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Clinical Observations on the Nature of Urogenital Gonorrhea1
CLINICAL OBSERVATIONS ON THE NATURE OF UROGENITAL GONORRHEA1 JOHN H . DOUGHERTY, M.D ., CARL S. D1LUCIA, CAPT., MC, ANGELO DIDONNA, CAPT., MC AND JOHN C. RIDDLER, CAPT., MC, AUS.
We realize that we are not presenting anything new, rather a reiteration of principles with which you as urologists are quite familiar. We have been stimulated to do this because of the recent trend in military medicine to take the problem of gonorrhea away from the urologist, and place it in the hands of those conceivably less well trained in the complicated nature of the disease. The trend to remove the responsibility from the Urological Section in the Army and to place it with Internal Medicine began in 1942. At this time it was stated that the change was being made because it was believed that the urologist had made the disease worse with his methods of treatment which, of course, included the sulfonamides. As a result, a new section was set up and an internist was designated a venereologist and placed in charge. It is my impression that the trend in Army medicine is now to return the responsibility back to the urologist. As a practical illustration, I recall one army installation in Southern . France that had accumulated such a census of gonorrhea due to the non-urologic method of treatment that it was designated as a V-D hospital. At the time a urologist was called into help with the problem, the census was over 1500 patients and those who should have been admitted were being turned away at the average rate of 60 per day; in addition, the ambulatory clinic was serving 150 to 200 soldiers each day. Admittedly some urologists proclaim that they do not treat gonorrhea. Perhaps they call it by some other name. In any event it is inconceivable that a private urologic office could be run without meeting the problem of gonorrhea in some form each day. It is sincerely believed that the urologist is the only one with sufficient training to properly comprehend the problem of gonorrhea. To say that he might make the disease worse by one or another form of treatment has no basis in fact, and to say that he should only see the complicated cases when chemo- and bio- therapeutic agents have failed is acknowledgement of the failure to understand the disease. The heralding news in the popular press and extravagant claims in meaical literature of 5 and 24 hour cures has turned everyone, even the naturopaths into "shot Doctor." We believe that there are more chronic cases of gonorrhea now than ever before. The following discussion to support such contentions is offered for your consideration. 1 Read at meeting, Southeastern Section, American Urological Association, Augusta, Ga., March 22, 1946.
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THE NATURE OF GONORRHEA
From a physio-pathological .standpoint it is inconceivable that gonorrhea could be a simple surfacejnfection; rather, by the time the clinical evidence of the disease appears, the infection is already active and deeply seated in the periurethral mucous glands. There are many of the latter necessary in the physiological function of the urethra. They radiate from that structure like the spokes of a wheel, and open on the surface of the channel. The glands are lined with a single layer of glandular epithelium and end distally with a blind sacculation, in the adventitia surrounding the mucosa! structure of the urethra. Around each gland there is a rich network of lymph and blood vessels. They are penetrated by the organism causing gonorrhea and act as a nidus for the changes to take place throughout the incubation period, before the commonly accepted evidence of the disease appears. Just what takes place between the act of exposure and the subsequent· appearance of signs and symptoms in the exposed, offers intriguing conjecture and particularly does it offer conclusive reasoning against the assumption that gonorrhea could be a surface infection. It is not likely that an affecting organism could lie peacefully on the surface of the tube frequently distended and washed many times during the arbitrarily accepted 7 day incubation period. Rather, the organism must, as a natural sequence of events, seek security in the depths of the periurethral glands, and there begins the changes which constitute its life cycle. The gonococcus is an exotoxin producing organism, this substance is produced in abundance, is quite irritating and probably depends in concentration on the virulence, the possibilities for dilution and the number of organisms present at any one site. To this substance may be attributed the extreme inflammatory reaction and the acute symptoms seen clinically with gonorrheal infections. From time to time various authors have alluded to the possibility that the gonococcus during its incubation period in any one particular host, exists in a pleomorphic or ultra-microscopic form. In view of the bizarre clinical picture presented in some cases, this may be a possibility but it has never been proven, nevertheless, just how the gonococcus gets into the urethra during intercourse and to the periurethral glands, and what activity goes on during the so called incubation period, provides interesting speculation. The possibility that the organism simply enters the urethra and moves to its nidus by direct extension is supported by the probability that many infections never take place when the individual takes the trouble to urinate within 30 minutes after intercourse. On the other hand, there is much to suggest that entry may not be direct, but may be from surface trauma to the glans or to immediately adjacent structures and thence to the periurethral glands by lymphogenous or hematogenous spread. This possibility is borne out by the frequent infection of Tyson's glands in the male, with clinical suggestions that their external opening may have initially received the coccus. Also in the female with primary acute gonorrhea the urethra usually shows the first clinical symptoms when one would expect the cervical glands to show the primary evidence, since an infected ejaculation would conceivably be deposited at that site.
