LYMPHOGRANULOMA VENEREUM a General Review Professor WALDEMAR E

Home , Lymphangitis, Psittacosis, Tabes dorsalis

Bull. World Hlth Org. 1950, 2, 545-562 31

LYMPHOGRANULOMA VENEREUM A General Review Professor WALDEMAR E. COUTTS Chief, Department of Social Hygiene, Public Health Administration, Santiago, Chile Member of the Expert Committee on Venereal Infections of the World Health Organization

Manuscript received in September 1949

Page 1. Epidemiology ...... 546 2. Etiology ...... 547 3. Clinical aspects...... 547 4. Diagnosis...... 556 5. Treatment...... 558 Summary...... 559 References ...... 559

Lymphogranuloma venereum, a widespread, communicable disease usually acquired venereally, was first reported in the literature in 1833, by Wallace.112 For almost a century little more was learned about the disease except that the theory of its climatic origin, which had given rise to its identification as climatic or tropical bubo, was discarded when Rost 19 concluded that the disease was not of climatic but rather of venereal origin. It has been described under a host of names in addition to tropical or climatic bubo, e.g., lymphogranuloma inguinale, poradenitis nostras, chronic elephantiasis with vulvar ulceration, lymphopathia venereum, Frei's disease, Nicolas-Favre disease, fourth venereal disease, and fifth venereal disease, to mention a few. The specific skin-test which Frei 53 introduced in 1925 enabled studies to be made which led to positive identification of the disease. Frei maintained that the transmission of the disease to animals, especially the intro- cerebral inoculation of monkeys by Hellerstrom and Wassen in 1930, expedited the knowledge of its etiology. The latest phases of investigation have been directed towards the cultivation of the agent in the yolk sac of the embryonated chicken's egg, with the object of producing a highly purified and specific antigen for use

- 545 - 546 W. E. COUTTS in the intradermal test as well as in complement-fixation testing of the serum of infected patients.43' 84, 94, 95

1. EPIDEMIOLOGY Specific and accurate information on the prevalence and distribution of lymphogranuloma venereum is not available, since reporting of the disease is not compulsory in the majority of countries, including the USA. Although incidence is greater in the tropics, the disease has a worldwide distribution.20' 51, 65, 66 Before 1920 it was observed in Mexico, the coastal cities of South America, British and Dutch Guinea, France, Germany, Italy, the British Isles, Denmark, Sweden, European Russia, Japan, China, the southern portion of Asiatic Russia, Manchuria, Iran, French Indochina, India, the Malay peninsula, Spain, Australia, Indonesia, and the Philippines. Since 1925 the Frei test has enabled clinicians in practically every country of the world to diagnose the disease among patients under their care. It appears that scarcely any country is exempt. The existence of asymptomatic carriers has been proved by several authors. The causal agent has been recovered from the urethra and vagina, and from the rectum of males and females, a fact of considerable epidemiological importance.13, 17, 28, 34, 57, 64, 71, 87, 100 Transmission by arthropods (Pediculus pubis) has also been considered as probable. 29, 91 Most cases of lymphogranuloma venereum are acquired venereally abnormal sexual intercourse (coitus analis or buccalis) is also a frequent means of transmission. Active open lesions are highly infectious and may remain undiagnosed owing to their subclinical character or because they are masked by a simultaneous syphilitic, gonococcal, or chancroidal infection. Conjugal contagion, as well as accidental contagion among children, physicians, laboratory workers, etc., through direct contact with open lesions or septic material, has been reported. As yet there exists no evidence that the disease is hereditarily transmissible. High incidence-rates are to be expected among young adults of both sexes since the disease is generally transmitted venereally. In countries with black and white populations, a correlation between race and incidence has been claimed by some authors, with a predominance being noted among negroes. However, if such a prevalence exists, it is not due to intrinsic biological factors of susceptibility, but rather is thought to be attributable to greater sexual promiscuity and a higher rate of exposure. Although morbidity varies in different countries, mass-screening of populations not infected with venereal diseases, employing the Frei or complement-fixation tests, in Chile,28 89, 111 France,'05 Puerto Rico,67 and the USA 8, 47, 59, 102, 116 has revealed a higher morbidity than usually anticipated. LYMPHOGRANULOMA VENEREUM 547

2. ETIOLOGY Lymphogranuloma venereum is caused by a virus of a lymphotropic nature. This lymphotropism is responsible for the differentiation in the type of involvement observed in clinical practice, as infection spreads mainly along the lymphatics. Specifically the virus, which belongs to the so-called lymphogranuloma-psittacosis group, may transmit the disease in dilutions as great as 1 in 10,000, is active at room temperature for 24-28 hours, is unaffected by freezing temperature, and remains active after drying for 30 days, but loses its virulence in 30 minutes at 460 C. and is killed in 10 minutes at 560 C. Lymphogranuloma venereum is not a local disease as was once believed but is a generalized infection.10' 21, 33, 44, 60, 61, 96, 97,107,110 Several authors incline to the view that general dissemination of the virus frequently occurs during the early stages of the disease, the pathogenic agent having been recovered from the circulating blood,9 from material obtained by puncture of the spleen,110 from the spinal fluid,33 etc., during the bubo-complex period. 3. CLINICAL ASPECTS The clinical manifestations of the disease may be grouped into three stages: primary, secondary, and tertiary.7 21 3.1 Primary Stage The initial lesion may be ulcerative (chancre) or catarrhal, and appears from 10 to 30 days after exposure. Cases have been recorded in which the incubation period was shorter (3 to 5 days) or longer (months). The primary sore may appear on the genitalia, rectum, mouth, etc. Finger chancres have been observed following accidental infection in surgeons and nurses or manipulations of genitalia. The initial lesion may be a small superficial asymptomatic ulcer (poradenic microchancre), circular or lenticular, sometimes multiple (herpetiform type), with clear-cut edges surrounded by a reddened zone, but without infiltration. The base of these ulcers is of a whitish-grey colour. When multiple, some ulcers may be larger than others and their nature erosive ; others may present a syphiloid aspect. Papular and nodular chancres have also been described. The most common sites of appearance of these lesions are the prepuce and glans penis in men and the vagina and cervix uteri in women. Lympho- granuloma-venereum chancres appearing on other parts than the genitalia are seldom diagnosed as such. Balanitis may be the earliest manifestation of this disease. Primary lesions of the ulcerative type are very often accompanied by local or regional oedema. In males this oedema produces varying degrees of phimosis and in females swelling of external genitalia. The phimosis 548 W. E. COUTTS

