures showed a hemolytic Staphylococc.~s aureus. Intramuscular penicillin (10~000 units every three hours~ doubled a f t e r five days) and sulfadlazine (0.2 Gin. per kilogram per day) were s t a r t e d on the eighteenth postoperative day. A f t e r ten days of this intensive eomblned t h e r a p y the left shoulder was noted to be swollen, l~oentgenogram showed osteomyelitis w i t h f r a g m e n t a t i o n of the cortex and periosteal elevation of the head and neck of the humerus. Aspiration of the shoulder joint released a sma]] amount of pus which contained a hemolytic Staph. a~reus (Table I). For the twenty-one succeeding days, 8,000 units (10~000 units once, 15,000 units twice) of penicillin in one to 2 e.e. of saline or distilled w a t e r were injected daily into the ]eft shoulder joint. Pus was not encountered on all occasions; when present~ cultures were positive for hemolytic Staph. aure~s, even on the twentyfirst day of intra-articu]ar therapy. Roentgenogram on the n i n t h day of topical therapy was i n t e r p r e t e d as pyarthrosls with infectious ehondritis and early osteomyelitis, and on the eighteenth day as pyogenic arthritis, a p p a r e n t l y hea]ing, With destruction of upper end of humerus. Intramuscular penicillin therapy was continued and the blood euiture became sterile. Perslstenee of leueoeytosis and f e v e r was a t t r i b u t e d to other active foei of infection, renal abscesses. The extreme resistance of the organism to penicillin was confirmed by in vitro tests (survival of organism in a concentration of 6 units per cubic centimeter). A single intraarticular injeetlon of 15,000 units of penieil]in was given on Dee. 13, t944. The foltowlng week three massive doses of 100,000 units in 2 e.e. of w a t e r were g i v e n intra-artieularly at two-day intervals. No pus was obtained for culture. Intramuscular penicillin was discontinued on Dee. 16, 1944, but sulfadiazine was maintained w i t h blood levels of 6 to 8 rag. per cent for three more'months. Roentgenograms two weeks a f t e r the last intra-artieular injection showed distention of the joint capsule w i t h residual osteomyelitis (Fig. 1). No f u r t h e r t r e a t m e n t was given nor were f u r t h e r roentgenograms taken. The child succumbed to chronic pyelonephritis eleven months later. Although the left shoulder remained larger than the right, there was no limitation in active or passive motion. On gross examination at autopsy, the left humerus and shoulder joint were found to be e n t i r e l y normal. From the New York Hosp]ta! and the Department of :Pediatrics, CornelI University Medical College. 711

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CASE 2 . - - J . P., a w h i t e girl of 5 m o n t h s , w a s a d m i t t e d on Feb. 13, 1945. Three weeks prior to admission t h e c h i l d ' s r i g h t a r m w a s forcibly pulled. The n e x t day she w a s irritable, lind a poor a p p e t i t e a n d r e s e n t e d m o v e m e n t of t h a t arm. H e r t e m p e r a t u r e w a s 38.3 ~ C. On p h y s i c a l e x a m i n a t i o n in t h e o u t p a t i e n t d e p a r t m e n t two d a y s later, it w a s n o t e d t h a t she f a v o r e d the r i g h t shoulder, b u t there were no objective signs. R o e n t g e n o g r a m of the shoulder was n e g a t i v e a n d the total w h i t e blood cell a n d differential counts were normal. The f u n c t i o n of the a r m improved, b u t she r a n a p e r s i s t e n t , low-g~ade f e v e r w h i c h rose to b e t w e e n 39.4 ~ C. a n d 40.6 ~ C. d u r i n g t h e l a s t t h r e e d a y s at home. On t h e m o r n i n g of a d m i s s i o n t h e r i g h t s h o u l d e r became red a n d swollen. The child a p p e a r e d acutely ill w i t h a t e m p e r a t u r e of 38.6 ~ C. The r i g h t a r m w a s held in p a r t i a l a b d u c t i o n and e x t e r n a l rotation. There was m a r k e d swelling of t h e deltoid a r e a e x t e n d i n g into t h e neck; the circumf e r e n c e of the r i g h t shoulder ( a r o u n d t h e axilla) being 51/2 cm. g r e a t e r t h a n t h e left. There was no increased h e a t or fluctuation. The remainder of the examination was negative.

