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The treatment of gonorrheal vaginitis with Corbus-Ferry gonococcus filtrate
T H E T R E A T M E N T OF GONOI%I{I-IEAL V A G I N I T I S W I T H C O l { B U S - F E R R Y GONOCOCCUS F I L T R A T E L o u i s E. GOLD~ERG, M.D., NE:WARK, N. J., A~I) Xt~NNET'H I3LANCI~AR,D, M.D., EAST ORANGE, N. J. v a r i e t y of empiric methods and new suggestions D EofS P tIrTeEa t mae nwide t we are still s t r u g g l i n g with gonococcus infections, one of the most resistant and age-old affections afflicting humans. S t o c k w e l P holds t h a t g o n o r r h e a existed t h i r t y - s i x centuries before Christ and was observed b y Juvenal, Persius, and Galen. Efforts at cure still continue b y new and old methods. While recent research devoted to the t r e a t m e n t of gonorrheal vaginitis with estrogenic substances is in process of development, the use of gonococcus filtrate for the condition has come to the fore. Controversial evidence seems to indicate t h a t evaluation of these n e w e r t h e r a p e u t i c agents awaits f u r t h e r c o r r o b o r a t i o n in order to be established as superior to the local remedies. This s t u d y on t r e a t m e n t by C o r b u s - F e r r y filtrate e was u n d e r t a k e n to determine the efficacy of the m e t h o d in a group of t w e n t y - f o u r children with gonorrheal vaginitis. I n order to a p p r e c i a t e the v a r i e t y of a p p r o a c h e s to combat the disease it is necessary to recall t h a t go.nocoeci can he acted upon in two ways, as pointed out b y E r n e s t Finger, 2 either directly b y destroying them or indirectly b y p r o d u c i n g a change in their soil, t h a t is, rendering the mucous m e m b r a n e u n f a v o r a b l e to t h e i r proliferation. Treatm e n t b y filtrate is an example of the first method, t h a t by estrogenic substances, of the second method. Chemical destructio.n of the gonococcus has yielded uncertain results because no chemical a g e n t as yet available kills the submucosal bacteria. The beginning of the method of p r o d u c i n g counteraction to overcome the inroad of the gonococcus is traceable to the middle of the nineteenth century. I t was P a s t e u r who laid the f o u n d a t i o ~ of the p r e s e n t activities, the principal f a c t o r being the p r o d u c t i o n in bouillon filtrate 0f a substance called the antivirus. As e a r l y as 1897 the first a t t e m p t s at dealing with a gonococcus toxin were r e p o r t e d by de Christmas. a The opinion is t h a t he used autolyzed cultures containing appreciable amounts of endotoxin, tIerrold; 4 in 1925, did some i m p o r t a n t e x p e r i m e n t a l work, obtaining a filtrate f r o m cultures of the gonococcus. Since w e are concerned with the effectiveness o f a bouillon filtrate containing a n t i v i r u s it would be well to define the m e a n i n g of this * W e a r e i n d e b t e d to P a r k e , D a v i s & C o m p a n y f o r s u p p l y i n g u s w i t h t h e m a t e r i a l f o r t h e t r e a t m e n t of t h e s e p a t i e n t s . 381
382
T H E J O U R N A L OP' PEDIATRICS
term. An antivirus, as described by Corbus and O'Conor 5 is an atoxic, nonantigenic, thermostable substance, f o r m e d in culture media, which is easily detached from the body of the bacterial cells and is antagonistic to them. I t is more a b u n d a n t in the liquid media when all the bacterial cells are dead or incapable of continued proliferation. The antivirus is said to cause the death of the bacteria in the culture medium. Besredka f o u n d that the action in vitro could be produced in viv0. To exert its specific activity the antivirus must come in cont a c t with the bacteria. Corbus, stimulated by the work of B e s r e d k a in specific immuuization by antivirus, directed his attention to the possibility of producing a gonococcal antigen solution. A f t e r p r o l o n g e d experimental work he and O'Conor G succeeded in producing a bouillon filtrate of the organism. The bouillon developed b y them at this time was toxic and antigenic. A f t e r a thorough trial of intra-urethral injections in eighteen cases b y Corbus and O"Conor, the results p r o v e d discouraging. The assistance of Dr. N. S. F e r r y was requested b y Corbus in making a new preparation. In the fall of 1929, Clark, F e r r y , and Steele, 3 using a hormone broth, p r o d u c e d a gonococcus bouillon filtrate and discovered t h a t it contained