is of a purplish colour and several authors consider that, when present and accompanying syphilitic or chancroidal sores, it is indicative of a simultaneous associated lymphogranuloma-venereum infection.25 81' 83' 9 Lymphangitis of the coronal sulcus and dorsal lymphatics ofthe penis is present in most instances and bubonules may appear along the course ofthe inflamed lymphatics. Occasionally these bubonules break down and leave draining sinuses. Scar tissue around them mayinterfere with normal erection. Primary manifestations of the catarrhal type are accompanied by inflammatory symptoms at the site of infection-urethritis, vulvitis, vaginitis, proctitis, stomatitis, amygdalitis, conjunctivitis, etc. In the pure type of infection, catarrhal symptoms are usually mild and fugacious, and are frequently overlooked by the patient or underestimated by the physician. Lymphogranulomatous urethritis is usually asymptomatic and follows a very mild course; pus and numerous epithelial cells are found in the discharge which is very often abacterial. Secretion may last for a few days or a longer period. Purplish oedema of the prepuce, with a varying degree of phimosis, is frequently present ; this fact is important in patients being examined for gonorrhoea. When the process extends to the posterior urethra, a slight pollakiuria may be present. Extension to prostate and seminal vesicles may be followed, at an early stage in the course of these complications, by epididymitis whose clinical evolution sometimes closely resembles that of tubercular infection of the epididymis. Catarrhal processes of vulva and vagina are also of a very mild nature. Infection of Bartholin's glands may appear early during the disease. The infection may extend rapidly and produce metritis, perimetritis, salpingitis, perisalpingitis, etc. Rectal inoculation of the virus produces, as a common early manifestation, the passage of blood by the anus; later, a purulent discharge appears with mild diarrhoea and occasional cramps. Primary lesions are followed by the appearance of an adenopathy in the lymphatic drainage-area corresponding to the site of penetration of the virus. In a large proportion of cases (50% to 70%) the bubo is the first noticeable manifestation of the disease. Some authors attribute this fact to a decapitated infection, but it is probably due either to the incon- spicuousness, fugacity, and lack of symptoms or to the location of the primary lesion, especially in women, in whom the most common sites of penetration of the virus are the posterior vaginal wall and the cervix uteri, which drain into deep iliac, perirectal, pelvic, and aortic lymph-nodes.

3.2 Secondary Stage The bubo appears from 10 to 30 days after the initial lesion and is only a part-usually the visible one-of a complex which constitutes the sympto- LYMPHOGRANULOMA VENEREUM 549 matology of the secondary or invasive period which includes a number and variety of clinical manifestations and humoral changes. Cases have been described in which the bubo appears as early as 4 to 6 days, or as late as 4 months, after the primary lesion. As most patients are seen a considerable time after the appearance of the bubo, our knowledge of its earliest aspects is limited. The affected gland is accompanied by a sensation of stiffness and aching, followed by swelling. Soon the process extends until all glands of the group are usually involved. Infected lymph-nodes, matted together by a periadenitis, become attached to the overlying skin, which is of a rather characteristic purplish colour,'07 forming one conglomerate mass. Softening appears in one or more zones, and formation of abscesses and fistulas, from which first pus, and later a sero-viscid fluid, drains, is a characteristic feature. The adenopathy usually subsides after 2 or 3 months ; in some cases draining sinuses may persist for years. Not infrequently the protracted suppuration and fistulization of lymph-nodes are accompanied by prolonged fever and general reactions. In some instances long periods of quiescence may be followed by an acute flare-up in the lymph-nodes. Such is the clinical evolution of most lymphogranuloma-venereum buboes. Sometimes symptoms subside rapidly after rest in bed; the process is reabsorbed and abscesses or fistulas are absent. These cases may be considered as abortive forms of the disease. In other cases spon- taneous, scarcely detectable forms of the bubo may be encountered ; one or two lymph-nodes are involved, but matting and periadenitis fail to occur, glands do not adhere to the overlying skin, and the process subsides gradually. When the primary lesion occurs in the inguinal lymphatic drainage-area, whether in males or females, inguinal buboes appear. The location is prevailingly inguinal or inguino-crural, and may be uni- or bilateral. The following varieties may be encountered: purely inguinal, inguino-iliac, inguino-femoral, inguino-femoro-iliac, involving only Cloquet's lymph- node, etc. Simultaneous involvement of deep iliac lymph-nodes is registered in over 75 % of cases. These iliac lymph-glands may form masses as large as a child's head and may suppurate in very rare instances. Inoculation in the vagina or cervix uteri, the most common sites in women, extends along the lymphatics of the recto-vaginal septum and cervico-vesical group to the lymphatics of the small and large pelvis (pouch of Douglas and broad ligament), lumbo-aortic chain, etc. Deep iliac lymph- nodes are constantly enlarged. Infection of the male urethra, when extending to the membranous and prostatic portions, is accompanied by involvement of deep iliac, perirectal, hypogastric, etc., lymph-nodes. 550 W. E. COUTTS