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DOUGHERTY, DELUCIA, DIDONNA AND RIDDLER MATERIAL STUDIED
As a basis for this discussion it is believed that sufficient evidence has been accumulated from a study of approximately 4600 cases of gonorrhea cared for by the authors from September 1942 to March 1946 in the following installations. a), In a station hospital in America, 1206 cases. b), In a general hospital in England, 52 cases. c), In a general hospital in France, 152 cases. d), In a urological center in Paris, France, 368 cases. e), In a urological and veneral disease hospital in Marseille, France, 1743 cases. f), In a veneral disease center near Aix, France, 1074 cases. g), In private practice, since November 1, 1945, 39 cases. METHODS OF TREATMENT USED
In the first instance the soldiers were treated according to directive with hospit alization, sulfonamides, irrigation, instillations and local manipulations (i.e. cautious instrumentation and prostatic massage) until April 1943. Following this date a preliminary course of ambulatory sulfonamide was carried out. This did not alter the hospital census for the disease; indeed for intermittent weeks it was actually higher in relation to the overall hospital census. Of this first group of 1206 patients only 33 were transferred to a General Hospital, 8 of these had arthritis and the remaining 25 varied with deep seated complications which had not responded to therapy in the time limit for Station Hospitals. The 52 cases studied in a General Hospital in England had been declared "sulfonamide resistant" by the referring Medical Officer. At least they had continued with clinical signs of the disease after repeated courses of either sulfadiazine or sulfathiazole. They were treated with penicillin but it must be admitted that the spectacular results reported by others were not evident in this small series. In a portion of the cases, it was remarkable to see the very acute signs and symptoms subside rapidly. However, when the pale thin urethral discharges and shreds were studied closely by smear and culture a high degree of positiveness was found. When these findings and the persistent urinary signs and symptoms with evidence of post-genital infection were considered one believed that the disease had reached a resistent indolent stage. With very few exceptions this sequence of events took place in all of the 52 cases, our first experience with penicillin. For the 1206 patients of the first group, the average time for "cure" was 6 weeks. In comparison it is believed that if the same measures of "cure" had been applied to the second group of 52, that the average would have been in the neighborhood of 6 weeks. The average hospital stay for the first group was 21 days and for the small group 14.5 days. It must be remembered however, that those in the first large group were made to conform to a much more strict criteria and were believed "cured" and non-infectious when discharged, while only a minority of those in the smaller group were believed so. The remainder of the cases, less the last 39, making a total of 3,337 were treated by different methods. During "The Bulge" when it was necessary to keep
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every soldier at duty if possible, only penicillin was given in most instances. Other methods of treatment were only used when very necessary, This plan was carried out with the conviction that none of the soldiers were being cured but rather that the disease was made less acute and in a measure controlled. Often repeated courses of penicillin were given and the dose range was from 100,000 to 2,000,000 units. After the emergency, methods combining urologic manipulation, along with chemo- and bio-therapeutic agents were reinstated. All methods of treatment were permissable by directive since the cases were seen in "speciality treatment installations." The average hospital stay was 10½ days. The hospital stay was not shortened because of unusual efficacy of any of the agents in obtaining a cure, but rather because the :majority of the cases were stationed in Southern France and could be further treated ambulatorily. The experience was still the same that it required approximately 6 weeks to control the acute stage of the disease, and remove the focus that would persist as a site of chronic infection, and obstruction to urine flow before a cure could be obtained. The last group of 39 cases is one that one of us has had in a newly set up office practice during the past 4 months. They are a portion of 159 strictly urologic patients that have come by one means or another. We believe that such a proportion will be true in any urologic office practice if we recognize all the broad ramifications of gonorrhea. Eight of these were acute cases, likely primary. The others possibly exacerbations. All had signs and symptoms relative to the gentio-urinary system, usually a discharge, dysuria and abnormalities with urination. Twenty six were veterans who had had their first infection while in the Army or Navy. All but 8 of the cases had received penicillin before coming to the office, either in the service or from a private physician. The discharges of these patients have been studied with a great deal of care. In all but 9 organisms have been found which are believed to be gonococci, whether they are potentially infectious in the patient, cannot be said. To confirm this sometimes requires searching a shred repeatedly for much longer periods than the usual technician uses. Of the total number of patients, approximately 4600 over 300 had urethroscopic examinations, some 1850 had urethral investigations with bougie a boule and approximately the same number corresponding to the latter figure had digital palpations of the lesion on a sound. These studies were carried out after the acute signs and symptoms of the disease had subsided. In every instance a lesion, or multiple ones were found, usually in the first 8 cm. of the urethra, and always proximal to the fossa navicularis. No lesion has ever been observed in that cavity. Urethroscopically, the lesion appears as a heaped up inflamed area of mucosa from 0.2 to 1.5 cm. in the antero-posterior diameter, usually most concentrated on the floor of the urethra and extended laterally onto the walls to fade out as the roof is reached. Some lesions have been observed however, which are most concentrated on the walls. On close observation occasionally, the opening of the urethral gland involved can b~ seen, often with a purulent exudate. The lateral
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extensions depend on the calibre of the channel, the lesions are well defined and fade out into the normal pattern of the urethra. Investigations with bougie a boule most frequently disclose a lesion that gives a definite hang sensation to motion up and down. It may vary however, from a sense of a fibrotic band to that of a soft passable obstruction. It is believed that the variations simply represent stages of progress in the natural sequences of events that takes place in any infectious process. The appropriate bougie a boule to use will be determined by one that will pass the anterior narrowing of the fpssa navicularis snugly but easily. Proximal to this structure the calibre of the majority of male urethras is the same. However, experience has shown a large penis has a correspondingly large urethral calibre so that a 20 to 24 bougie will not disclose the primary lesion, while a 26 to 30 will reveal its existence definitely. THE OBSTRUCTIVE NATURE OF THE PRIMARY LESION