a soluble toxin and was not an antivirus. This gonococcus filtrate p r o v e d a difficult problem in analysis because of lack of adaptability to artificial conditions of culture and the inherent tendency of cultures of gonococcus to autolyze. In dilutions of 1:1,000 and 1:1,500, the toxin: was f o u n d capable of causing skin effects similar to the Dick reaction. In experimenting with animals it was f u r t h e r revealed t h a t this toxin stimulated the formation of an antitoxin which neutralized in vitro as well as in vivo. Using this new p r e p a r a t i o n by F e r r y , Corbus and 0 ' C o n o r injected it intradermally in two patients. Their results encouraged them to believe t h a t intradermal injections of gonococcus bouillon filtrate, p r o p e r l y controlled, b r o u g h t about specific immunizing effects destructive to the organism in most instances. 7 In vivo bacteria are lodged in certaL~ tissues or ceils. In the application of the antivirus-containing filtrates the biologic fact t h a t skin cells are capable of producing i m m u n i t y has been utilized. In other words, t h e y f o u n d that the antigenetie response from some toxihs, if given intradermally, seems to have the power of inducing general i m m u n i t y for their respective bacteria. I t is generally believed t h a t every virus has its cell and every cell its immunity. But such local i m m u n i t y forms only a p a r t of the general immunity which can be stimulated by i n t r a d e r m a l injections i n t r o d u c e d anywhere in the body. S Corbus and O'Conor 7 later observed t h a t by withholding all other therapeutic methods they could influence the course of the disease
GOLDBERG A N D B L A N C I I A R D :
COI~BUS-FF_,I~I%Y G O N O C O C C U S F I L T R A T E
383
favorably in acute cases but that the rapidity of the cure did not always exceed that attained by means of medicaments. Treatment of eight women with gonorrheal endoeervicitis yielded most encouraging results. In three young girls with vulvovaginitis of specific origin the outcome was equally promising. They felt that in some persons at least the gonococcus was eliminated permanently by these injections alone. In 1932 Corbus again reported on the results of treatment with filtrate in a series of 151 male patients with gonorrheal infection2 Other investigators (~[cKay, Storts, Stockwell, Townsend, and Spence)lo also sought to determine the effectiveness of this type of therapy. The Council of Pharmacy and Chemistry of the American Medical Association made two prMiminary reports, 11 both times awaiting furt her evidence of the clinical value of the Corbus-Ferry filtrate. A recent survey of a number of urologists regarding their opinion of this product, based on actual trial, showed that with but few exceptions, its use has been discontinued either because of lack of therapeutic results or the too common precipitation of serious complications after its administration.12 Experimental observations, however, continued, with both favorable and unfaxorable results (Jamieson, Deakin, Gardner, Whitehonse, and Anwyl-Davies).13 After further consideration the Council of Pharmacy and Chemistry made its final report, 14 declaring that the Corbus-F'erry gonococcus filtrate is not acceptable for new and nonofficial remedies. In the meanwhile we had undertaken our investigation. PI%ESI~NT C L I N I C A L S T U D Y
A series of twenty-four consecutive cases of gonorrheal vaginitis in children at the Essex County Hospital for Contagious Diseases, at Belleville, New Jersey, was made the subject of intensive study. Each child had a history of vaginal infection, associated with a purulent discharge, burning, and itching. The clinical experiment to determine the therapeutic value of Corbus-Ferry gonococcus filtrate in the treatment of this disease was begun on June 9, 1936, and terminated on J ul y 13, 1937. The ages of the children ranged from 2 to ;10 years. The duration of the gonorrheal infection in these patie~ts before institution of the new form of therapy varied from eleven to seventynine days. Previous treatment by local antiseptics had been given over a period varying from one to fifty-four days. In most of the cases it consisted of argyrol, 10 and 20 per cent twice a day, instilled locally, followed by a potassium permanganate douche of 1.8,000 twice a day. Some of the children were given a 2 per cent boric acid douche, followed by application of metaphen ointment ( ~ of 1 per cent) tri-weekly.