A.

B.

Fig. 1 (Case 1 ) . ~ A , l~oentgenogram on ninth day of topical therapy. weeks after last intra-articular injection.

B, Roentgenogram two

The leucocyte count was 34,200 w i t h 5 per cent l y m p h o c y t e s , i per cent monoeytes, 72 per cent m a t u r e a n d 22 per c e n t i m m a t u r e p o l y m o r p h o n u c l e a r cells. Cultures of t h e nose~ t h r o a t a n d blood showed p n e u m o e o c c u s t y p e VII. I n i t i a l r o e n t g e n o g r a m showed dist e n t i o n of the right shoulder joint, rarefaction of the proximal metaphyseal end of the h u m e r u s and obliteration of the smaller, proximal, epiphyseal center (Fig. 2).

~ i g . 2 ( C a s e 2 ) . - - - A , t ~ o e ~ t g e n o g r a m on a d m i s s i o n .

A,

B, t ~ o e n t g e n o g r t ~ m a f t e r discharge.

~)~ one w e e k ,

C, R o e n t g e n o g r a m

C. one

year

after

O$

-q

~V

cr~

O

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T~

CASES

1

3

NA~E AND AGE M.P., 10 days

DURATION OF ILLNESS BEFORE AI)MIS-

0RGAIqISI~ JOINT tIemolytic Left Staph. shoulaurvus der

BLOOD CUL-

TUm~

TO TA L UNITS INTKA ARTICULAR PENICILLIN

INTRAARTICULAR DOSES

(NO.)

OTHE~ TEE~.'~ME~ . AND DURATION Sulfadiazine thro~ out; penicillin I.] until 4 days beret last intra-articul~ injection

17 d a y s

Pos.

504,000

25

20 days

Pos.

500,000

7

Sulfadiazine from~ to 20th day; pe~i, ]in I.M. first 6 da,

J.P., 5 me.

Pneumococcus VII

Right shoalder

C. 8., 31~ yr.

Beta hemolytic strepto-

l~ight knee

2 days

I~eg.

1,101,000

10

Sulfadiuzine 2rid to 15th day; penieil I.NL first 11 days

Left elbow

3 me.

Neg.

765,000

8

Penicillin I.M. bef( admission and 7~ days in hospital

COCCUS

4

1%.H., 7 yr.

Hemolytic Staph. aureus

The diagnosis of acute p y a r t h r o s i s of the r i g h t shoulder a n d osteomyelitis of the a d j a c e n t humerus w a s confirmed b y a s p i r a t i o n of the j o i n t w h i c h produced 10 c.c. of creamy pus. Smear of the exudate revealed m a n y white cells a n d i n t r a c e l l u l a r and extracellular gram-positlve dip]ococei, p r o v e d on culture to be pneumococcus type V I I . Sodium penicillin (100,000 u n i t s dissolved in 10 c.e. of sterile w a t e r ) was i n j e c t e d w i t h ease into the joint. Concomltantly~ 10,000 u n i t s of penicillin were g i v e n i n t r a m u s c u l a r l y e v e r y three hours. A s p i r a t i o n of the j o i n t a f t e r t h i r t y - s i x hours yielded 6 c.e. of pus containing m a n y w h i t e cells and a few organisms. I n all, penicillin was i n j e c t e d i n t r a - a r t l c u l a r l y seven times over a period of nine days in doses of 50,000 to 100,000 u n i t s dissolved in 2 to 10 e.c. of water, the total dosage b e i n g 500,000 units. I n t r a m u s c u l a r penicillin was discontinued on t h e sixth day, a n d sulfadiazine was b e g u n and continued for the n e x t two weeks in a daily dosage of 0.2 Gin. per kilogram of body w e i g h t per day. Blood levels r a n g e d between 4 and l0 rag. per cent. P h y s i o t h e r a p y was confined to hot packs from t h e e l e v e n t h to the twentieth day. Small, whole blood transfusions were administered early in the course a s supportive therapy. All except the first culture o f the a s p i r a t e d pus were n e g a t i v e ; no organisms were seen o n smear a f t e r the f o u r t h treatment. E i g h t days a f t e r the last topical injection; no fluid could be aspirated from the joint. On the sixth hospital day, motion of the shoulder became f r e e r and less painful. Passive motion was painless i n one week, a n d vigorous active motion r e t u r n e d in one month. Serial roentgenograms showed progressive improvem e n t (Fig. 2). The t e m p e r a t u r e was n o r m a l a f t e r the first twelve hours. The w h i t e blood cell count fell to 17,000 t h e day a f t e r admission, remained between 1G500 and 20,0.00 w i t h a s h i f t to the left for t h i r t e e n days, a f t e r w h i c h i t was normal. Nose, .throat, a n d b l o o d cultures were n e g a t i v e f o r pneumocoecus on the t e n t h day. S e d i m e n t a t i o n r a t e was normal o n t h e s i x t e e n t h day. The p a t i e n t was discharged M a r c h 16~ 1945. The last r o e n t g e n o g r a m t a k e n one year a f t e r t h e onset (Fig. 2) showed no a b n o r m a l i t y in the j o i n t an(] minimal t h i c k e n i n g of