This common involvement of deep iliac lymph-nodes in vagino-cervical or urethrogenous penetration of the virus is of great diagnostic importance. Symptoms originating from their inflammation, such as peritonism, reten- tion of urine, cystitis, etc., may cause clinicians to err and diagnose appen- dicitis, pelvi-peritonitis, periprostatitis, vesiculitis, etc. In the anal or rectal types of inoculation, lymphatic response depends on the site of penetration of the virus. If the primary lesion is around the anus, inguinal adenopathy is usually present ; in the rectal type of invasion, deep iliac, perirectal, hypogastric, etc., lymph-nodes are involved. When infection occurs through the mouth, the commonest sites of the primary lesion being the tongue and tonsils, inflammation of submaxillary and cervical glands is present. If the chancre is close to the tip of the tongue, lymph-node involvement is usually bilateral. In cases of tonsillar penetration, involvement of jugular lymph-nodes may result in severe headache owing to compression of the vasculo-nervous packet and subsequent circulatory disturbances. Cases of involvement of the supraclavicular lymph-nodes with mediastinal lymphadenopathy and pericarditis have been recorded.'04 Inoculation through the conjunctiva is accompanied by swelling of the regional preauricular and submaxillary lymph-nodes. Several authors maintain that Parinaud's so-called oculo-glandular syndrome is of lymphogranuloma-venereum origin. A similar opinion has been upheld as regards Mickulicz's dacryo-adenitis. Infection penetrating through the hands is followed by axillary-gland involvement. Cases of simultaneous inoculation of the virus into mouth, genitalia, or other regions may be observed in patients indulging simultaneously in acts of normal and perverted sexuality.6 16 38 Polyadenopathy has been recorded and, according to some authors, is of fairly common occurrence in the early stages of the secondary period. Differential diagnosis of inflamed glands must be made with syphilis, tuberculosis, leprosy, mycosis, plague, tularaemia, Chagas's disease, malignancies, etc. There is a considerable variation in the severity and duration of the constitutional reactions preceding or attending the invasion of lymphatic nodes. While not highly specific, clinical symptomatology is characterized by lassitude, malaise, headache, fever, vomiting, rheumatoid manifestations, skin eruptions, etc. These reactions, which are of the same character as those seen in general invasion by specific agents, owing to their severity often overshadow the local manifestations of the disease and lead the patient to seek medical advice. Headache may be slight or severe ; pain is sometimes of a pressing nature in the forehead and radiates to the temples and eye sockets or towards the base of the neck, as observed in cases of meningeal irritation. Cases of true lymphogranulomatous meningitis have been observed during LYMPHOGRANULOMA VENEREUM 551 this period, a fact to be kept in mind when estimating the significance of headache. Mild fever preceding, and lasting for some days after, the appearance of the bubo is present in a large number of cases. Occasionally there is hyperpyrexia which may lead to a tentative diagnosis of typhoid fever, especially in cases with scarcely detectable forms of adenopathy. In other cases, chills followed by high temperature and sweating may simulate a septic process. Such reactions must be kept in mind as they are more frequently observed in cases where penetration of the virus is not in the inguinal lymphatic territory. Nausea and occasional vomiting are also observed, especially in cases with high fever and large inguino-iliac buboes. Abdominal pains, sometimes accompanied by the clinical picture of acute gastro-enteritis, pains in the lower lumbar and sacral regions, common in women and characteristic of involvement of deeper pelvic and abdominal lymph-nodes, are not infrequent. A considerable proportion of patients complain of transitory myalgia and arthralgia ; occasionally reactions occurring in the small or large joints simulate rheumatic fever. Arthritis of joints close to or distant from the site of initial involvement, with or without effusion, has been observed. Skin lesions belonging chiefly to the erythema group-nodosum, morbiliform, etc.,-are not infrequently present during this phase of the disease. Enlarged liver and spleen have been noted by several authors ; existence of a " head cold " with pains in the chest and cough during the first weeks of the disease has also been recorded. Renal involvement is evidenced by the frequent occurrence of traces of albumin in the urine, elevation of blood urea, alterations in the blood-urine urea secretory constants, etc. Cases of phlebitis, both related and unrelated to vascular irrigation of the bubo, have been observed on several occasions.12' 42, 80 During the secondary period, eyeground changes have been registered by several authors in 50 % to 75 % of the cases examined. Changes consist in an oedema of the fibre layer of the optic nerve with increased tortuosity of the blood-vessels and capillary hyperaemia.49 5568 An incomplete eyeground symptom-complex is frequently observed.50 A moderate secondary anaemia and leucocytosis are almost invariably present. White blood-corpuscles show an unstable differential count, but mononucleosis and eosinophilia are frequently encountered. Erythrocyte sedimentation-rate is considerably increased. Serum lipids are uniformly decreased ; hyperglobulinaemia is outstanding and most marked in the late stages of the disease. According to several authors this hyperglobulinaemia may be responsible for confusing and abnormal findings in the blood of patients suffering from lymphogranuloma venereum-false 3 552 W. E. COUTI'S

Wassermann tests, high sedimentation-rate, etc. Evidence of damage to the reticulo-endothelial system has been demonstrated by means of the Congo red test. 2, 29, 56 Apart from the constitutional reactions accompanying the acute phase of the disease, the remote systemic effects have received little recognition, although several authors, especially in the Americas, have demonstrated the presence of the pathogenic agent in different organs. According to most writers on the subject the greater number of patients end their subacute or acute course during the secondary period, remaining asymptomatic thereafter; others, whose course is complicated, protracted, or relapsing, present extremely varied clinical pictures and develop well- defined syndromes. Most of these syndromes correspond to mRanifestations appearing on or around genitalia. Humoral changes registered during the tertiary period are similar to those observed during earlier phases of the disease, but some have lost intensity while others have become more evident.