Observation on this reasonably large group of patients has shown definitely that the lesion offers obstruction to the physiological flow of urine. The accumulated evidence shows that variations in the obstruction offered by different lesions naturally depends on their character, but that it exists in every case is beyond question. This may vary from simple ballooning of the urethra proximal to the structure, to trabeculation and cellule formation in the bladder, and even upper urinary tract changes from retrograde pressure. For clarity, the situation is reasonably comparable to a tube of small size calibre just large enough to fit snugly into another tube, the rim of the smaller tube simulating the pathological structure in the disease. In this manner it would offer obstruction to a column of fluid. A conceivable point, though unproven, is that the eddying currents of urine flow, when obstructed by such a dam mechanism, may play a part in the extension of the disease process to points higher in the urinary tract. The old text book term and the one of common parlance for the primary manifestation of gonorrhea is stricture. But in the conception of many, the malformation to which the term is applied does not exist until it is something either completely stopping the flow of urine or a structure stretched across the urethral canal like a bow string. Such an extreme state represents the finished product in the prolonged sequence of destruction and repair. In addition, many people are firm in their belief, and the layman is not alone in this, that so called "stricture" is only the result of some "strong medicine, or incautious instrumentation." One recognized authority has even said that "strictures" are not encountered any longer. Acriflavin for many years was pointed to as a certain stricture producer if used injudiciously. HOW THE LESION PROGRESSES
From the time of the clinical manifestations of the disease it is believed that the gonococcus is multiplying in the sac of the periurethral glands, pouring out its exotoxin which produces the severe irritation of the gland duct and urethral mucosa. Abscess formation although microscopic, is taking place and the minute lympatic system about the gland is involved. If destruction does not overwhelm
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the process of repair, the noxious products are retained in a limited area and fibroblastic activity ensues with the formation of a healing process. It is believed that there are many variations in this process with many clinical gradients. The latter being dependent on the number of infecting organisms, their virulence, the strain\ the resistance of the host, the degree of circulation at the focus, immune processes, the amount of obstruction offered by the lesion to the urine fl.ow and in present therapeusis, the concentration of bacteriostatics at the site of the lesion. It is also believed that should the process of repair be overwhelmed as it seems to be in many cases, that the mechanism is set for posterior extension of the disease, most likely by lymphogenous or hematogenous spread and conceivably by direct extension to the posterior genitalia and the middle and even upper urinary tracts. , PRESENT TREATMENT METHODS
The evidence gained in the study of this group of patients has led to the conviction that urethral gonorrhea is a disease of destruction and repair, one of microscopic abscess formation ordinarily, but one often extending beyond such limits. It is one where adequate drainage is a prime requisite and hence, it falls into the category of surgical diseases. How drainage is to be instituted and maintained requires a specialized knowledge of the parts involved and the nature of the disease. It may vary from something as simple as forced diuresis to surgery of the perineum. Rest. Much has been said about the need for rest of the parts involved, particularly, and of the body in general, in the treatment of gonorrhea. The subject has passed out of vogue for the present. In this study 385 of the first group were admitted to the hospital between September 1942 and April 1943 fortreatment as soon as the diagnosis was made, and after April 1943, only those patients were admitted who had had the previous ambulatory course of either sulfathiazole or sulfadiazine. The evidence shows that the hospital stay for the latter portion of the group was increased from 5 to 8 days. If this figure is added to the 12 day period where the soldier was under ambulatory treatment and reasonably ineffective, the day loss reaches considerable proportions. It is belie'ved that hospitalization offers a distinct advantage in the treatment of the disease, although, it is not always practical. An important public health point in this consideration is that the infected patient is much better controlled. Although there is no definite proof, sufficient information has been gained to show that a very probable interval exists during the early period of the disease in which the patient is producing a degree of immunity, the latter depending upon inherent factors in the host and those manifest by the invading organism. It is believed that such a mechanism is active up to about the seventh day after the appearance of the signs and symptoms. Diuresis has an extremely important role in the treatment of gonorrhea. It is best accomplished by water alone and the patient who can maintain an intake of 4500 cc in each 24 hours, greatly enhances the shortening of his period of cure. However, in the present day use of bacteriostatics, a medium line must be struck,
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or the dilution and rapid excretion of the drugs and biologicals will diminhis their effectiveness. The sulfonamides. The authors have great respect, not to mention fear, for these drugs but it is not believed that they are curative agents in the strict sense of the term. Rather they are extremely important adjuncts in the armamentarium of treatment. They definitely shorten the course of the disease but in this series it was borne out that they did so only by influencing the acuteness of the course, and allowing for more active measures of treatment to be instituted at an earlier date than was ever realized before their use. They did this most effectively when they were not active in the treatment until a period had elapsed (5 to 7 days) after the appearance of the signs and symptoms. This period is possibly necessary for the establishment of natural immune processes. Whether or not chemotherapy disturbs the immune mechanism is not definitely known, but there is a very definite suspicion that it does. Mention should be made here too of the observations leading to the belief that the sulfonamides often give a false sense of security, by making the disease less morbid as long as they are being given, only to have the picture turn to one of renewed severity as soon as they are stopped. Finally, to a group of urologists need not be mentioned the dangers of the drugs. Penicillin. There is no question that the discovery of penicillin and its application in therapeusis will be a hall mark. It is an extremely valuable agent in the treatment of gonorrhea (the results similar to, but better than those to be gained from the sulfonamides). We have used this drug in almost all but the first group of cases. Certain results were repeated often enough to lead to the conclusion that these are part of the disease picture when penicillin is used. Indeed, they occur so frequently that they may be expected. In the larger series of cases in which penicillin was used, division is arbitrarily made into 3 groups. Before beginning discussion of them, it definitely may be stated that there were no spectacular results of "cures" as some have been wont to call them. It is true that in the majority or cases, signs and symptoms improved greatly, particularly the heavy purulent discharge and the dysuria. But only 402 cases had these two primary evidences of the disease disappear within 48 hours and 16 of these had both discharge and dysuria return in renewed severity within 6 days. The problem of definite cure was a very difficult one and in the strict sense of the term, it must be stated that many of the patients were returned to duty for ambulatory treatment in the clinic without the conviction on the part of the authors that they were "cured." In fact, it was believed that a chronic indolent stage had been reached that would require a number of weeks of attention with bi-weekly to weekly visits to effect a "cure." Never did the authors have the complete conviction ·that these patients were not carriers of organisms, even though attenuated and avirulent, capable of reproducing the disease in vivo on new media. The criteria for "cure" for the hospitalization and ambulatory course was set up as follows: a) No urethral discharge; 2) no exudate that would give a positive
CLINICAL OBSERVATIONS ON UROGENITAL GONORRHEA