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FOLLOW-UP

INTERVAL BEFORE NEGATIVE JOINT CULTURE

iNTEEVAL BEFORE NORMAL TEmPERATURE

INTERVAL REPORE NORMAL W.B,C.

Never (see history)"

Never (see history)

12 hours

13 days

1 day

30

1 year

General health excellent ; afebrile ; no local pain or deformity; no limitation of motion in joint; x-ray negative

8 days

8 days

2 days

30

9months

General health excellent ; afebrile ; no local pain or limitation of motion; metaphysis broader in involved leg; x-ray shows roughening of articular surface

6 days

86

3 months

General health excellent ; afebrile ; persistent wasting of musculature of arm; extension limited to 170~ still gets physical therapy; x-ray shows healing bone and normal joint

36days

Never elevated

About 28 days

DAYS IN HOSPITAL 401 (see his: tory)

DUlgATION

I

CONDITION

Died at 13.months o f c h r o n l c pyelonephritis; postmortem examination of joint was negative

the lateral cortex of the upper humerus. When last seen on March 22, 1946, the child was in excellent general health, and there was no pain, deformity, or limitation of motion in the r i g h t shoulder. CASE 3.--0. S., a white girl of 31/2 years, had a tonsillectomy and adenoidectomy at another hospital nine days prior to admission. Seven days later she complained of pain in the right leg and f e l t feverish. She was a d m i t t e d on May 16, 1945, appearing acutely ill, w i t h a t e m p e r a t u r e of 40.8 ~ C. Impetiginous lesions were present on the face; the tonsillectomy site was healing. The right knee was hot~ red, and swollen , held rigidly at a 90 degree angle, and was extremely painful on motion. The leucocyte count was 19,000 with 74 per cent polymorph0nuclear cells, 10 per cent of which were b a n d forms. Nose and t h r o a t cultures produced a heavy growth of beta hemolytic streptococcus; blood culture was sterile, l~oentgenpgram demonstrated nmrked distention o f the joint space, bu]glng in the popliteal fossa, and anterior displacement of the patella (Fig. 3). The joint was aspirated, and 2 c.c. of thick, yellow-green pus was w i t h d r a w n which contained beta hemolytic streptococcus by culture; organisms and pus cells were seen on smear. Treatment consisted of dally aspirations and instillations o f 100,000 units of peril cillln for two days, t h e n 100,000 units in both the medial and lateral compartments of the right knee for four days; the diluent was distilled w a t e r in amounts equal to the pus withdrawn and ranged from 2 to 8 c.e. The total intra-articular dose was 1,101,000 units. In addition, penicillin was given intramuscularly, 20,000 units every three hours for a week, t h e n 10,000 units at three-hour intervals for five days. Two blood transfusions were given during the first f o r t y - e i g h t hours. All cultures f r o m the knee were sterile a f t e r the second day, but smears continued to show gram-positive cocci for six days. A f t e r n o o n f e v e r of 38.6 ~ C. persisted for eight days a f t e r admission; t h e r e a f t e r temperature was normal. The white blood count fell steadily and reached normal on the eighth day. For the first three days the c h i l d ' s gen-

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eral condition was critical, but t h e n r a p i d i m p r o v e m e n t ensued. Active motion of the leg was achieved on the fifth day; w e i g h t b e a r i n g was ]permitted on t h e t e n t h day~ and a f t e r two weeks she could walk alone w i t h o u t p a i n and w i t h only a slight ]imp. There was no l i m i t a t i o n to passive motion. She was discharged on J u n e 15, ]945, and t h e r e a f t e r received a course of i n f r a r e d t h e r a p y and actlve-passive exercises. A.