3.3 Tertiary Stage Tertiarisms present themselves, early or late during the course of the disease, as well-defined syndromes or as isolated or associated manifestations in different organs or systems. Among the first and most easily recognized at present are esthiomene, urethro-genito-perineal syndrome, elephantiasis of the penis and scrotum, rectal stenosis, and plastic induration of the penis. 3.3.1 Esthiomene This term includes a variety of lesions of the vulva. Its principal manifestation is a chronic ulcerative process appearing on the external surface of the labia majora, on the genito-crural folds, lateral and anterior regions of perineum, mons veneris, etc. Two types are recognized: erythematous and serpiginous. In the earliest stages lesions are superficial, but gradually become destructive and invasive involving vulva, urinary meatus, first portion of vagina, etc. Condylomata lata may be found around the urethral orifice and myrtiform vegetations in the neighbourhood of carunculae. Infiltration of the labia majora and the neighbouring skin produces elephantiasis. When it affects the prepuce of the clitoris it creates a peni- form growth.36 In some cases such lesions are associated with rectal stricture and constitute the so-called genito-ano-rectal syndrome (Jersild) whose principal manifestations are : elephantiasis of external genitalia; ulcerations; condylomata around urethral and anal orifices; anorectitis with stenosis of rectum; occasional proliferative colosigmoiditis; anal, perianal, or recto-vaginal fistulas. LYMPHOGRANULOMA VENEREUM 553 3.3.2 Urethro-genito-perineal syndrome This syndrome is characterized by the appearance of penile, scrotal, or perineal sinuses from which drains a sero-viscid fluid or urine or a mixture of both. It may be present with or without urethral stenosis. There is infiltration into surrounding and neighbouring skin and papillomatous growths may be found close to the fistular openings.19 A comprehensive review of the literature leaves very little doubt that most of the early, as well as present-day, authors regard inflammatory stricture of the male urethra as a manifestation of gonorrhoea ; however, considering the enormous number of people with insufficiently treated or untreated gonorrhoea, it would seem improbable that this disease is a frequent cause of stricture. Moreover, infrequency of development of rectal stricture after gonococcal proctitis speaks against this disease as an etiological factor. Therefore, it would appear that in cases of urethral stenosis a lymphogranuloma-venereum infection, either alone or in association with a gonorrhoeal infection, is the determining cause of fibrosis. Study of the lymphatics has proved that anastomoses exist between the lymph-vessels of the anterior urethral mucosa and the scrotal and anal regions. The drainage of the posterior urethra is into the posterior lymphatic pedicles of the prostate which empty into the rectal branches and thence into the rectal absorbing-pedicles. Such connexions between the posterior urethra and perirectal lymph-nodes are of great importance as it is through such channels that infections of the posterior urethra reach the lymphatics around the rectum. Differential diagnosis must be made with tuberculosis. Cases of associated lymphogranuloma-venereum and tuberculosis infections have been registered. 3.3.3 Peno-scrotal elephantiasis This syndrome appears from 1 to 20 or more years after infection. In its single unassociated form the syndrome may manifest itself as: (a) elephantiasis of the prepuce ; (b) elephantiasis of the prepuce and penis ; (c) elephantiasis of the scrotum ; and (d) elephantiasis of the penis and scrotum.27 Any of the varieties just mentioned may be associated with any or all of the lymphogranuloma-venereum syndromes affecting the male. Before the true elephantiasic stage is reached, several attacks of oedema lasting for varying periods of time may be registered. The oedema is hard and indepressible. The degree of elephantiasis is variable ; in some cases it is considerable and deforms the penis. The scrotum may reach a monstrous size. Sexual intercourse is impaired and, in many cases, is impracticable owing to the size of the penis or of the scrotum. Azoospermia is present due to impairment of the thermo-regulating function of the scrotum.39 554 W. E. COUTTS Elephantiasis is not a consequence of lymphatic stasis, as is maintained by many authors, but is a direct result of activity of the virus.5 35 Differential diagnosis must be made with filariasis, syphilis, mycosis, chronic pyoderma, etc.

3.3.4 Rectal stenosis All benign strictures of the rectum cannot be attributed to lymphogranuloma venereum, but a comprehensive review of the literature leaves little doubt that many described under diverse etiologies are due to this disease. Lymphogranuloma-venereum stricture of the rectum may present itself as the only manifestation of the disease or as a complication or inte- grant of genital syndromes. Because of variations in the course of some lymph-channels and of the different locations of the primary lesion (anal, rectal, or genito-urinary), the stricture may be found at different levels. The lesion usually appears from 1 to 10 or more years after infection. Several types of stricture may be observed, depending mostly on whether the infection was primarily of the anus or of the rectal mucosa, or whether it extended from neighbouring structures by way of the perirectal or rectal lymphatics.4 18, 78 In the former cases, perianal abscesses and fistulas and papillomatous growths around the anus appear after establishment of rectal symptoms; in the latter, perianal abscesses and fistulas frequently precede the strictural symptomatology. Because a large number of strictures is found in patients infected by both the genital and the rectal routes, a mixed type of stricture is very frequently encountered. Ano-rectal strictures are due to a rectogenous penetration of the virus ; anular diaphragms or funnel-shaped strictures are usually produced by a perirectal attack. The ano-recto-sigmoid type is due to a concomitant rectogenous-exogenous attack by the virus. In advanced stages of the disease the clinical picture is unmistakable flat tapeworm-like depositions, bloody mucous discharge, pruritus, and tenesmus, with intermittent periods of varying degrees of constipation, recurring attacks of ileus with pain, distension and fever, etc. Some cases, in which intestinal obstruction appears, perforate and die of peritonitis. Several cases of rupture of the stricture during childbirth and subsequent death from peritonitis have been described. On this account obstetricians recommend caesarean section in such patients. Differential diagnosis must be made with tuberculosis, syphilis, bilhar- ziasis (Schistosoma mansoni), malignancies, etc. Lymphogranuloma-venereum infections may exist in association with any of the aforementioned diseases. 3.3.5 Plastic induration ofpenis Plastic induration of the corpora cavernosa of the penis has been in- corporated as a syndrome of a lymphogranuloma-venereum nature.79. 86, 92 LYMPHOGRANULOMA VENEREUM 555

