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·DONOVANOSIS
(Granuloma Inguinale, Granuloma Venereum)
R. V. RAJAM, M.S., F.R.C.P.
Director, Venereal Diseases Department, Government General Hospiral, Madras
Professor of Venereal Diseases, Madras Medical College, Madras
Formerly WHO Consultant on Venereal Infections and Treponematoses
P. N. RANGIAH, M.D.
Associate Professor of Venereal Diseases, Madras Medical College, Madras
Physician, Venereal Diseases Department, Government General Hospital, Madras
WORLD HEALTH ORGANIZATION
PALAIS DES NATIONS
GENEVA
1954

·A French edition of this monograph 19 in preparation
NOTE
Authors alone are responsible for views
expressed in the Monograph Series of the
World Health Organization

·CONTENTS
Page
9
12
15
21
1 Nomenclature and history
2 Features of distribution
3 Etrology
4 Epidemiology
5 Clinical features
6 Diagnosis
7 Treatment
Conclusion
References
Illustrations
24
32
40
44
44
47

·ILLUSTRATIONS 1 Donovan bodies 2 Technique for obtaining smears for Donovan bodies 3 Hyperplasia of marginal epithelium with massive cellular reaction in corium 4 Acanthosis, with irregular elongation of rete pegs forming an interlacing network enclosing Islands of cellular exudates 5 Histological section, showing intradermal abscesses 6 Granulation tissue showing plasma cells, lymphocytes, and scattered large mononuclear cells 7 Granulation tissue with marked hyperplasia of endothelial cells of the capillares 8 Extensive fibrous tissue reaction with collections of cells in crevices of inter lacıog strands of fibrous tissue 9 Histological section of granuloma inguinale showing pathognomonic cell stained with DelaGeld's haematoxylın 10 Early granuloma inguinale with daughter lesions often mistaken for condyloma lata 11 Muluple unbroken button like nodules on glans penis and inner lining of retracted prepuce 12 Granuloma inguinale of labia 13 Pseudo-bubo in groun 14 Early granulomatous ulcer on left side of prepuce 15 Early granulomatous lesion at frenulum 16 Extensive ulceration on dorsal aspect of prepuce and glans penis 17 Ulceration of labia minora, fourchet, and clitoris 18 Extensive granuloma of prepuce and glans penus extending upwards to both groins 19 Tendency of ulceration in female to spread downwards and backwards towarda perineum and peri anal regions 20 Granuloma of inner side of Lips and check secondary to genital disease 21 Fleshy type of granuloma of neck secondary to genital and buccal granuloma 22 Histological section of liver biopsy showing liver parenchyma cells containing Donovan organisms in varying numbers Dieterle stain 23 Histological section of liver biopsy showing capsulated organismis in the liver parenchyma celts Giemsa stam 24 Hypertrophic type of granuloma involving prepuce, right groin, and upper part of thigh in male 25 Hypertrophic type of granuloma involving major labia, clitoris, perineum, and peri anal region in female 26 Sclerotic type of granuloma in male, involving penis, penitc shaft, and inder aspect of both groins ·ILLUSTRATIONS 7 27 Destructive necrotic type of granuloma involving external genitalia perineum and pen anal region in female 28 Pseudo-elephantiases of penis secondary to healed donovanosis 29 Pseudo-elephantiasis of external genitalia in fepsale with long-standing dono yanosis 30 Almost complete obliteration of puderdal cleft 31 Complete destruction of penis secondary to dodovanosis 32 Pseudo-epitheliomatous hyperplasia grade II in a case of donovanosis 33 Pseudo-epitheliomatous hyperplasia grade in in a case of donovanosis 34 Extragenital granuloma inguinale of neck 35 Extensive granuloma of grains and of inguinal and pubic regions with defor muty of pedis (A) before and ) after treatment with streptomycin 36 Successful transplantation of chemo-resistant dodovanosis in group and forearm of a volunteer 37 Granuloma inguinale of cervix (often mistaken for cervical carcinoma) before treatment with chloramphenicol 38 Granuloma inguinale of cervix (often mustaken for cervical carcinoma) after treatment with chloramphenicol