Fig. 3 (Case 3).---A, l~oentgenogram on admission. B, l~oentgenogram nine months after discharge. The last roentgenogram was t a k e n on 3~arch 22, 1946 (ten months a f t e r onset), d e m o n s t r a t e d residual irregularity of the articular surfaces. The child has remained w i t h o u t pain or limitation o f motion in the r i g h t knee and runs w i t h o u t difficulty. region over the medial aspect of the m e t a p h y s i s of the r i g h t knee was prominent, t h a t leg was half an inch greater in circumference than the left.

and well The and

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717

CASE 4.--R. H., a white boy of 7 years, was in good health until July 29, 1945, when he developed a f e v e r of 38.9 ~ C. and severe ~pain and swelling of the left elbow. He was put to bed and given salicylates and local heat for one week. The f e v e r subsided but the local ~ain and swelling persisted. In early August, four intramuscular injections of penicillin in b e e s w a x were given at two-day intervals, 300,000 units per dose. The pain di-

minisheff promptly.

Despite infrared radiation for one month and alternating ten-day

courses of salicylates and sulfadiazine for approximately six weeks, the swelling of the elbow increased and local heat and pain recurred. On Sept. 7 and Sept. 20, 1945, the j o i n t was aspirated; the cloudy fluid was sterile on culture and roentgenogram of the elbow was reported as negative. A cast was applied for two weeks. The patient remained in bed with an evening oral temperature of 37.8 ~ C. The boy was a d m i t t e d to the New York Hospital on Oct. 24j 1945, eleven weeks a f t e r the onset of the illness. He was welt nourished, not appearing acutely ill, w i t h temperature of 38.5 ~ C. There was moderate w a s t i n g of the musc]e groups of the l e f t arm and forearm. The elbow was swollen, fluctuant, slightly red, and tender about the olecranon. Motion in all planes (including pronation and supination) was limited to 10 degrees.

A.

~.

Fig. 4 (Case 4).--A, ~oentgenogram on admission. B, Roentgenogram two months after discharge. Hemoglobin was 10 Gin., red cell count 4,500,000; the leucocytes were 12,200 with 41 per cent polymorphonuc]ear cells, of which 12 per cent were band forms. Corrected sedimentation rate was 1.45 mm. per minute (normal up to 0.4). Mantoux t e s t and blood culture were negative. Roentgenogram of the elbow on admission showed destruction of the ca,pite]lum and trech]ea, thickening of the periosteum of the humerus, and fusiform distention of the joint capsule, diagnosed as suppurative a r t h r i t i s with associated osteomyelitis (Fig. 4). Five cubic centimeters of purulent fluid were aspirated from the involved joint; no organism was observed on smear, but hemolytic Staph. aureus was cultured. I t was later found to be sensitive to 0.082 units of penicillin per cubic centimeter in vitro. I n the first two weeks the p a t i e n t was given 10,000 units of penicillin sodium intramuscularly every three hours. Seven joint aspirations were performed, each with replacement by

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100,000 units of penicillin in distilled water. Ten days after the last dose of this intensive regimen, aspiration yielded no pus, and 65,000-units were injected, making a total iutraarticular dosage of 765,000 units. I n t r a m u s c u l a r penicillin was continued for eleven weeks for a total of 8,132,000 units. A f t e r the first two aspirations, all cultures and smeais were negative, l~oentgenographic evidence of improvement was slow. The total white count was normal~ but there was p e r s i s t e n t elevation of band forms. Sedimentation rate reached a normal level a f t e r seventy days. Low-grade fever disappeared a f t e r thirty-six days. The arm was never immobilized, and active motion was encouraged. Physical t h e r a p y (whirlpool and active-passive exorcise) was instituted a f t e r the fiftieth day. The return in the range of motion is tabulated in Table II. The boy was discharged on Jan. 18, 1946, a f t e r twelve weeks of hospitalization, physical t h e r a p y being continued. TABLE II.