It is of interest to note that this condition has been found in a few persons presenting at the same time retraction of the palmar aponeurosis (Dupuy- tren's syndrome). 3.3.6 Other manifestations In general, the syndromes described are usually accompanied by weak- ness, loss of weight, pronounced secondary anaemia, mental depression, etc. A synoptical review of tertiarisms appearing in different body structures and systems follows. Many of them may be found accompanying some of the established lymphogranuloma-venereum syndromes or may be present alone or in association with each other. 3.3.6.1 Skin. Manifestations of the skin usually accompany some of the well-defined syndromes and may be: (a) papillomatous, but unlike condylomata acuminata or papillomatous syphilitic lesions, (b) ulcerative, (c) ecthymatous, (d) psoriasiform, (e) vesiculo-pustulous, or (f) dermo- epidermic nodules that frequently break down leaving draining sinuses. Most of these lesions are found on the skin covering genitalia, lower abdomen, buttocks, thighs, legs, etc. The virus has been recovered from these lesions and potent antigens have been prepared from scrapings.52, 85 3.3.6.2 Cardiovascular system. Evidence of lymphogranuloma-venereum infection has been found in : pericardial symphysis, arteriosclerosis- especially of young adults-obliterative arteritis (Leo Buerger type), symmetric gangrene of extremities, periarteritis nodosa, etc.31, 82, 93 3.3.6.3 Respiratory system. The virus may reach the lungs by lymphatic or haematic routes. Some authors have described cases of atypical pneu- monitis associated with lymphogranuloma venereum. Cases of strange and extensive fibrosis of the lungs have been found at necropsy of patients who died from lymphogranuloma venereum.26 3.3.6.4 Digestive system and adnexa. Lymphogranuloma-venereum virus may be swallowed during coitus buccalis or during a linguo-vulvar approach, and also from primary lesions of the mouth. Inclusion bodies resist the action of acids. Among tertiarisms we may consider certain forms of cheilitis, glossitis, oesophageal ulcers and stenosis, chronic gastritis, chronic ulcers of stomach and duodenum, leather-bottle stomach, strictures of ileum, regional enteritis, chronic ulcerative colitis, segmentary strictures of ascending, transverse, or descending colons, etc." 30, 37, 72, 74, 88 The virus has been found and recovered from the gall-bladder wall in cases of chronic non-calculous cholecystitis, from cirrhotic livers, etc.77 109 It has also been found in fibrous perihepatic (Fitz-Hugh's syndrome), abdominal, and pelvic adhesions.23 32, 76 3.3.6.5 Genito-urinary system. In the male, we may consider cases of chronic balanitis, Stiihmer's disease, chronic ulcers of the penis, etc., as being of 556 W. E. COUTTS

lymphogranuloma-venereum origin. In the female, stenosis of vagina, stenosis of the cervical canal, etc., may be due to this disease. Internal genitalia may also be affected by the virus: chronic metritis, stenosis of Fallopian tubes, sclerosis of ovaries, parametritis, ligneous infiltration of perigenital and perirectal cellular tissues, etc., are the most common lesions observed in relation to lymphogranuloma-venereum infection. In the urinary system we may find chronic perimeatic oedema ; urethral stenosis; infiltrative processes of the male posterior urethra ; fibrosis of the neck of the bladder ; chronic interstitial cystitis (Hunner's ulcer) ; vesico-rectal, vesico-vaginal, etc., fistulas, etc.22 24, 40, 41, 46, 69, 75, 98 3.3.6.6 Nervous system. Several authors have considered that tabes dorsalis might be due to the action of the lymphogranuloma-venereum virus; others, on the basis of a positive Frei test, have suggested that in some cases the virus may give rise to progressive muscular atrophy, medullary sclerosis, etc. 3.3.6.7 Sense organs. Most important manifestations have been registered in ears and eyes. Lymphogranuloma venereum has been considered as a determining cause of otosclerosis,14' 15 pterygium, certain types of iritis, stenosis of lachrymal duct, etc.48 3.3.6.8 Malignant growths. It has been proved experimentally that the virus of lymphogranuloma venereum has a marked affinity for tumour cells. On the other hand, more than twenty cases of cancer developing at the site of lesions of esthiomene and on lymphogranuloma-venereum strictures of the rectum, colon, etc., have been published in the current medical literature of the past few years.

4. DIAGNOSIS The diagnosis of lymphogranuloma venereum can be made by different methods and procedures: Frei intracutaneous test, complement-fixation test, culture of the virus, search for visible forms of the virus in secretions and tissues, and histopathological changes.

4.1 Frei Test Routine diagnosis is principally based on Frei's intracutaneous test. The introduction of this test has helped the recognition of lymphogranuloma venereum in its multiple manifestations and has removed some differential diagnostic difficulties. The test is specific and life-long ; a positive reaction does not prove in all cases that the disease still exists. One negative reaction is not sufficient to rule out lymphogranuloma venereum. Any disease which causes destruction of the allergic power of an individual (transitory LYMPHOGRANULOMA VENEREUM 557 or constant anergy) may produce a negative Frei reaction in an otherwise positive case. The technique followed for the Frei skin test is the same for both antigen and antigen-control. The skin of the flexor area of the forearm is swabbed with alcohol prior to the intradermal inoculation of the specific antigen and antigen-control. Reaction readings are made 48 and 72 hours after the injections by measuring the diameters of the resulting papules. The appearance of erythema, regardless of its extent, surrounding the point of injection is of no significance. A papule of 6x6 mm., or greater, resulting from yolk-sac antigen indicates a positive reaction if the papule originating from antigen-control is 5 x 5 mm., or smaller. A positive reaction to yolk-sac antigen exhibits a central induration with surrounding erythema, whereas the control reaction produces slight induration of less than 5 mm. in diameter. The erythematous crown of a positive reaction is not always readily perceived in the negro.108 When interpreting tertiarisms we must keep in mind that a positive Frei reaction is suggestive but requires interpretation. Like Kahn or Wassermann reactions, it may be unrelated to the present lesion. Thus, care should be taken not to interpret a positive reaction too dogmatically without resorting to other complementary procedures. In order to avoid interpretative errors it is advisable to use standardized antigens prepared from chick-embryo cultures of the virus. 4.2 Complement-Fixation Test Complement-fixation reactions with specific lymphogranuloma-venereum antigen (chick-embryo) in persons with positive Frei tests give a very high proportion of positive results (95 % to 98 %). In healthy individuals who have not had clinical lymphogranuloma venereum and have a negative Frei test reactions are negative. Although this evidence seems conclusive, it has been proved that individuals known to have been infected by other members of the psittacosis-lymphogranuloma-venereum group of viruses give positive serological reactions with lymphogranuloma- venereum antigens.47' 102 The simplicity and rapidity of performance of the complement-fixation test are among its many practical advantages. A test can be performed with as little as 1.6 ml. of serum and does not require return visits by the patient as in the case of the intradermal test. Results obtained so far with the complement-fixation test have proved it to be more specific than the intradermal test.63 '0 It would serve as a useful instrument in mass- screening of population groups for gauging the incidence of lymphogranuloma venereum, and has a special epidemiological significance since it could be performed concomitantly whenever existing legislation neces- sitates a serological examination for syphilis. 558 W. E. COUTTS