38~t
TI={]~ J O U R N A L
OF P]~DIATR.ICS,
I n all cases the e m p l o y m e n t of local m e d i c a m e n t s was s u p p l e m e n t e d b y hygienic measuces. F o r the purpose of ascertaining if the results in the types of gonorrhea would differ, the cases were divided i.nto two groups: acute and chronic. This classification was m a d e arbitrarily, the disease of a d u r a t i o n of f o r t y days or less being considered acute and over f o r t y days, chronic. The entire n u m b e r consisted of fifteen acute eases and nine chronic eases. All patients originally showed positive gonococcus smears, t h a t is, the preseace of g r a m - n e g a t i v e intracellular diplococci of morpho]ogic resemblance to gonococci, which is the criterion f o r the diagnosis of g o n o r r h e a l infection. I n all but two c a s e s the s m e a r s were positive f o r gonococcus at the beginning of the experim e n t a l t h e r a p y w i t h the filtrate. These two patients, in w h o m the discharge h a d not cleared up b y p r e v i o u s local t r e a t m e n t , were included in the series to determi.ne the effect, if any, of the new treatm e n t on the presence of the discharge. Their smears contained pus, b u t no microorganisms could be isolated. The children were given v a r i e d dosages of the C o r b u s - F e r r y gonococcus filtrate i n t r a c u t a n e o u s l y with the purpose of d e t e r m i n i n g the o p t i m u m dosage. I n eight eases the dosages given twice w e e k l y r a n g e d as follows: 0.00'83~, 0.1, 0,.075, 0.1, 0.125, 0,.15, 0.175, and 0.2 c.e. Ln f o u r t e e n eases, f r o m 0.01 to 0'.02 c.c. of the filtrate were given twice weekly. Two patients received a bi-wcekly constant dosage of 0.01 e.e. J u d g i n g f r o m the response to the v a r i e d dosages we f o u n d t h a t the smaller the dosage the b e t t e r was the result. P r o b a b l y a dosage in the n e i g h b o r h o o d of 0.01 e.e. of C o r b u s - F e r r y gonococcus filtrate given i n t r a c u t a n e o u s l y twice weekly is the o p t i m u m for use in children with g o n o r r h e a l vaginitis. R e g a r d i n g local reactions f r o m filtrate injeetions, these varied f r o m none whas which h a p p e n e d in a f e w instances, to cutaneous wheals of 50 to 75 ram. in t w e n t y - f o u r hours. In r a r e instances, in which there was an absence of a n y local reactions, they occurred in the l a t t e r p a r t of the disease. These reactions did ~ot tend to disapp e a r as the patients became cured of the disease. I n other words, there was no relationship between the presence or absence of a local rear. tion a n d the progress of the disease. I n some instances (seven) a rise in t e m p e r a t u r e to a m a x i m u m of 101.6 ~ F. was observed. These constitutional reactions a p p e a r i n g in v a r i a b l e periods of the disease showed no dependence on the s t r e n g t h of the dosage. I n a f e w cases, a f t e r the filtrate was given i n t r a c u t a n e o u s l y it caused an increased vaginal discharge. This was such a~ inconstant f a c t o r t h a t no definite s t a t e m e n t can be m a d e in r e g a r d to it. P r e v i o u s to the institution of filtrate t h e r a p y the following diseases were p r e s e n t d n association w i t h the g o n o r r h e a l vaginitis, gonoeoecic
GOLDBERG AND B I ~ N C H A R D :
COR~US-F]gP~RY G0'NOCOCCUS FILTRATE
385
pelvic peritonitis (two eases), congextital syphilis (on e ease), chronic r h e u m a t i c endoearditis (one ease), scabies (one ease), r i n g w o r m of the scalp (one ease), a n d scarlet f e v e r (one ease). D u r i n g t r e a t m e n t with filtrate t h e r a p y two complications occurred, nameIy, cellulitis of the left leg (one ease), and acute tonsillitis (one ease). Three p o s t u l a t e s governed the clinical results of t r e a t m e n t , n a m e l y : (1) the cessation of vaginal discharge, (2) absence of pus cells, a n d (3) the d i s a p p e a r a n c e of gonococci in the smears. B e f o r e the children were dismissed as cured we h a d evidence of 22 to 44 consecutive negative v a g i n a l smears. The n u m b e r of days b e f o r e the v a g i n a l discharge ceased varied f r o m 22 to 149 days. Before consecutive negative smears were obtained the ehildreaa were u n d e r t r e a t m e n t f r o m 6 to 119 days. I n the eighteen eases in which the p a t i e n t s were considered cured at the hospital the duration o f t r e a t m e n t with filtrate r a n g e d f r o m the shortest of 28 days. to the longest of 165 days, before dismissal and c o m m i t m e n t to follow-up at the H e a