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·CHAPTER 1 NOMENCLATURE AND HISTORY The disease to be described in this study suffers from a multiplicity of names It is not surprising, therefore, that it has been confused by medical students and physicians, and even in medical literature and text books, with another disease--lymphogranuloma vencreum or lymphogranuloma inguinale The subject of this study has been described under the following names Serpiginous ulceration of the groin Lupoid form of groin ulceration Ulcerating granuloma of the pudenda Granuloma inguinale Granuloma venereum Granuloma genito-inguinale Granuloma venereum genito-inguinale Infective granuloma Granuloma inguinale tropicum Chronic venereal sores Ulcerating sclerosing granuloma We agree with Marmell & Santora 5 that there is urgent need for a proper nomenclature for the disease, based upon the three fundamental etiological factors of (1) the discovery by Donovan *1 of the intracellular bodies constantly present in the lesions of the disease, (2) the establishment of the relationship of the intracellular bodies to the disease by Greenblatt and his associates, 92 who successfully reproduced the disease in a human volunteer by the subcutancous injection of material rich in Donovan bodies, and (3) the successful isolation of the organism by Anderson, who placed it in the new genus Donovania Hence the name " donovanosis ", suggested by Marmel1,64 seems to us an appropriate designation The advantages claimed for the new term are that it will rıd the eusting literature of the babel of names, stress the essential etiology of the disease, and give it a definite clinical entity and individuality On a personal note, the senior author (R.VR), as one of Donovan's former students, feels a certain satisfaction in the new designation, since it will remind present and future students and physicians -9- ·10 DONOVANOSIS of the Madras Medical College and the associated General Hospital of Major Charles Donovan who, as professor and physician there, 48 years ago discovered and described the tatracellular organisms from the buccal lesions of donovanosis in a patient under his care Donovanosis is a chronic, slowly progressive, muldly contagious disease of venereal origin, characterized by granulomatous ulceration of the genitalia and neighbouring sites, with little or no tendency to spontaneous healing It was first recognized in India by McLeod 50 (1882), who described the condition under the name of " serpiginous ulcer in Madras Conyers & Daniels 15 (1896) reported cases from British Guiana as "the lupoid form of the so called groin ulceration", and gave a good clinical description of the disease Galloway 25 (1897), under the term "ulcerating granuloma of the pudenda", gave a detailed description from a single case seen 10 London in a native of the West Indies The credit for discovering and describing the presence of certain intracellular bodies in the exudate from an oral lesion of donovanosis in Madras belongs to Donovan 2 (1905), the co discoverer of the etiological agent of kala azar Carter (1910) gave an account of six cases of ulcerating granuloma of the pudenda seen by him in India, and described large mononuclear cells filled with bodies resembling the gregarinform stage of a herpetomonas or crithidium" The description of the organisms by both Donovan 1 and Carter resembles that of what are now known as Donovan bodies Gnadon 3(1913) was the first to report cases from the United States of America Goldzieher & Peck ** (1926) gave a classical description of the disease, they claimed to have cultivated an intracellular capsulated bacıllus and were the first disease, in its clinical, cultural, pathological, diagnostic, anu terapuu aspects In any historical review, the contribution of the workers of the Medical School of the University of Georgia, under the indefatigable leadership of Greenblatt, must have a large place Pund & Greenblatt ** (1937), under the title " specific histology of granuloma inguinale", described a large mononuclear cell, filled with intracytoplasmic cysts containing deeply staining bodies, which they called the pathognomonic cell" of granuloma Greenblatt and co-workers 5* (1939) reproduced the disease in a human volunteer by the subcutaneous injection of pus containing Donovan organisms in pure culture, aspirated from a case of unruptured pseudo bubo The experiment was repeated successfully by transplanting subcutaneously, in another human volunteer, a piece of granulomatous ussue removed from a lesion 10 the same patient Many workers have claimed to have cultivated the organism of donovanosis in ordinary laboratory media, but their claims have not been confirmed ·NOMENCLATURB AND IDISTORY 11 Anderson (1943) reported the successful cultivation of Donovan bodies in the yolk sаc of a developing chick embryo , other workers have confirmed her claim Secondary cultivation of the organism in artificial media after primary isolation in chick embryo was successfully carried out by Dienst et al 10 (1947), Dunham & Rake(1948), and Dulaney et al * (1948) Within the past few years, the therapeutic effects of a battery of the newer antibiotics have changed the prognostic outlook of the disease Donovanosis should be clearly distinguished from