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smear or culture; 3) a negative anterior urethra to 28 F. bougie a, boule; 4) a negative anterior urethra to basal palpation on a 26 F. sound; 5) negative prostate and vesicles on rectal examination; 6) negative prostato-vesicular smear, i.e. no organisms and not over 5 white blood cells. 7) If any of the 3 urine glasses showed shreds, they svere not to show gonococci-on careful examination or over 10 white blood cells per oil immersion field. Shreds showing mucus strands with epithelial cells, lymphocytes and more than 10 white blood cells were not acceptable. Admittedly, the above is an ideal and it is sincerely stated that none of the 52 cases in the second series met the criteria before they were discharged from the hospital. The same criteria ,Yere used in consideration of the other series, but conditions of the war kept them from being as applicable for conclusions to be drawn. Conversely within a 6 week period, which includes the hospitalized and ambulatory course, it was believed that 31 had met the requirements for cure, Of the remaining 21 cases, the course of treatment was prolonged up to 14 weeks and longer, due to persistent evidence of the disease. With this group, when the acute signs and symptoms did subside with conservative treatment, further care was individualized with the principle in view of establishing drainage for the primary lesion and the extended focus of infection. In this group there were 26 cases. Whether or not penicillin therapy may influence the immune mechanism is not known. There is a suspicion that it does, although, so far, reasoning concerning it is purely empirical. As with sulfonamides, it has been noticed that the response to penicillin is better when the clinical signs and symptoms have existed without treatment for a period from 5 to 8 clays. OLD METHODS OF TREATMENT
Silver protein solutions and irrigating solutions, such as permanganate, have a place in the treatment of gonorrhea. To them may be added the local use of sulfonamide solutions in strengths of 5 to 20 per cent, of the latter solutions, the sodium salts seem to work better. The important factor though, is to realize the histo-pathological nature of urethral gonorrhea and that unless surgical drainage is established, local application of medicinals has little chance of improving the situation. It is necessary to localize the lesion in the urethra by a bougie a boule and then establish drainage by over-dilatation and massage on sounds. Depending on the constrictive circumference of the primary lesion, the plan of treatment can be outlined, if small, the size of the instrument will necessarily be small, gradually increasing ,Yith each treatment. Arbitrarily, it can be said that sounds may be used for dilatations between 20 and 34 F., below 20 F., it is safer to use filiforms and followers in the early stages of treatment directed at the primary lesion. In the results obtained from the study of these two groups of patients, dilation and massage through 34 F. were predominantly necessary a number of times before complete control of the disease was manifest. Eradication of the primary lesion as far as an obstructing and inflammatory manifestation is concerned is the principle in the treatment of this disease. Do-
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ing so accomplishes two extremely important things: It enhances drainage of the underlying focus of infection in the periurethral glands, and decreases the obstruction to urine flow by the inflammatory portion of the lesion and that portion of it composed in the fibrous ring, resulting from the healing process. When there is involvement of the post genital structures such as Cowper's glands, posterior urethral glands, the subcervical glands of the prostate, the more distal gland of the prostate, the vesicles and the epididymes, surgical drainage must be established; this can usually be done by massage with discharge of the infected material into the urethra. However, treatment must be cautious and specialized. The old method of needling or incising the epididymes to secure drainage is outof vogue. However, it is notoriously true that epididymitis tends to become chronic and offers a focus of infection for years, in addition to a very real source of complaint on the part of the active patient. When it is acute, heat, rest, elevation and bacteriostatics certainly favor subsidence of the acute picture. However, when the chronic indurated a-vascular stage is reached, none of those agents help very much, it is likely that to effect a cure, open surgery with eradication of the focus is advisable. In time, it may find favor again as a method of curing those so affected. Fever therapy. The authors have had little acutal experience with this form of therapy. The senior author had occasion to study cases urologically treated with fever in 1939 while in Boston and in 1944 while on detached service with a Canadian General Hospital in England. Because of its rigorous nature, this plan of therapy is reserved for those patients who have resisted all other forms of treatment. None of these cases had been treated 1Yith penicillin or with therapeutic measures outlined in this paper with the concept of the primary manifestation of gonorrhea in mind. Following fever therapy the patients who were examined still had evidence of the primary lesion and needed a program of treatment to eradicate it, to finally effect a cure. It seems safe to say that if the true nature of the disease is borne in mind, and the methods of treatment discussed in this paper applied, that the need for fever therapy will become much less, if not disappear altogether. SUMMARY
The clinical observations on 4,635 cases of gonorrhea, treated from September 1942 through February 1946 are presented. Methods of diagnosis and of treatment of these patients are described. An attempt has been made to evaluate the efficiency of different forms of treatment. No attempt has been made to disparage modes of treatment, but rather to weigh the results gained with their use in the light of a conceivable and believedly true concept of the nature of the disease. CONCLUSION
Gonorrhea is a pyogenic, highly infectious disease, which because of its mode of transmission involves the periurethral glands.
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Clinically, it is manifest by a very definite picture which the authors choose to label the "primary lesion of gonorrhea." This lesion conforms to a persistent histo-pathological pattern, only varying in degree, depending on many factors, such as virulence, resistance, diuresis, immune mechanism and anatomical variations. In order to effect a true cure of the disease, both from an infectious and obstructive point of view, the true concept of the disease must be borne in mind and used as a basis for treatment. Moreover, in order to eradicate the infectious factor of the disease, it is necessary to remove the obstructive factor at the same time. Without doing this, it is not believed that a true cure can be obtained and that many individuals in whom it is neglected become chronic carriers of the disease. A soldier with shreds in his urine is almost always a potential carrier. Chemotherapeutic and biotherapeutic agents are not "cure alls" in any sense, but rather are valuable adjuncts to treatment. The usual study of discharge by smear and culture is too inexact and fraught with too many variables on the part of different examiners. The neglect of the close study of shreds by smear and culture is prevalent. It is believed that this is an extremely important factor in the care of those with the disease and is the responsibility of those who assume a specialized knowledge of the disease. For this reason, a small, simply equipped laboratory is a necessity in any urological clinic. When gonorrhea spreads to glandular-structures, other than the periurethral glands, as Cowper's glands, the prostate, or to the vesicles and epididymes, treatment must be cautious, even in the hand of the specialized, but the principles are the same, drainage must be established inorder to promote circulation and enhance the activity of immune forces in addition to the free flow with greater concentration of bacteriostatics.