l t h D e p a r t m e n t centers. These eases were checked periodieally up to Jan. 7, 1938. The a v e r a g e length of t r e a t m e n t resulting in cure was 73.44~ days. I t was f o t m d t h a t of the eighteen p a t i e n t s cured b y filtrate t h e r a p y , five h a d recurrences. The length of time a f t e r dismissal f r o m tile hospital w i t h o u t a recurrence v a r i e d f r o m 180 to 508 days. Thirteen, or 5t.17 p e r cent, of the t w e n t y - f o u r p a t i e n t s in the series h a v e continued w i t h o u t t r a c e of the disease. Six patients, r e p r e s e n t i n g 25 per cent, w h o m we were uaable to cure by m e a n s of this f o r m of t h e r a p y , were t r e a t e d over a period r a n g i n g f r o m 93 to 165 days, with v a r i e d dosages twice weekly, without apparent improvement. I n the two eases in which the p a t i e n t s h a d a v a g i n a l discharge b u t did not show a positive smear, the infection cleared up in one and r e c u r r e d in the other. I t m a y be definitely stated t h a t no complication followed as the resu'lt of treatm.ent by gonococcus filtrate in a n y ease u n d e r observation. COM]Y[ENT
We realize that twenty-four cases do not comprise a large number on which to p a s s j u d g m e n t concerning the value of a n y t h e r a p e u t i c agent. B u t the f a c t should be stressed t h a t these p a t i e n t s were u n d e r close o b s e r v a t i o n at all times, d a t a were a c c u r a t e l y recorded, and smears were t a k e n a n d examined daily. The question arises w h e t h e r the duration of the infection or the t y p e of ease w a s a f a e t o r in the cure. Of our t h i r t e e n p a t i e n t s who continue t o be w i t h o u t trace of the disease, six were acute eases, a n d seven, chronic eases. Of the five recurrences three were acute and two, chronic cases. Obviously the difference is not suffieieat to war-
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TI-IE JOUI~NAL OF PEDIATRICS
rant any other conclusion except that the effect of t r e a t m e n t by gonococcus filtrate is the same in acute as in chronic cases. In the opinion of some investigators the filtrate is a means of reducing the possibility of complications and attaining a safe postinfectious period. Our s t u d y permits us only to point out t h a t there were no complications following t r e a t m e n t by filtrate t h e r a p y in our cases of children with gonorrheal vaginitis. I n reviewing the literature on the use of gonococcus filtrate one is impressed by conflicting evidence in r e g a r d to its value. We can discern belief in the p r o d u c t as a worth-while discovery oil a sound biologic basis and the hope of progress along this line. Others have expressed doubt and condemnation of its use. It is our opinion based on our experience that C o r b n s - F e r r y gonococens filtrate has some value, f o r 54.17 per cent of cures ca,nnot plausibly be considered b y us as accidental. B u t we hold t h a t more scientific work is necessary and should be done before definite and absolute j u d g m e n t is passed on the t h e r a p e u t i c value of the filtrate. SUMMARY
l~eview of the literature on the t r e a t m e n t of gonorrheal infection by C o r b u s - F e r r y gonoeoccus filtrate shows diverse and conflicting evidemee of its therapeutic value. The present s t u d y on t h e use of this therapeutic agent was undert a k e n in an attempt to determine the efficacy of the method in a group of t w e n t y - f o u r children with g o n o r r h e a l vaginitis. V a r i e d dosages of the filtrate, r a n g i n g f r o m 0.0083~ c.c., initially, to 0.01 and 0.2 c.c. were given bi-weekly over a period of 28 to 165 days. There appeared to be no differea~ce in the results between the chronic and acute cases. Of the eighteen patients cured by Corbus-Ferry gonococcus filtrate, five had recurrences. Thirteen, or 54.17 per cent, of the t w e n t y - f o u r patients in the series continue to be without trace of the disease. P r o m our experience we are inclined to believe t h a t f u r t h e r experimental w o r k scientifically carried out is indicated before the value of gonococcus filtrate as a cure for gonorrheal infection can be definitely determined. We wish to acknowledge our indebtedness to :Dr. 1%se Bass and Dr. Frank @iuffra for their assistance in checking the cases following the dismissal of the patients from the hospital. R,EFERIgNC]~S 1. Stoekwell~ A . L . : J. Missouri M. A. 32: 387, 1935. 2. Ref. 1, p. 388. 3. De Christmas: Quoted by Clark, L. T , Ferry, N. S,, and Steele, A. tI.: Immunol. 2!: 233~ 1931.