lymphogranuloma vedereum, wbich is a virus disease affecting the lymphatic systems of the inguino genito-ano-rectal regions and associated with constitutional syraptoms ·CHAPTER 2 FEATURES OF DISTRIBUTION Geographical The disease has a fairly wide geographical distribution in both hemspheres It is endemic in southern China, the East Indies, northern Australia, West and Central Africa, some countries of Central, South, and North America, and the West Indies Epidemics have been reported from South America and New Guinea In the USA, with its nation wide reporting of morbidity, it would appear that the disease is by far most prevalent along the Gulf of Mexico from Louisiana at the mouth of the Mississippi river eastward to the Atlantic, although about 25% of cases are reported from the rest of the country 12 In India the disease is endemic in the States of Madras and Orissa, with the greatest incidence in the districts along the eastern seaboard of the peninsula 56 57 Recently Cutler et al 10 have brought to light another endemic focus of the disease among the Pahari hill dwellers of the Himachal Pradesh a northwestern hill State of the Indian Republic In a limited survey of 1,092 individuals in the Ghund area of the State, seven males and an equal number of females were found to be suffering from donovanosis Information on the prevalence of the disease in the other States of the vast subcontinent is sadly lacking, but it is the authors' impression that cases are missed, 10cc rectly diagnosed, or described under a wrong name in the other areas of the country where, probably, the incidence is low A greater awareness of the disease on the part of the physician and a routine examination of smears from suspected lesions will help to uncover more patients suffering from the disease in the various Indian States Racial The overwhelming predominance of the disease in the Negroes of the USA (Negroes, 88%, whites", 12%) and the Dravidians of southern India seems to point to some racial susceptibility Its occurrence among the “poor whites" of the USA, the Paharis of the Simla Hills (though to a diminished extent), and other coloured peoples of the tropics, would, however, suggest that low socIO-economic status, with its concomitant evils - 12 - ·FEATURES OF DISTRIBUTION 13 of ignorance, lack of personal and sexual hygiene, and debased sexual standards, may account for the differences in racial incidence The same environmental factors account for the greatly increased incidence of syphilis and other vedereal diseases It is stated that the stratum corneum of the genito-inguinal region is thinnest among the coloured races, and the apocrme glands more abundantly distributed Is it possible that these two factors in the composition of the skin account for the greater predisposition of the coloured races ? American writers 27 are fond of quoting the figures furnished by Nair & Pandalai and Menon on the much greater incidence of the disease among the Hindus than among the Mohammedans of India (the ratios respectively being 70 1 and 57 4) m support of the theory of racial susceptibility In the first place, however, the figures they report are from Madras State only, where the disease is endemic, and do not apply to India as a whole Secondly, the Hindus and Mohammedans of southern India belong to the same racial stock, distinguished only by their religion Thirdly, the Hindus constitute 92% of the population of the State Fourthly, the Mohammedans practise circumcision, and the incidence of diseases such as syphilis and Penile cancer is much less common among them Lastly, in both cases donovanosis is almost exclusively a disease of the unhygienic and sexually promiscuous sections of the population Climatic Although it is true that the disease is more prevalent in countries with a warm and humid climate, this alone cannot be a determining factor because the Negroes, living in the northern and north-eastern States of North America, which have a temperate climate, and the Paharis, living in the Simla Hills in a similar climate, are equally victims of the disease Europeans living in the hot and humid tropics have rarely suffered from the infection Age and sex An analysis of the records of the venereal diseases clinic at the Government General Hospital, Madras, for a 20-year period (1931 51) shows that 1,350 males and 652 females were diagnosed and treated for donova nosis Fox's 24 records also showed a preponderance of males other observers however-Galloway,* Manson Bahr, 52 and Nair & Pandala: 57... reported that the disease is more common in the female sex It may be stated in this connexion that the patients who attended the clinic at Madras were drawn from all over the State and were more representative than those who attended clinics 10 regional or linguistic areas It was a matter of great difficulty to determine accurately the marital status of the woman Although