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We realize that we are not presenting anything new, rather a reiteration of principles with which you as urologists are quite familiar. We have been stimulated to do this because of the recent trend in military medicine to take the problem of gonorrhea away from the urologist, and place it in the hands of those conceivably less well trained in the complicated nature of the disease. The trend to remove the responsibility from the Urological Section in the Army and to place it with Internal Medicine began in 1942. At this time it was stated that the change was being made because it was believed that the urologist had made the disease worse with his methods of treatment which, of course, included the sulfonamides. As a result, a new section was set up and an internist was designated a venereologist and placed in charge. It is my impression that the trend in Army medicine is now to return the responsibility back to the urologist. As a practical illustration, I recall one army installation in Southern . France that had accumulated such a census of gonorrhea due to the non-urologic method of treatment that it was designated as a V-D hospital. At the time a urologist was called into help with the problem, the census was over 1500 patients and those who should have been admitted were being turned away at the average rate of 60 per day; in addition, the ambulatory clinic was serving 150 to 200 soldiers each day. Admittedly some urologists proclaim that they do not treat gonorrhea. Perhaps they call it by some other name. In any event it is inconceivable that a private urologic office could be run without meeting the problem of gonorrhea in some form each day. It is sincerely believed that the urologist is the only one with sufficient training to properly comprehend the problem of gonorrhea. To say that he might make the disease worse by one or another form of treatment has no basis in fact, and to say that he should only see the complicated cases when chemo- and bio- therapeutic agents have failed is acknowledgement of the failure to understand the disease. The heralding news in the popular press and extravagant claims in meaical literature of 5 and 24 hour cures has turned everyone, even the naturopaths into "shot Doctor." We believe that there are more chronic cases of gonorrhea now than ever before. The following discussion to support such contentions is offered for your consideration. 1 Read at meeting, Southeastern Section, American Urological Association, Augusta, Ga., March 22, 1946.
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CLINICAL OBSERVATIONS ON UROGENITAL GONORRHEA
85
THE NATURE OF GONORRHEA
From a physio-pathological .standpoint it is inconceivable that gonorrhea could be a simple surfacejnfection; rather, by the time the clinical evidence of the disease appears, the infection is already active and deeply seated in the periurethral mucous glands. There are many of the latter necessary in the physiological function of the urethra. They radiate from that structure like the spokes of a wheel, and open on the surface of the channel. The glands are lined with a single layer of glandular epithelium and end distally with a blind sacculation, in the adventitia surrounding the mucosa! structure of the urethra. Around each gland there is a rich network of lymph and blood vessels. They are penetrated by the organism causing gonorrhea and act as a nidus for the changes to take place throughout the incubation period, before the commonly accepted evidence of the disease appears. Just what takes place between the act of exposure and the subsequent· appearance of signs and symptoms in the exposed, offers intriguing conjecture and particularly does it offer conclusive reasoning against the assumption that gonorrhea could be a surface infection. It is not likely that an affecting organism could lie peacefully on the surface of the tube frequently distended and washed many times during the arbitrarily accepted 7 day incubation period. Rather, the organism must, as a natural sequence of events, seek security in the depths of the periurethral glands, and there begins the changes which constitute its life cycle. The gonococcus is an exotoxin producing organism, this substance is produced in abundance, is quite irritating and probably depends in concentration on the virulence, the possibilities for dilution and the number of organisms present at any one site. To this substance may be attributed the extreme inflammatory reaction and the acute symptoms seen clinically with gonorrheal infections. From time to time various authors have alluded to the possibility that the gonococcus during its incubation period in any one particular host, exists in a pleomorphic or ultra-microscopic form. In view of the bizarre clinical picture presented in some cases, this may be a possibility but it has never been proven, nevertheless, just how the gonococcus gets into the urethra during intercourse and to the periurethral glands, and what activity goes on during the so called incubation period, provides interesting speculation. The possibility that the organism simply enters the urethra and moves to its nidus by direct extension is supported by the probability that many infections never take place when the individual takes the trouble to urinate within 30 minutes after intercourse. On the other hand, there is much to suggest that entry may not be direct, but may be from surface trauma to the glans or to immediately adjacent structures and thence to the periurethral glands by lymphogenous or hematogenous spread. This possibility is borne out by the frequent infection of Tyson's glands in the male, with clinical suggestions that their external opening may have initially received the coccus. Also in the female with primary acute gonorrhea the urethra usually shows the first clinical symptoms when one would expect the cervical glands to show the primary evidence, since an infected ejaculation would conceivably be deposited at that site.