J.
GOLDB]~RG AND BLANCI-IARD: 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
14.
COICBUS-FERRY GO.NOCOCCUS FILTRATI~
389
Herrold, 1%. D.: J . A . M . A . 84: 391, 1925. Corbus, B. C., and 0'Conor, V . J . : J. Urol. 24: 336, 1930. Ref. 5, pp. 336, 338. l~ef. 5, p. 340. Corbus, B. C.: J. Urol. 26: 730, 1931. Corbus, B . C . : J . A . i~f. A. 98: 532, 1932. MeKay~ 1%. W.: South. M. J. 97: 152, 1935; Storts, B . P . : Arch. Pedlar. 52: 567, ]935; Stockwell: Idem, Footnote 1, p. 389; Townsend, J. M.: t(entacky lV[. J. 33: 463, 1935; Spence, tI. M.: J. Oklahoma M. A. 28: 443, 1935. Report of the Council of Pharmacy and Chemistry: J . A . M . A . 98: 554, 1932; Ibid. 104: 1825, 1935. Queries and Minor Notes: J. s 1VL A. 107: 302, 1936. Jamieson, W . R . : Southwestern Med. 20: 251, 1936; Dcakin, R.: J . A . lYi. A. 107: 956, 1936; Gardner, M . E . : J. Med. 17: 488, 1936; Whitehouse, A. J . : Am. J . Obst. & Gynec. 33: 523, 19371 A~wyl-Davies~ T.: Brit. M. J. 1: 321j 1937. Report of the Council of Pharmacy and Chemistry: J . A . M . A . 110: 47. 1938.
382
T H E J O U R N A L OP' PEDIATRICS
term. An antivirus, as described by Corbus and O'Conor 5 is an atoxic, nonantigenic, thermostable substance, f o r m e d in culture media, which is easily detached from the body of the bacterial cells and is antagonistic to them. I t is more a b u n d a n t in the liquid media when all the bacterial cells are dead or incapable of continued proliferation. The antivirus is said to cause the death of the bacteria in the culture medium. Besredka f o u n d that the action in vitro could be produced in viv0. To exert its specific activity the antivirus must come in cont a c t with the bacteria. Corbus, stimulated by the work of B e s r e d k a in specific immuuization by antivirus, directed his attention to the possibility of producing a gonococcal antigen solution. A f t e r p r o l o n g e d experimental work he and O'Conor G succeeded in producing a bouillon filtrate of the organism. The bouillon developed b y them at this time was toxic and antigenic. A f t e r a thorough trial of intra-urethral injections in eighteen cases b y Corbus and O"Conor, the results p r o v e d discouraging. The assistance of Dr. N. S. F e r r y was requested b y Corbus in making a new preparation. In the fall of 1929, Clark, F e r r y , and Steele, 3 using a hormone broth, p r o d u c e d a gonococcus bouillon filtrate and discovered t h a t it contained a soluble toxin and was not an antivirus. This gonococcus filtrate p r o v e d a difficult problem in analysis because of lack of adaptability to artificial conditions of culture and the inherent tendency of cultures of gonococcus to autolyze. In dilutions of 1:1,000 and 1:1,500, the toxin: was f o u n d capable of causing skin effects similar to the Dick reaction. In experimenting with animals it was f u r t h e r revealed t h a t this toxin stimulated the formation of an antitoxin which neutralized in vitro as well as in vivo. Using this new p r e p a r a t i o n by F e r r y , Corbus and 0 ' C o n o r injected it intradermally in two patients. Their results encouraged them to believe t h a t intradermal injections of gonococcus bouillon filtrate, p r o p e r l y controlled, b r o u g h t about specific immunizing effects destructive to the organism in most instances. 7 In vivo bacteria are lodged in certaL~ tissues or ceils. In the application of the antivirus-containing filtrates the biologic fact t h a t skin cells are capable of producing i m m u n i t y has been utilized. In other words, t h e y f o u n d that the antigenetie response from some toxihs, if given intradermally, seems to have the power of inducing general i m m u n i t y for their respective bacteria. I t is generally believed t h a t every virus has its cell and every cell its immunity. But such local i m m u n i t y forms only a p a r t of the general immunity which can be stimulated by i n t r a d e r m a l injections i n t r o d u c e d anywhere in the body. S Corbus and O'Conor 7 later observed t h a t by withholding all other therapeutic methods they could influence the course of the disease
GOLDBERG A N D B L A N C I I A R D :
COI~BUS-FF_,I~I%Y G O N O C O C C U S F I L T R A T E
383