4.3 Other Methods Culture of the virus is still a specialized laboratory procedure. Investigation of visible forms of the virus in secretions and tissues is an excellent diagnostic aid. Elementary and inclusion bodies and granulo- corpuscles can be found both outside and inside cells. They usually appear in clumps or in formations like Russell-body formations. These structures are resistant to the action of acids and are best stained by Mann's or Macchiavello's methods. Under the electronic microscope elementary bodies of several members of the psittacosis-lymphogranuloma-venereum group of viruses propagated in the yolk sac of developing chick-embryos show that most of them are essentially similar in size and shape and that all are identical in structure.70 Unfortunately biopsy is not commonly used for the diagnosis of lymphogranuloma venereum. The histological picture of this disease has received little attention although, according to several authors, changes registered in chancres, bubonules, and lymph-nodes are sufficiently distinct to permit a reasonably accurate diagnosis from similar lesions of other known venereal diseases.62, 101, 106 The lymphogranuloma-venereum bubo is readily distinguishable from that of syphilis or tuberculosis, especially by the type of necrosis ; but the stellate abscess cannot be differentiated from that of tularaemia and is closely simulated in filarial infection.3 The necrosis associated with tertiarisms, which is prominent in early lesions and is caused by compression and obliteration of capillaries owing to an intense perivascular small-cell infiltration, is replaced by marked fibrosis. Only isolated foci of epithelial cells surrounded by plasma cells remain. In zones of viral activity, however, typical lesions are found.

5. TREATMENT Medical and surgical therapies have, up to the present, been rather unsatisfactory. Antimony compounds, which were widely used during the 1920-1930 decade, had little effect on lesions and probably scarcely affected the virus. The advent of sulfa drugs raised hopes of obtaining definite cures but, as was subsequently proved, these drugs failed to give complete cures and created a carrier state. Some strains of the virus became sulfa- resistant. During the bubo-complex period the best results were obtained with sulfapyridine and sulfamerazine. The oral or local administration of sulfa drugs is still of great value when secondary infections are present.'158 Gramicidin, tyrothricin, and streptothricin proved valueless. The action of penicillin is surprisingly weak, although experimentally it shows some activity in vivo and in vitro. Streptomycin has no effect whatever on the virus. So far, the best results seem to be obtained with aureomycin, LYMPHOGRANULOMA VENEREUM 559

but experience with this antibiotic is still very limited and the time elapsed since its first use is too short to evaluate it definitely. Experimental studies with aureomycin,113 demonstrating its virucidal and antirickettsial activity, soon led to its clinical trial. The first report 115 of the use of aureomycin in the treatment of lymphogranuloma venereum in its secondary and tertiary stages indicated that the antibiotic would play a major role in future treatment. One week after treatment had begun no elementary or inclusion bodies could be detected from smears made by aspiration of buboes. Decided improvement in patients with proctitis was noted four to eight days after the first injections of aureomycin. The rectal mucosa was normal at the end of treatment. In cases suffering from benign rectal stricture, treatment produced no gross change in the fibrous rectal stricture, but there was a marked decrease in rectal pain, discharge, and bleeding. Later reports confirmed the original optimism which aureomycin had created.73 114 Surgery has not proved to be of much value, but in some instances it is the only means of improving the patient's condition. Inguinal lymph- node extirpation has no anatomo-clinical basis; iliac and pelvic lymph- nodes are left behind. Operations on the rectum and colon are only pallia- tive. Plastic operations on the vulva, penis, and scrotum permit reinitiation of sexual intercourse. Impaired or abolished spermiogenesis is improved or restored for some time but relapses when the syndrome reappears.39 X-ray therapy is only helpful in reducing fibrosis. As lymphogranuloma venereum is more common than has been generally supposed, especially in its latent from, physicians should attempt to detect it systematically, and biochemists and bacteriologists should give more attention to the search for a specific virucide.

SUMMARY 1. The history, epidemiology, and etiology of lymphogranuloma venereum are discussed. Its incidence is not definitely known but it has been established that the disease has a worldwide distribution. 2. The course of the disease involves three stages: primary, secondary, and tertiary. Clinical manifestations observed during the three stages are given in detail, and the importance of differential diagnosis is stressed in the case of tertiary syndromes. 3. Diagnosis of the disease, especially by means of the Frei and complement- fixation tests, is considered. 4. At present, the best results in treatment are realized with aureomycin. How- ever, sulfa drugs are still of great value in the treatment of secondary infections.