IMPROVEMENTIN I:,.ANGE OF I~V[OTION FOLLOWING INTI%A-ARTICULAI~ PENICILLIN T HEF.APY FLEXION-

DATE 10/24/45 11/15/45 1 / 7/46 1/17/46

3/26/46

DAYS Admission 22 75 85 (Discharge) 153

PEONATION-

EXTENSION 10 degrees 45 degrees 80 degrees 140 degrees

SUPINATION 10 degrees 80 degrees 80 degrees 90 d e g r e e s

170 degrees

90 degrees

The last roentgenogram on April 11, 1946, demonstrated t h a t the capitellum and troehlea were beginning to reform and there was no distention of the joint capsule (Fig. 4). Periosteal proliferation was decreased and general appearance of bone structure improved. There was no evidence of active destructive process. A t this time the boy seemed in excellent health and had no complaints. There was still some w a s t i n g of the muscle g r o u p s of the left arm which exaggerated the bony prominences about the elbow. Extension of the arm Gould a c t be performed beyond 170 degrees, b u t he used t h a t extremity without pain or awkwardness. No other movements were limited. DISCUSSION

Organism.--The infecting organisms were all gram-positive: helnolytic Staph. aureus in two cases ; beta hemolytic streptococcus ill one; pneumococeus type VII in one. Blood cultures were positive in two cases. As in the experience with other penieillin-treatecl infections, hemolytic Staph. aureus was the most difficult to manage. The strain in Case 1 was resistant in vitro to penieilIin concentrations of 6 units per cubic centimeter. Source of Infection. In one case (Case 4) no a n t e c e d e n t cause could be identified; whether the pyarthrosis was p r i m a r y or secondary to osteomyelitis could not be determined. The n e w b o r n infant (Case 1) m a y have developed bacteriemia from an infected cut-down site. 0steomyelitis p r o b a b l y preceded the joint infection here and in Case 2, where local t r a u m a initiated the disease. The other ease (Case 3) was an uncomplicated pyarthrosis, the blood stream presumably having been invaded from open wounds in the throat or on the face. Treatment.--Intra-articular injections of penicillin in large dosage were continued for as long as pus could be aspirated from the joint, even if previous cultures Were negative. When the pus was sterile on culture it was interpreted as being due to the presence of penicillin in the exudate and the resultant" inNbition o f growth on eutture media.

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719

The hazard of undertreatment should be emphasized. Sterilization of the joint was not achieved in the infant (Case 1) with twenty-one daily intraarticular injections of 8,000 units each. The extreme resistance of the organism which was then discovered justified the massive dose (100,000 units) used thereafter. The small amount of diluent (2 e.e.) was determined by the limited amount of pus withdrawn on aspiration. Treatment was discontinued arbitrarily after three such doses with no recurrence. Dosage of this magnitude and in these high concentrations did not increase local discomfort; similar intensive topical therapy has been reported. 7 In Case 4, inadequate therapy at home served only to ameliorate the symptoms and to send the disease into a chronic course. The large total dosage in Case 3 was due to the presence of two noncommunicating pus pockets in the knee, each being treated separately. Intramuscular penicillin was administered because of the gravity of the disease, the presence of positive blood cultures in two cases, and Qf osteomyelitis in three eases. Whether systemic t he rapy is necessary in all cases of pyarthrosis is not definitely determined. Rammelkamp and Keefer 8 demonstrated penicillin in the blood stream after intra-artieular injection, and Bagley 7 has proposed this site as the preferred one for parenteral injection, even in the absence of joint disease. By use of massive dosage he showed that therapeutic blood levels can be achieved. On theoretical grounds, intra-artieular penicillin should sterilize the joint directly hnd the blood stream and other loci of infection secondarily. ~ This remains to be proved clinically. On the other hand, it has been demonstrated by Tillett and associates 9 that intravenous penicillin can sterilize a pneumoeoeeal infection of the joint; and Balbon) and associates 1~ found that intramuscular penicillin penetrates the joint in a high concentration, disappears slowly, and does not accumulate. These results might imply that aspiration and intra-artieular therapy are not necessary. Nevertheless, it would seem preferable to evacuate the pus by aspiration in the presence of pyarthrosis and to allay concomitant discomfort rather than to await spontaneous resorption. The optimal route of administration and dosage is still to be determined. In three eases oral sulfadiazine was given. The first infant (Case 1) was desperately ill, and all available therapeutic agents seemed indicated. However, the pyarthrosis developed after a three-week course of sulfadiazine. In Case 3, the child remained critically ill after twenty-four hours of penicillin therapy, hence sulfadiazine was added to the therapeutic armamentariuni. Sulfadiazine was given late in Case 2 after marked clinical improvement on penicillin alone. We have no definite evidence that sulfadiazine shortened the course of the pyarthrosis in these eases. The question of the advisability of surgical intervention was raised in Cases 3 and ~ because of the failure of immediate response and the development of separate pus pockets within the same joint in the former and the chronicity of the disease and adjacent osteomyelitis in the latter. A recent paper 1~ recommends early surgery as a means of facilitating local instillation of penicillin when pyarthrosis complicates staphylococcal osteomyelitis, tIowever, opgn drainage increases the likelihood of subsequent limitation of motion