favorably in acute cases but that the rapidity of the cure did not always exceed that attained by means of medicaments. Treatment of eight women with gonorrheal endoeervicitis yielded most encouraging results. In three young girls with vulvovaginitis of specific origin the outcome was equally promising. They felt that in some persons at least the gonococcus was eliminated permanently by these injections alone. In 1932 Corbus again reported on the results of treatment with filtrate in a series of 151 male patients with gonorrheal infection2 Other investigators (~[cKay, Storts, Stockwell, Townsend, and Spence)lo also sought to determine the effectiveness of this type of therapy. The Council of Pharmacy and Chemistry of the American Medical Association made two prMiminary reports, 11 both times awaiting furt her evidence of the clinical value of the Corbus-Ferry filtrate. A recent survey of a number of urologists regarding their opinion of this product, based on actual trial, showed that with but few exceptions, its use has been discontinued either because of lack of therapeutic results or the too common precipitation of serious complications after its administration.12 Experimental observations, however, continued, with both favorable and unfaxorable results (Jamieson, Deakin, Gardner, Whitehonse, and Anwyl-Davies).13 After further consideration the Council of Pharmacy and Chemistry made its final report, 14 declaring that the Corbus-F'erry gonococcus filtrate is not acceptable for new and nonofficial remedies. In the meanwhile we had undertaken our investigation. PI%ESI~NT C L I N I C A L S T U D Y
A series of twenty-four consecutive cases of gonorrheal vaginitis in children at the Essex County Hospital for Contagious Diseases, at Belleville, New Jersey, was made the subject of intensive study. Each child had a history of vaginal infection, associated with a purulent discharge, burning, and itching. The clinical experiment to determine the therapeutic value of Corbus-Ferry gonococcus filtrate in the treatment of this disease was begun on June 9, 1936, and terminated on J ul y 13, 1937. The ages of the children ranged from 2 to ;10 years. The duration of the gonorrheal infection in these patie~ts before institution of the new form of therapy varied from eleven to seventynine days. Previous treatment by local antiseptics had been given over a period varying from one to fifty-four days. In most of the cases it consisted of argyrol, 10 and 20 per cent twice a day, instilled locally, followed by a potassium permanganate douche of 1.8,000 twice a day. Some of the children were given a 2 per cent boric acid douche, followed by application of metaphen ointment ( ~ of 1 per cent) tri-weekly.
38~t
TI={]~ J O U R N A L
OF P]~DIATR.ICS,
I n all cases the e m p l o y m e n t of local m e d i c a m e n t s was s u p p l e m e n t e d b y hygienic measuces. F o r the purpose of ascertaining if the results in the types of gonorrhea would differ, the cases were divided i.nto two groups: acute and chronic. This classification was m a d e arbitrarily, the disease of a d u r a t i o n of f o r t y days or less being considered acute and over f o r t y days, chronic. The entire n u m b e r consisted of fifteen acute eases and nine chronic eases. All patients originally showed positive gonococcus smears, t h a t is, the preseace of g r a m - n e g a t i v e intracellular diplococci of morpho]ogic resemblance to gonococci, which is the criterion f o r the diagnosis of g o n o r r h e a l infection. I n all but two c a s e s the s m e a r s were positive f o r gonococcus at the beginning of the experim e n t a l t h e r a p y w i t h the filtrate. These two patients, in w h o m the discharge h a d not cleared up b y p r e v i o u s local t r e a t m e n t , were included in the series to determi.ne the effect, if any, of the new treatm e n t on the presence of the discharge. Their smears contained pus, b u t no microorganisms could be isolated. The children were given v a r i e d dosages of the C o r b u s - F e r r y gonococcus filtrate i n t r a c u t a n e o u s l y with the purpose of d e t e r m i n i n g the o p t i m u m dosage. I n eight eases the dosages given twice w e e k l y r a n g e d as follows: 0.00'83~, 0.1, 0,.075, 0.1, 0.125, 0,.15, 0.175, and 0.2 c.e. Ln f o u r t e e n eases, f r o m 0.01 to 0'.02 c.c. of the filtrate were given twice weekly. Two patients