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DOUGHERTY, DELUCIA, DIDONNA AND RIDDLER MATERIAL STUDIED
As a basis for this discussion it is believed that sufficient evidence has been accumulated from a study of approximately 4600 cases of gonorrhea cared for by the authors from September 1942 to March 1946 in the following installations. a), In a station hospital in America, 1206 cases. b), In a general hospital in England, 52 cases. c), In a general hospital in France, 152 cases. d), In a urological center in Paris, France, 368 cases. e), In a urological and veneral disease hospital in Marseille, France, 1743 cases. f), In a veneral disease center near Aix, France, 1074 cases. g), In private practice, since November 1, 1945, 39 cases. METHODS OF TREATMENT USED
In the first instance the soldiers were treated according to directive with hospit alization, sulfonamides, irrigation, instillations and local manipulations (i.e. cautious instrumentation and prostatic massage) until April 1943. Following this date a preliminary course of ambulatory sulfonamide was carried out. This did not alter the hospital census for the disease; indeed for intermittent weeks it was actually higher in relation to the overall hospital census. Of this first group of 1206 patients only 33 were transferred to a General Hospital, 8 of these had arthritis and the remaining 25 varied with deep seated complications which had not responded to therapy in the time limit for Station Hospitals. The 52 cases studied in a General Hospital in England had been declared "sulfonamide resistant" by the referring Medical Officer. At least they had continued with clinical signs of the disease after repeated courses of either sulfadiazine or sulfathiazole. They were treated with penicillin but it must be admitted that the spectacular results reported by others were not evident in this small series. In a portion of the cases, it was remarkable to see the very acute signs and symptoms subside rapidly. However, when the pale thin urethral discharges and shreds were studied closely by smear and culture a high degree of positiveness was found. When these findings and the persistent urinary signs and symptoms with evidence of post-genital infection were considered one believed that the disease had reached a resistent indolent stage. With very few exceptions this sequence of events took place in all of the 52 cases, our first experience with penicillin. For the 1206 patients of the first group, the average time for "cure" was 6 weeks. In comparison it is believed that if the same measures of "cure" had been applied to the second group of 52, that the average would have been in the neighborhood of 6 weeks. The average hospital stay for the first group was 21 days and for the small group 14.5 days. It must be remembered however, that those in the first large group were made to conform to a much more strict criteria and were believed "cured" and non-infectious when discharged, while only a minority of those in the smaller group were believed so. The remainder of the cases, less the last 39, making a total of 3,337 were treated by different methods. During "The Bulge" when it was necessary to keep
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every soldier at duty if possible, only penicillin was given in most instances. Other methods of treatment were only used when very necessary, This plan was carried out with the conviction that none of the soldiers were being cured but rather that the disease was made less acute and in a measure controlled. Often repeated courses of penicillin were given and the dose range was from 100,000 to 2,000,000 units. After the emergency, methods combining urologic manipulation, along with chemo- and bio-therapeutic agents were reinstated. All methods of treatment were permissable by directive since the cases were seen in "speciality treatment installations." The average hospital stay was 10½ days. The hospital stay was not shortened because of unusual efficacy of any of the agents in obtaining a cure, but rather because the :majority of the cases were stationed in Southern France and could be further treated ambulatorily. The experience was still the same that it required approximately 6 weeks to control the acute stage of the disease, and remove the focus that would persist as a site of chronic infection, and obstruction to urine flow before a cure could be obtained. The last group of 39 cases is one that one of us has had in a newly set up office practice during the past 4 months. They are a portion of 159 strictly urologic patients that have come by one means or another. We believe that such a proportion will be true in any urologic office practice if we recognize all the broad ramifications of gonorrhea. Eight of these were acute cases, likely primary. The others possibly exacerbations. All had signs and symptoms relative to the gentio-urinary system, usually a discharge, dysuria and abnormalities with urination. Twenty six were veterans who had had their first infection while in the Army or Navy. All but 8 of the cases had received penicillin before coming to the office, either in the service or from a private physician. The discharges of these patients have been studied with a great deal of care. In all but 9 organisms have been found which are believed to be gonococci, whether they are potentially infectious in the patient, cannot be said. To confirm this sometimes requires searching a shred repeatedly for much longer periods than the usual technician uses. Of the total number of patients, approximately 4600 over 300 had urethroscopic examinations, some 1850 had urethral investigations with bougie a boule and approximately the same number corresponding to the latter figure had digital palpations of the lesion on a sound. These studies were carried out after the acute signs and symptoms of the disease had subsided. In every instance a lesion, or multiple ones were found, usually in the first 8 cm. of the urethra, and always proximal to the fossa navicularis. No lesion has ever been observed in that cavity. Urethroscopically, the lesion appears as a heaped up inflamed area of mucosa from 0.2 to 1.5 cm. in the antero-posterior diameter, usually most concentrated on the floor of the urethra and extended laterally onto the walls to fade out as the roof is reached. Some lesions have been observed however, which are most concentrated on the walls. On close observation occasionally, the opening of the urethral gland involved can b~ seen, often with a purulent exudate. The lateral
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extensions depend on the calibre of the channel, the lesions are well defined and fade out into the normal pattern of the urethra. Investigations with bougie a boule most frequently disclose a lesion that gives a definite hang sensation to motion up and down. It may vary however, from a sense of a fibrotic band to that of a soft passable obstruction. It is believed that the variations simply represent stages of progress in the natural sequences of events that takes place in any infectious process. The appropriate bougie a boule to use will be determined by one that will pass the anterior narrowing of the fpssa navicularis snugly but easily. Proximal to this structure the calibre of the majority of male urethras is the same. However, experience has shown a large penis has a correspondingly large urethral calibre so that a 20 to 24 bougie will not disclose the primary lesion, while a 26 to 30 will reveal its existence definitely. THE OBSTRUCTIVE NATURE OF THE PRIMARY LESION