·CHAPTER 2
FEATURES OF DISTRIBUTION
Geographical

·FEATURES OF DISTRIBUTION 13 of ignorance, lack of personal and sexual hygiene, and debased sexual standards, may account for the differences in racial incidence The same environmental factors account for the greatly increased incidence of syphilis and other venereal diseases It is stated that the stratum corneum of the genito-ingwnal region is thinnest amoog the coloured races, and the apocrine glands more abundantly distributed Is it possible that these two factors in the composition of the skin account for the greater predisposition of the coloured races ? American writers are fond of quoting the figures furnished by Nair & Pandalai and Medon on the much greater incidence of the disease among the Hindus than among the Mohammedans of India (the ratios respectively being 70 1 and 57 4) in support of the theory of racial susceptibility In the first place, however, the figures they report are from Madras State only, where the disease is endemic, and do not apply to India as a whole J LE practise circumcision, and the incidence of diseases such as syphilis and pende cancer is much less common among them Lastly, in both cases donovanosis is almost exclusively a disease of the unhygienic and sexually promiscuous sections of the population Climatic Although it is true that the disease is more prevalent in countries with a warm and humid climate, this alone cannot be a determining factor because the Negroes, living in the northern and north-eastern States of North America, which have a temperate climate, and the Pabarıs, living in the Simla Hills in a similar climate, are equally victims of the disease Europeans living in the hot and humid tropics have rarely suffered from the infection Age and sex An analysis of the records of the venereal diseases clinic at the Government General Hospital, Madras, for a 20-year period (1931-51) sbows that 1,350 males and 652 females were diagnosed and treated for donova nosis For's 24 records also showed a preponderance of males, other observers, however-Galloway." Manson Babr, 5+ and Nair & Pandala: 57– reported that the disease is more common in the female sex It may be stated in this connexion that the patients who attended the clinic at Madras were drawn from all over the State and were more representative than those who attended clinics in regional or linguistic areas It was a matter of great difficulty to determine accurately the marital status of the woman Although ·14 DONOVANOSIS the records, as entered on the case-cards, showed a slight predominance of married women over unmarried, a closer investigation into the so-called mantal status reveals many deserted wives, frequently-exchanged mistresses, and widows The marital bond is almost non-existent among certain sections of the population, partners are discarded and new partpers are taken, for economic reasons, wives practise clandestine prostitution To sum up, it is our impression that particularly unhygienic sexual promiscuty is the background of patients suffering from donovanosis A ten year break down of 858 patients according to age and sex is shown in table I TABLE 1 DISTRIBUTION OF DONOVANOSIS ACCORDING TO AGE GROUP 1932-41 Age goup (years) Male Female Total Percentage Under 12 3 2 5 13.20 77 59 136 16 21-30 292 139 431 70 31-40 123 54 177 41-50 5S 24 79 51-60 20 4 24 12 Over 61 S 1 6 Total 578 283 658 As in the case of other venereal diseases, the incidence of donovanosis is greatest during the period of sexual matunty from 20 to 40 years of age, patients in this age group comprise about 70% of the admissions in the venereat diseases clinic at Madras The next age group in the order of incidence is 13 20, forming 16% of the admissions A few cases in immature persons have been reported in our study there were five such cases-two female and three male, all under 12 years of age, the former with genital granuloma and the latter with peri anal granuloma as a result of pederasty Other The clinical incidence of donovanosis, as compared with that of other venereal diseases such as syphilis and gonorrhoea, is negligible, giving rise to about 1 5% of the total admissions for all venereal diseases Many observers have raised the question whether donovanosts is from its inception a clear cut separate disease or a condition superimposed on a pre-existing traumatic or venereal lesion such as chancroids, bubo, etc Many cases of donovanosis are