received a bi-wcekly constant dosage of 0.01 e.e. J u d g i n g f r o m the response to the v a r i e d dosages we f o u n d t h a t the smaller the dosage the b e t t e r was the result. P r o b a b l y a dosage in the n e i g h b o r h o o d of 0.01 e.e. of C o r b u s - F e r r y gonococcus filtrate given i n t r a c u t a n e o u s l y twice weekly is the o p t i m u m for use in children with g o n o r r h e a l vaginitis. R e g a r d i n g local reactions f r o m filtrate injeetions, these varied f r o m none whas which h a p p e n e d in a f e w instances, to cutaneous wheals of 50 to 75 ram. in t w e n t y - f o u r hours. In r a r e instances, in which there was an absence of a n y local reactions, they occurred in the l a t t e r p a r t of the disease. These reactions did ~ot tend to disapp e a r as the patients became cured of the disease. I n other words, there was no relationship between the presence or absence of a local rear. tion a n d the progress of the disease. I n some instances (seven) a rise in t e m p e r a t u r e to a m a x i m u m of 101.6 ~ F. was observed. These constitutional reactions a p p e a r i n g in v a r i a b l e periods of the disease showed no dependence on the s t r e n g t h of the dosage. I n a f e w cases, a f t e r the filtrate was given i n t r a c u t a n e o u s l y it caused an increased vaginal discharge. This was such a~ inconstant f a c t o r t h a t no definite s t a t e m e n t can be m a d e in r e g a r d to it. P r e v i o u s to the institution of filtrate t h e r a p y the following diseases were p r e s e n t d n association w i t h the g o n o r r h e a l vaginitis, gonoeoecic
GOLDBERG AND B I ~ N C H A R D :
COR~US-F]gP~RY G0'NOCOCCUS FILTRATE
385
pelvic peritonitis (two eases), congextital syphilis (on e ease), chronic r h e u m a t i c endoearditis (one ease), scabies (one ease), r i n g w o r m of the scalp (one ease), a n d scarlet f e v e r (one ease). D u r i n g t r e a t m e n t with filtrate t h e r a p y two complications occurred, nameIy, cellulitis of the left leg (one ease), and acute tonsillitis (one ease). Three p o s t u l a t e s governed the clinical results of t r e a t m e n t , n a m e l y : (1) the cessation of vaginal discharge, (2) absence of pus cells, a n d (3) the d i s a p p e a r a n c e of gonococci in the smears. B e f o r e the children were dismissed as cured we h a d evidence of 22 to 44 consecutive negative v a g i n a l smears. The n u m b e r of days b e f o r e the v a g i n a l discharge ceased varied f r o m 22 to 149 days. Before consecutive negative smears were obtained the ehildreaa were u n d e r t r e a t m e n t f r o m 6 to 119 days. I n the eighteen eases in which the p a t i e n t s were considered cured at the hospital the duration o f t r e a t m e n t with filtrate r a n g e d f r o m the shortest of 28 days. to the longest of 165 days, before dismissal and c o m m i t m e n t to follow-up at the H e a l t h D e p a r t m e n t centers. These eases were checked periodieally up to Jan. 7, 1938. The a v e r a g e length of t r e a t m e n t resulting in cure was 73.44~ days. I t was f o t m d t h a t of the eighteen p a t i e n t s cured b y filtrate t h e r a p y , five h a d recurrences. The length of time a f t e r dismissal f r o m tile hospital w i t h o u t a recurrence v a r i e d f r o m 180 to 508 days. Thirteen, or 5t.17 p e r cent, of the t w e n t y - f o u r p a t i e n t s in the series h a v e continued w i t h o u t t r a c e of the disease. Six patients, r e p r e s e n t i n g 25 per cent, w h o m we were uaable to cure by m e a n s of this f o r m of t h e r a p y , were t r e a t e d over a period r a n g i n g f r o m 93 to 165 days, with v a r i e d dosages twice weekly, without apparent improvement. I n the two eases in which the p a t i e n t s h a d a v a g i n a l discharge b u t did not show a positive smear, the infection cleared up in one and r e c u r r e d in the other. I t m a y be definitely stated t h a t no complication followed as the resu'lt of treatm.ent by gonococcus filtrate in a n y ease u n d e r observation. COM]Y[ENT