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in the joint. Therefore, we p r e f e r r e d to allow a t h e r a p e u t i c trial of intram u s c u l a r and i n t r a - a r t i c u l a r penicillin first, and were gratified with the outcome both in curing the p a t i e n t s and in r e s t o r i n g full f u n c t i o n to the involved joints. Course.--The hospital course was r e m a r k a b l y brief and uneventful, considering the nature of the disease, except in the first patient, who had other complications. I n the other three cases, w i t h i n a week a f t e r the first i n t r a - a r t i c u l a r dose the children h a d r e g a i n e d p a r t i a l use of the affected joint a n d seemed well on the w a y to recovery. T h e y w e r e s p a r e d immobilization in c u m b e r s o m e dressings a n d casts, a n d the only t r a u m a was f r o m the aspirations. T h e i r general i m p r o v e m e n t in health was g r a t i f y i n g . SUMMARY F o u r cases of s u p p u r a t i v e arthritis in infants and children have been presented, in which surgical i n t e r v e n t i o n was not required. Three were in the acute stage of the disease a n d one in the chronic stage, a n d a d j a c e n t osteomyelitis was p r e s e n t in three. All w e r e t r e a t e d b y joint a s p i r a t i o n a n d intraa r t i c u l a r instillation of penicillin. S u p p l e m e n t a l t h e r a p y consisted of intram u s c u l a r penicillin in all, oral sulfadiazine in three, transfusions, and physiotherapy. Three surviving p a t i e n t s were seen a f t e r discharge at three, nine, and t w e l v e months, respectively, w i t h complete r e t u r n of ~unction in th~ tast two a n d w i t h o u t r e c u r r e n c e in any. I t is suggested on a theoretical basis t h a t i n t r a - a r t i c u l a r penicillin t h e r a p y alone in large dosage m a y be adequate. Acknowledgment is made to Dr. It. Temple and Dr. A. J. Tillinghast of the Department of Roentgenology of the New York Hospital for reviewing the films. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.

Keefer, C. S., and others: J . A . M . A . 122: 1217, 1943. Ravdin, I. S, and Johnston, C.G.: Am. J. M. Sc. -008: 248, ]944. Dawson, IV[.H., and Hobby~ G.L.: J . A . M . A . 124: 611, 1944. }Ierrell, W. E., Nichols, D. R.~ and }teilman, D.H.: J.A. 5/[. A. 125: 1003~ 1944. Anderson, D.G.: New England J. ~ed. 232: 400, 1945. l=~erre]~,W. E., and I~ennedy, L.J.: J. P~DIAT.25: 505, ]944. Bagley, W. 1~.: South. lV[ed. & Surg. 107: 180, 1945. Rammelkamp, C. H., and }~eefer, C.S.: J. Clin. Investigation 22: 425, ]943. Til]ett, W. S., McCormack, J. E., and Cambier, M.J.: J. Clin. Investigation 24: 595, 1945. 10. Balboni, V. G., Shapiro, L. ]V[., and Kydd, D. 1VL: Am. J. M. Sc. 210: 588, ]945. 11. Anderson, D. G.: New England J. Med. 232: 423, ]945.