found without other venereal infections Traumata such as circum- CISIOD or opening of buboes help only to promote spreading of a prerusting infection ·CHAPTER 3 ETIOLOGY la 1905, Donovan 2 at Madras described the presence of certain intracellular bodies in the exudate from the oral granuloma of a patient who also suffered from genital lesions According to him they looked like " gigantic bacıllı with rounded ends" (see fig 1) Since then a number of workers have confirmed Donovan's findings These micro-organisms are so constantly present in the lesions of the disease that a clinical diagnosis donovanosis is not complete without their demonstration With the successful reproduction of the disease in human volunteers by Greenblatt and co-workers, and more recently by us in the clinic at Madras by injecting a pure substance of Donovan organisms obtained from an unruptured bubo, or by transplanting subcutaneously a small piece of granulation tissue from an infected one, a step forward has been taken to corroborate Donovan's observation that the organisms he described are the causative agents of the disease The nature of the Donovan organisms remained until recently a matter of controversy The earliest workers (Donovan 21 Carter," and Symmers & Frost) believed the organism to be a protozoan belonging to the gregarine order of Sporozoa Later workers (Walker, Goldzieher & Peck,24 De- Monbreun & Goodpasture, 17 and Menon 58) as the result of their cultural studies classified it as a bacterium Still later, in 1938, Dienst and co-workers 19 of the University of Georgia Medical School attempted to revive the protozoal theory when they failed to grow the organism in various artificial media A study of the literature on the subject up to 1943 leaves us in great doubt as to whether the causal agent of donovanosis had even been cultivated all A great advance our knowledge of the disease came in 1943 when Anderson successfully cultivated the Donovan organisms in the yolk and yolk sаc of the developing chick embryo Several investigators »1 23 have since confirmed her findings, and have succeeded in culturing the organism from the primary culture in cell free medium consisting of unmatured yolk to which agar is added So far, however, ao success has attended attempts at primary cultivation of the organism in any artificial medium It is surmised that some factor furnished by living cells, whether in human cutaneous tissues or in developing chick embryo, is necessary for the growth of the organism - 15 - ·14 DONOVANOSIS the records, as entered on the case-cards, showed a slight predominance of married women over unmarried, a closer lavestigation into the so-called marital status reveals many deserted wives, frequently-exchanged mistresses, and widows The marital bond is almost non-existent among certain sections of the population, partners are discarded and new partners are taken, for economic reasons, wives practise clandestine prostitution To sum up, it is our impression that particularly unhygienic sexual promiscurty is the background of patients suffering from donovanosis A ten year break down of 858 patients according to age and sex is shown in table I TABLE 1 DISTRIBUTION OF DONOVANOSIS ACCORDING TO AGE-GROUP, 1932441 Age group (years) Male Female Total Percentage Under 12 3 2 5 13 20 77 59 136 16 2130 292 139 431 70 31-40 123 54 177 41-50 55 24 79 51-60 20 4 24 12 Over 61 5 1 6 Total 575 283 859 As in the case of other venereal diseases, the incidence of donovanosis is greatest during the period of sexual maturity from 20 to 40 years of age, patients in this age group comprise about 70% of the admissions in the venereal diseases clinic at Madras The nert age group in the order of incidence is 13 20, forming 16% of the admissions A few cases in immature persons have been reported In our study there were five such cases-two female and three male, all under 12 years of age, the former with genital granuloma and the latter with peri anal granuloma as a result of pederasty Other The clinical incidence of donovanosis, as compared with that of other venereal diseases such as syphilis and gonorrhoea, is negligible, giving rise to about 15% of the total admissions for all venereal diseases Many observers have raised the question whether donovanosis is from its inception a clearcut separate disease or a condition superimposed on a pre-existing traumatic or venereal lesion such as chancroids, bubo, etc Many cases of donovanosis are found without other venereal infections Traumata such as circumcision or opening of buboes help only to promote spreading of a pre-existing infection ·CHAPTER 3 ETIOLOGY * In 1905, Donovan " at Madras