We realize that twenty-four cases do not comprise a large number on which to p a s s j u d g m e n t concerning the value of a n y t h e r a p e u t i c agent. B u t the f a c t should be stressed t h a t these p a t i e n t s were u n d e r close o b s e r v a t i o n at all times, d a t a were a c c u r a t e l y recorded, and smears were t a k e n a n d examined daily. The question arises w h e t h e r the duration of the infection or the t y p e of ease w a s a f a e t o r in the cure. Of our t h i r t e e n p a t i e n t s who continue t o be w i t h o u t trace of the disease, six were acute eases, a n d seven, chronic eases. Of the five recurrences three were acute and two, chronic cases. Obviously the difference is not suffieieat to war-
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rant any other conclusion except that the effect of t r e a t m e n t by gonococcus filtrate is the same in acute as in chronic cases. In the opinion of some investigators the filtrate is a means of reducing the possibility of complications and attaining a safe postinfectious period. Our s t u d y permits us only to point out t h a t there were no complications following t r e a t m e n t by filtrate t h e r a p y in our cases of children with gonorrheal vaginitis. I n reviewing the literature on the use of gonococcus filtrate one is impressed by conflicting evidence in r e g a r d to its value. We can discern belief in the p r o d u c t as a worth-while discovery oil a sound biologic basis and the hope of progress along this line. Others have expressed doubt and condemnation of its use. It is our opinion based on our experience that C o r b n s - F e r r y gonococens filtrate has some value, f o r 54.17 per cent of cures ca,nnot plausibly be considered b y us as accidental. B u t we hold t h a t more scientific work is necessary and should be done before definite and absolute j u d g m e n t is passed on the t h e r a p e u t i c value of the filtrate. SUMMARY
l~eview of the literature on the t r e a t m e n t of gonorrheal infection by C o r b u s - F e r r y gonoeoccus filtrate shows diverse and conflicting evidemee of its therapeutic value. The present s t u d y on t h e use of this therapeutic agent was undert a k e n in an attempt to determine the efficacy of the method in a group of t w e n t y - f o u r children with g o n o r r h e a l vaginitis. V a r i e d dosages of the filtrate, r a n g i n g f r o m 0.0083~ c.c., initially, to 0.01 and 0.2 c.c. were given bi-weekly over a period of 28 to 165 days. There appeared to be no differea~ce in the results between the chronic and acute cases. Of the eighteen patients cured by Corbus-Ferry gonococcus filtrate, five had recurrences. Thirteen, or 54.17 per cent, of the t w e n t y - f o u r patients in the series continue to be without trace of the disease. P r o m our experience we are inclined to believe t h a t f u r t h e r experimental w o r k scientifically carried out is indicated before the value of gonococcus filtrate as a cure for gonorrheal infection can be definitely determined. We wish to acknowledge our indebtedness to :Dr. 1%se Bass and Dr. Frank @iuffra for their assistance in checking the cases following the dismissal of the patients from the hospital. R,EFERIgNC]~S 1. Stoekwell~ A . L . : J. Missouri M. A. 32: 387, 1935. 2. Ref. 1, p. 388. 3. De Christmas: Quoted by Clark, L. T , Ferry, N. S,, and Steele, A. tI.: Immunol. 2!: 233~ 1931.
J.
GOLDB]~RG AND BLANCI-IARD: 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
14.
COICBUS-FERRY GO.NOCOCCUS FILTRATI~
389
Herrold, 1%. D.: J . A . M . A . 84: 391, 1925. Corbus, B. C., and 0'Conor, V . J . : J. Urol. 24: 336, 1930. Ref. 5, pp. 336, 338. l~ef. 5, p. 340. Corbus, B. C.: J. Urol. 26: 730, 1931. Corbus, B . C . : J . A . i~f. A. 98: 532, 1932. MeKay~ 1%. W.: South. M. J. 97: 152, 1935; Storts, B . P . : Arch. Pedlar. 52: 567, ]935; Stockwell: Idem, Footnote 1, p. 389; Townsend, J. M.: t(entacky lV[. J. 33: 463, 1935; Spence, tI. M.: J. Oklahoma M. A. 28: 443, 1935. Report of the Council of Pharmacy and Chemistry: J . A . M . A . 98: 554, 1932; Ibid. 104: 1825, 1935. Queries and Minor Notes: J. s 1VL A. 107: 302, 1936. Jamieson, W . R . : Southwestern Med. 20: 251, 1936; Dcakin, R.: J . A . lYi. A. 107: 956, 1936; Gardner, M . E . : J. Med. 17: 488, 1936; Whitehouse, A. J . : Am. J . Obst. & Gynec. 33: 523, 19371 A~wyl-Davies~ T.: Brit. M. J. 1: 321j 1937. Report of the Council of Pharmacy and Chemistry: J . A . M . A . 110: 47. 1938.