Observation on this reasonably large group of patients has shown definitely that the lesion offers obstruction to the physiological flow of urine. The accumulated evidence shows that variations in the obstruction offered by different lesions naturally depends on their character, but that it exists in every case is beyond question. This may vary from simple ballooning of the urethra proximal to the structure, to trabeculation and cellule formation in the bladder, and even upper urinary tract changes from retrograde pressure. For clarity, the situation is reasonably comparable to a tube of small size calibre just large enough to fit snugly into another tube, the rim of the smaller tube simulating the pathological structure in the disease. In this manner it would offer obstruction to a column of fluid. A conceivable point, though unproven, is that the eddying currents of urine flow, when obstructed by such a dam mechanism, may play a part in the extension of the disease process to points higher in the urinary tract. The old text book term and the one of common parlance for the primary manifestation of gonorrhea is stricture. But in the conception of many, the malformation to which the term is applied does not exist until it is something either completely stopping the flow of urine or a structure stretched across the urethral canal like a bow string. Such an extreme state represents the finished product in the prolonged sequence of destruction and repair. In addition, many people are firm in their belief, and the layman is not alone in this, that so called "stricture" is only the result of some "strong medicine, or incautious instrumentation." One recognized authority has even said that "strictures" are not encountered any longer. Acriflavin for many years was pointed to as a certain stricture producer if used injudiciously. HOW THE LESION PROGRESSES
From the time of the clinical manifestations of the disease it is believed that the gonococcus is multiplying in the sac of the periurethral glands, pouring out its exotoxin which produces the severe irritation of the gland duct and urethral mucosa. Abscess formation although microscopic, is taking place and the minute lympatic system about the gland is involved. If destruction does not overwhelm
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the process of repair, the noxious products are retained in a limited area and fibroblastic activity ensues with the formation of a healing process. It is believed that there are many variations in this process with many clinical gradients. The latter being dependent on the number of infecting organisms, their virulence, the strain\ the resistance of the host, the degree of circulation at the focus, immune processes, the amount of obstruction offered by the lesion to the urine fl.ow and in present therapeusis, the concentration of bacteriostatics at the site of the lesion. It is also believed that should the process of repair be overwhelmed as it seems to be in many cases, that the mechanism is set for posterior extension of the disease, most likely by lymphogenous or hematogenous spread and conceivably by direct extension to the posterior genitalia and the middle and even upper urinary tracts. , PRESENT TREATMENT METHODS
The evidence gained in the study of this group of patients has led to the conviction that urethral gonorrhea is a disease of destruction and repair, one of microscopic abscess formation ordinarily, but one often extending beyond such limits. It is one where adequate drainage is a prime requisite and hence, it falls into the category of surgical diseases. How drainage is to be instituted and maintained requires a specialized knowledge of the parts involved and the nature of the disease. It may vary from something as simple as forced diuresis to surgery of the perineum. Rest. Much has been said about the need for rest of the parts involved, particularly, and of the body in general, in the treatment of gonorrhea. The subject has passed out of vogue for the present. In this study 385 of the first group were admitted to the hospital between September 1942 and April 1943 fortreatment as soon as the diagnosis was made, and after April 1943, only those patients were admitted who had had the previous ambulatory course of either sulfathiazole or sulfadiazine. The evidence shows that the hospital stay for the latter portion of the group was increased from 5 to 8 days. If this figure is added to the 12 day period where the soldier was under ambulatory treatment and reasonably ineffective, the day loss reaches considerable proportions. It is belie'ved that hospitalization offers a distinct advantage in the treatment of the disease, although, it is not always practical. An important public health point in this consideration is that the infected patient is much better controlled. Although there is no definite proof, sufficient information has been gained to show that a very probable interval exists during the early period of the disease in which the patient is producing a degree of immunity, the latter depending upon inherent factors in the host and those manifest by the invading organism. It is believed that such a mechanism is active up to about the seventh day after the appearance of the signs and symptoms. Diuresis has an extremely important role in the treatment of gonorrhea. It is best accomplished by water alone and the patient who can maintain an intake of 4500 cc in each 24 hours, greatly enhances the shortening of his period of cure. However, in the present day use of bacteriostatics, a medium line must be struck,
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or the dilution and rapid excretion of the drugs and biologicals will diminhis their effectiveness. The sulfonamides. The authors have great respect, not to mention fear, for these drugs but it is not believed that they are curative agents in the strict sense of the term. Rather they are extremely important adjuncts in the armamentarium of treatment. They definitely shorten the course of the disease but in this series it was borne out that they did so only by influencing the acuteness of the course, and allowing for more active measures of treatment to be instituted at an earlier date than was ever realized before their use. They did this most effectively when they were not active in the treatment until a period had elapsed (5 to 7 days) after the appearance of the signs and symptoms. This period is possibly necessary for the establishment of natural immune processes. Whether or not chemotherapy disturbs the immune mechanism is not definitely known, but there is a very definite suspicion that it does. Mention should be made here too of the observations leading to the belief that the sulfonamides often give a false sense of security, by making the disease less morbid as long as they are being given, only to have the picture turn to one of renewed severity as soon as they are stopped. Finally, to a group of urologists need not be mentioned the dangers of the drugs. Penicillin. There is no question that the discovery of penicillin and its application in therapeusis will be a hall mark. It is an extremely valuable agent in the treatment of gonorrhea (the results similar to, but better than those to be gained from the sulfonamides). We have used this drug in almost all but the first group of cases. Certain results were repeated often enough to lead to the conclusion that these are part of the disease picture when penicillin is used. Indeed, they occur so frequently that they may be expected. In the larger series of cases in which penicillin was used, division is arbitrarily made into 3 groups. Before beginning discussion of them, it definitely may be stated that there were no spectacular results of "cures" as some have been wont to call them. It is true that in the majority or cases, signs and symptoms improved greatly, particularly the heavy purulent discharge and the dysuria. But only 402 cases had these two primary evidences of the disease disappear within 48 hours and 16 of these had both discharge and dysuria return in renewed severity within 6 days. The problem of definite cure was a very difficult one and in the strict sense of the term, it must be stated that many of the patients were returned to duty for ambulatory treatment in the clinic without the conviction on the part of the authors that they were "cured." In fact, it was believed that a chronic indolent stage had been reached that would require a number of weeks of attention with bi-weekly to weekly visits to effect a "cure." Never did the authors have the complete conviction ·that these patients were not carriers of organisms, even though attenuated and avirulent, capable of reproducing the disease in vivo on new media. The criteria for "cure" for the hospitalization and ambulatory course was set up as follows: a) No urethral discharge; 2) no exudate that would give a positive