REFERENCES 1. Adams, T. R., Edwards, M. & Netterville, R. E. (1948) Sth. med. J., Nashville, 41, 1080 2. Agliati-Beltrami, J. (1934) Tesis de la Facultad de Medicina, Universidad de Chile 560 W. E. COUTTS

3. Ash, J. E. (1947) Amer J. trop. Med. 27, 483 4. Barthels, C. & Biberstein, H. (1931) Beitr. klin. Chir. 152, 161 5. Barthels, C. & Biberstein, H. (1931) Beitr. klin. Chir. 152, 325 6. Bassas-Grau, E. & Bassedas-Vidiella, J. (1943) Act. dermo-sifilogr. Madr. 34, 487 7. Becker, B. J. P. (1940) E. Afr. med. J. 17, 131 8. Beeson, P. B. & Miller, E. S. (1944) Amer. J. publ. Hith, 34, 1076 9. Beeson, P. B., Wall, M. J. & Heyman, A. (1946) Proc. Soc. exp. Biol., N. Y. 62, 306 10. Bloom, D. (1938) N.Y. St. J. Med. 38, 616 11. Brandt, R. & Greenglatt, R. B. (1941) Sth. med. J., Nashville, 34, 941 12. Caffa, L. & Fulga, G. (1932) Bull. Soc. mid. Hop. Bucarest, 14, 501 13. Caminopetros, J. (1935) Bull. Soc. Path. exot. 28, 408 14. Chiarino, A. (1942) Rev. argent. Dermatosif. 26, 537 15. Correa Netto, 0. & Mourao, B. M. (1945) Brasil-mid. 59, 192 16. Costello, M. J. & Cohen, J. A. (1940) Arch. Derm. Syph., Chicago, 41, 557 17. Coutts, W. E. (1933) Ann. Mal. vene'r. 28, 721 18. Coutts, W. E. (1933) Bol. Soc. Cirug. Chile, 11, 111 19. Coutts, W. E. (1934) Ann. Surg. 99, 188 20. Coutts, W. E. (1934) J. trop. Med. Hyg. 37, 97 21. Coutts, W. E. (1936) J. trop. Med. Hyg. 39, 13 22. Coutts, W. E. (1938) Hig. Med. prev. 1, 237 23. Coutts, W. E. (1939) Rev. chil. Hig. 2, 1 24. Coutts, W. E. (1943) J. Urol. 49, 595 25. Coutts, W. E. (1944) Ginec. Obstet. tatinoamer. 2, 385 26. Coutts, W. E. (1944) Rev. chil. Hig. 6, 163 27. Coutts, W. E. (1946) Dermatologica, Basel, 93, 337 28. Coutts, W. E. & Banderas-Bianchi, T. (1933) Arch. Derm. Syph., Chicago, 28, 32 29. Coutts, W. E. & Banderas-Bianchi, T. (1934) Urol. cutan. Rev. 38, 263 30. Coutts, W. E. & Brieva, I. (1942) Rev. chil. Hig. 5, 105 31. Coutts, W. E. & Davila, M. (1945) J. trop. Med. Hyg. 48, 46 32. Coutts, W. E., Greene, E. & Martini-Herrera, J. (1939) Rev. mefd. Chile, 67, 700 33. Coutts, W. E., Landa, F. & Martini, J. (1933) Med. moderna, 6, 553 34. Coutts, W. E., Lerner, J. & Said, A. (1941) Rev. chilt. Hig. 4, 31 35. Coutts, W. E., Martini-Herrera, J. & Hewitt, R. (1939) Rev. chil. Hig. 2, 81 36. Coutts, W. E. & Monetta, 0. (1940) Arch. Derm. Syph., Chicago, 42, 438 37. Coutts, W. E., Opazo, L. & Montenegro, M. (1940) Amer. J. digest. Dis. 7, 287 38. Coutts, W. E. & Saez, E. (1936) Ann. Mal. vener. 31, 24 39. Coutts, W. E. & Vargas-Zalazar, R. (1940) Urol. cutan. Rev. 44, 277 40. Coutts, W. E. & Vargas-Zalazar, R. (1945) Brit. J. Urol. 17, 136 41. Coutts, W. E. & Vargas-Zalazar, R. (1945) Urol. cutan. Rev. 49, 166 42. Coutts, W. E. & Vargas-Zalazar, R. (1946) Urol. cutan. Rev. 50, 526 43. Cox, H. R. (1938) Publ. Hlth Rep., Wash. 53, 2241 44. Da Silva-Lacaz, C. (1941) Folia clin. biol. 13, 25 45. D'Aunoy, R. & Haam, E. von (1936) J. Amer. med. Ass. 106, 1642 46. D'Erizans, H. (1943) Rev. Urol. No. 3 47. Dulaney, A. D. & Packer, H. (1947) J. Immunol. 55, 53 48. Espildora, C. & Coutts, W. E. (1942) Amer. J. Ophthal. 25, 916 49. Espildora-Luque, C. & Coutts, W. E. (1934) Rev. med. Chile, 62, 633 50. Espildora-Luque, C., Coutts, W. E., Prats, G. F. & Chaigneau, A. (1936) Arch. sudamer. Oftal. 1, 10 51. Favre, M. & Hellerstrom, S. (1939) Rev. Hyg. Med. prev. 61, 401 52. Franchi, F. (1934) Bull. Soc. franc. Derm. Syph. 41, 165 53. Frei, W. (1925) Klin. Wschr. 4, 2148 54. Frei, W. (1938) J. Amer. med. Ass. 110, 1653 LYMPHOGRANULOMA VENEREUM 561