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smear or culture; 3) a negative anterior urethra to 28 F. bougie a, boule; 4) a negative anterior urethra to basal palpation on a 26 F. sound; 5) negative prostate and vesicles on rectal examination; 6) negative prostato-vesicular smear, i.e. no organisms and not over 5 white blood cells. 7) If any of the 3 urine glasses showed shreds, they svere not to show gonococci-on careful examination or over 10 white blood cells per oil immersion field. Shreds showing mucus strands with epithelial cells, lymphocytes and more than 10 white blood cells were not acceptable. Admittedly, the above is an ideal and it is sincerely stated that none of the 52 cases in the second series met the criteria before they were discharged from the hospital. The same criteria ,Yere used in consideration of the other series, but conditions of the war kept them from being as applicable for conclusions to be drawn. Conversely within a 6 week period, which includes the hospitalized and ambulatory course, it was believed that 31 had met the requirements for cure, Of the remaining 21 cases, the course of treatment was prolonged up to 14 weeks and longer, due to persistent evidence of the disease. With this group, when the acute signs and symptoms did subside with conservative treatment, further care was individualized with the principle in view of establishing drainage for the primary lesion and the extended focus of infection. In this group there were 26 cases. Whether or not penicillin therapy may influence the immune mechanism is not known. There is a suspicion that it does, although, so far, reasoning concerning it is purely empirical. As with sulfonamides, it has been noticed that the response to penicillin is better when the clinical signs and symptoms have existed without treatment for a period from 5 to 8 clays. OLD METHODS OF TREATMENT
Silver protein solutions and irrigating solutions, such as permanganate, have a place in the treatment of gonorrhea. To them may be added the local use of sulfonamide solutions in strengths of 5 to 20 per cent, of the latter solutions, the sodium salts seem to work better. The important factor though, is to realize the histo-pathological nature of urethral gonorrhea and that unless surgical drainage is established, local application of medicinals has little chance of improving the situation. It is necessary to localize the lesion in the urethra by a bougie a boule and then establish drainage by over-dilatation and massage on sounds. Depending on the constrictive circumference of the primary lesion, the plan of treatment can be outlined, if small, the size of the instrument will necessarily be small, gradually increasing ,Yith each treatment. Arbitrarily, it can be said that sounds may be used for dilatations between 20 and 34 F., below 20 F., it is safer to use filiforms and followers in the early stages of treatment directed at the primary lesion. In the results obtained from the study of these two groups of patients, dilation and massage through 34 F. were predominantly necessary a number of times before complete control of the disease was manifest. Eradication of the primary lesion as far as an obstructing and inflammatory manifestation is concerned is the principle in the treatment of this disease. Do-
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ing so accomplishes two extremely important things: It enhances drainage of the underlying focus of infection in the periurethral glands, and decreases the obstruction to urine flow by the inflammatory portion of the lesion and that portion of it composed in the fibrous ring, resulting from the healing process. When there is involvement of the post genital structures such as Cowper's glands, posterior urethral glands, the subcervical glands of the prostate, the more distal gland of the prostate, the vesicles and the epididymes, surgical drainage must be established; this can usually be done by massage with discharge of the infected material into the urethra. However, treatment must be cautious and specialized. The old method of needling or incising the epididymes to secure drainage is outof vogue. However, it is notoriously true that epididymitis tends to become chronic and offers a focus of infection for years, in addition to a very real source of complaint on the part of the active patient. When it is acute, heat, rest, elevation and bacteriostatics certainly favor subsidence of the acute picture. However, when the chronic indurated a-vascular stage is reached, none of those agents help very much, it is likely that to effect a cure, open surgery with eradication of the focus is advisable. In time, it may find favor again as a method of curing those so affected. Fever therapy. The authors have had little acutal experience with this form of therapy. The senior author had occasion to study cases urologically treated with fever in 1939 while in Boston and in 1944 while on detached service with a Canadian General Hospital in England. Because of its rigorous nature, this plan of therapy is reserved for those patients who have resisted all other forms of treatment. None of these cases had been treated 1Yith penicillin or with therapeutic measures outlined in this paper with the concept of the primary manifestation of gonorrhea in mind. Following fever therapy the patients who were examined still had evidence of the primary lesion and needed a program of treatment to eradicate it, to finally effect a cure. It seems safe to say that if the true nature of the disease is borne in mind, and the methods of treatment discussed in this paper applied, that the need for fever therapy will become much less, if not disappear altogether. SUMMARY
The clinical observations on 4,635 cases of gonorrhea, treated from September 1942 through February 1946 are presented. Methods of diagnosis and of treatment of these patients are described. An attempt has been made to evaluate the efficiency of different forms of treatment. No attempt has been made to disparage modes of treatment, but rather to weigh the results gained with their use in the light of a conceivable and believedly true concept of the nature of the disease. CONCLUSION
Gonorrhea is a pyogenic, highly infectious disease, which because of its mode of transmission involves the periurethral glands.
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Clinically, it is manifest by a very definite picture which the authors choose to label the "primary lesion of gonorrhea." This lesion conforms to a persistent histo-pathological pattern, only varying in degree, depending on many factors, such as virulence, resistance, diuresis, immune mechanism and anatomical variations. In order to effect a true cure of the disease, both from an infectious and obstructive point of view, the true concept of the disease must be borne in mind and used as a basis for treatment. Moreover, in order to eradicate the infectious factor of the disease, it is necessary to remove the obstructive factor at the same time. Without doing this, it is not believed that a true cure can be obtained and that many individuals in whom it is neglected become chronic carriers of the disease. A soldier with shreds in his urine is almost always a potential carrier. Chemotherapeutic and biotherapeutic agents are not "cure alls" in any sense, but rather are valuable adjuncts to treatment. The usual study of discharge by smear and culture is too inexact and fraught with too many variables on the part of different examiners. The neglect of the close study of shreds by smear and culture is prevalent. It is believed that this is an extremely important factor in the care of those with the disease and is the responsibility of those who assume a specialized knowledge of the disease. For this reason, a small, simply equipped laboratory is a necessity in any urological clinic. When gonorrhea spreads to glandular-structures, other than the periurethral glands, as Cowper's glands, the prostate, or to the vesicles and epididymes, treatment must be cautious, even in the hand of the specialized, but the principles are the same, drainage must be established inorder to promote circulation and enhance the activity of immune forces in addition to the free flow with greater concentration of bacteriostatics.
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