55. Funakawa, Y. (1934) Acta Soc. ophthal. Japon. 38, 1595 56. Gaudenzi, C. de (1934) G. ital. Derm. Sif. 60, 363 57. G6mez-Carpio, M. (1944) Tesis de la Facultad de Medicina, Universidad de Chile 58. Grace, A. W. (1941) Bull. N.Y. Acad. Med. 17, 627 59. Gray, S. H., Hunt, G. A., Wheeler, P. & Blache, J. 0. (1936) J. Amer. med. Ass. 106, 919 60. Gutman, A. B. (1939) N.Y. St. J. Med. 39, 1420 61. Haam, E. von & D'Aunoy, R. (1936) Amer. J. trop. Med. 16, 527 62. Hansmann, G. H. (1924) Surg. Gynec. Obstet. 39, 72 63. Harrop, G. A., Rake, G. & Shaffer, M. F. (1941) Trans. Amer. Clin. Climatol. Ass. 56, 154 64. Hashimoto, T. & Koyama, S. (1935) Japan. J. Derm. Urol. (Abstr. Sect.) 38, 133 65. Heller, W. (1943) Z. Hyg. InfektKr. 125, 386 66. Hellerstrom, S. & Wassen, E. (1933) Hygiea, Stockholm, 95, 545 67. Hernandez-Morales, F. & Carrera, C. M. (1943) P.R.J. trop. Med. Hyg. 19, 95 68. Kitagawa, K. (1934) J. oriental Med. 20, 48 69. Kleeberg (1928) Z. Haut- u. GeschlKr. 41, 194 70. Kurotchkin, T. J., Libby, R. L., Gagnon, E. & Cox, H. R. (1947) J. Immunol. 55, 283 71. Lerner, M. J. (1941) Rev. chil. Hig. 3, 247 72. Llombart, A. & Maneru, J. (1939) Ann. Anat. Path. 16, 597 73. Long, P. H., et al. (1949) Calif. Med. 70, 157 74. Luciani, D. (1941) Gac. med. Caracas, 48, 249 75. Marshall, V. F. & Endicott, E. (1943) J. Urol. 50, 76 76. Martini-Herrera, J. (1939) Rev. chil. Hig. 2, 325 77. Martini-Herrera, J. (1943) Rev. chil. Hig. 6, 53 78. Mathewson, C. (1938) J. Amer. med. Ass. 110, 709 79. May, J. (1937) Rev. urug. Derm. Sif. 2, 158 80. May, J. (1938) Rev. urug. Derm. Sif. 3, 318 81. May, J. (1939) Rev. urug. Derm. Sif. 4, 97 82. May, J. (1943) Rev. argent. Dermatosif. 27, 581 83. May, J. & Castiglione, J. B. (1938) Rev. urug. Derm. Sif. 3, 315 84. McKee, C. M., Rake, G. & Shaffer, M. F. (1940) Proc. Soc. exp. Biol., N.Y. 44, 410 85. Midana, A. (1937) G. ital. Derm. Sif. 63, 1014 86. Midana, A. (1939) Dermosifilografo, 14, 163 87. Nicolau, S. (1935) Bull. Off. int. Hyg. publ. 27, 505 88. Paulson, M. (1938) J. Bact. 35, 45 89. Ponce, T. (1934) Tesis de la Facultad de Medicina, Universidad de Chile 90. Prats, G. F. & Vaisman, B. (1943) An. brasil. Derm. Sif. 18, 205 91. Quintanilla-Braga, M. (1939) Arch. Biol., S. Paulo, 23, 41 92. Quiroga, -M. I. (1937) Rev. argent. Dermatosif. 21, 565 93. Quiroga, M. I. & Ambrosetti, F. E. (1943) Rev. argent. Dermatosif. 27, 624 94. Rake, G., McKee, C. M. & Shaffer, M. F. (1940) Proc. Soc. exp. Biol., N. Y. 43, 332 95. Rake, G., Shaffer, M. F., Grace, A. W., McKee, C. M. & Jones, H. P. (1941) Amer. J. Syph. 25, 687 96. Ramos e Silva, J. (1938) Arch. Derm. Syph. S. Paulo, 2, 87 97. Ravaut, P., Boulin & Rabeau (1922) Pr. mid. 30, 453 98. Rodriguez-Diaz, L. H. (1942) Rev. Urol. No. 2 99. Rost, G. (1912) Arch. Schiffs- u. Tropenhyg. 16, 677. Quoted by Frei (1938) 100. Said, A. (1942) Tesis de la Facultad de Medicina, Universidad de Chile 101. Sepulveda, R. (1942) Rev. argent. Dermatosif. 26, 139 102. Shaffer, M. F. & Rake, G. (1947) J. Lab. clin. Med. 32, 1060 103. Shaffer, M. F., Rake, G., Grace, A. W., McKee, C. M. & Jones, H. P. (1941) Amer. J. Syph. 25, 699 562 W. E. COUTTS

104. Sheldon, W. H., Wall, M., Slade, J. R. & Heyman, A. (1948) Amer. J. Med. 5, 320 105. Simon, C. & Bralez, J. (1937) Bull. Soc. franc. Derm. Syph. 44, 818 106. Smith, E. B. & Custer, R. P. (1948) Trans. Stud. Coll. Phys. Phila. 16, 91 107. Stannus, H. S. (1934) Trop. Dis. Bull. 31, 437 108. Sulkin, S. E., Fletcher, P. F., Huber, E. T. & Reh, E. P. (1941) J. Amer. med. Ass. 116, 2663 109. Tommasi, L. (1940) Rif. med. 20, 102 110. Videla, C. A. & Pedace, E. A. (1940) Rev. Med. Cienc. af. 2, 428 111. Vigueras, A. (1948) Tesis de la Facultad de Medicina, Universidad de Chile 112. Wallace, W. (1833) A treatise on the venereal disease and its varieties, London, p. 371 113. Wong, S. C. & Cox, H. R. (1948) Ann. N.Y. Acad. Sci. 51, 290 114. Wright, L. T., Sanders, M., Logan, M. A., Prigot, A. & Hill, L. M. (1948) Ann. N. Y. Acad. Sci. 51, 318 115. Wright, L. T., Sanders, M., Logan, M. A., Prigot, A. & Hill, L. M. (1948) J. Amer. med. Ass. 138, 408 116. Wright, L. T., Spencer, G. A. & Oppenheim, A. (1947) Amer. J. Syph. 31, 282