described the presence of certain intracellular bodies in the exudate from the oral granuloma of a patient who also suffered from genital lesions According to him they looked like gigantic bacill with rounded ends" (sce fig 1) Since then a number of workers have confirmed Donovan's findings These micro-organisms are so constantly present in the lesions of the disease that a clinical diagnosis of donovanosis is not complete without the demonstration With the successful reproduction of the disease in human volunteers by Greenblatt and co-workers," and more recently by us in the clinic at Madras by injecting a pure substance of Donovan orgadisms obtained from an unruptured bubo, or by transplanting subcutaneously a small piece of granulation tissue from an infected one, & step forward has been taken to corroborate Dodovan's obscrvation that the organisms he described are the causative agents of the disease The nature of the Donovan organisms remained until recently a matter of controversy The earliest workers (Donovan, Carter,' and Symmers & Frost®) believed the organism to be a protozoan belonging to the gregarde order of Sporozoa Later workers (Walker, ** Goldzieher & Peck, a De- Monbreun & Goodpasture, and Menon 5) as the result of their cultural studies classified it as a bacterium Sull later, in 1938, Dienst and co-workers as of the University of Georgia Medical School attempted to revive the protozoal theory when they failed to grow the organism in various artificial media A study of the literature on the subject up to 1943 leaves us a great doubt as to whether the causal agent of donovanosis had even been cultivated at all A great advance in our knowledge of the disease came in 1943 when Anderson successfully cultivated the Donovan organisms in the yolk and yolk sаc of the developing chick embryo Several investigators 11 * e bave since confirmed her findings, and have succeeded ia culturing the organism from the primary culture in cell free medium Consisting of unmatured yolk to which agar is added So far, however, no success has attended attempts at primary culuvation of the organism in any artificial medium It is surmised that some factor furnished by living cells, whether in human cutaneous tissues or in developiog chick embryo, is accessary for the growth of the organism 15 ·16 DONOVANOSIS From a morphological and cultural point of view it is concluded that the Donovan micro-organism is bacterial and bacıllary. It is not pathogenic to any of the laboratory animals Anderson et al: carried out both complement-fixation tests and skin sensitivity tests with the cultured organisms, and established an immunological relationship to the disease, but the experimental inoculation of the cultured organisms in human volunteers failed to reproduce it These workers have proposed the creation of a new genus of pathogenic bacteria with the cultivated strain as the type For the genus they have proposed the name Donovania, and for the specific type, the name Donovania granulomatis Rake,70 from his studies, suggested that D granulomatis may be related to members of the tribe Eschericheae because of the similarity of antigenic pattern between the former and the latter He put forward the hypothesis that D granulomatis may be faecal in origin, with a strongly developed tissue tropism On this hypothesis he tried to explain the peculiar epidemiology of the disease which occurs in individuals whose personal hygiene is low, and in regions of the body likely to be constantly contaminated with faecal material Packer & Goldberg ® studied the specificity of D granulomatis antigens against sera from patients with ulcerative lesions of the rectum and genitalia other than donovanosis, and subject to faecal contamination, but failed to observe any non-specific reaction Further, if the hypothesis of faecal origin of D granulomasis is to be accepted, the most frequent site of the disease should be the rectum and anus rather than the genitals and groin Morphology of Organism The open lesions of donovanosis should be thoroughly and repeatedly cleansed with saline-soaked gauze, followed by gentle wiping with dry gauze As the Donovan micro organisms are strict parasites of the large mononuclear tissue cells, a fragment of granulation tissue must be obtained for their successful demonstration (see fig 2) It is waste of time and effort to examine the surface exudate for the parasites, especially in long standing grossly infected lesions A small piece of the friable granulation tissue may be obtained from the edge of the lesion by means of a curette, forceps, the sharp end of a broken shde, or the edge of a safety razor blade The tissue is placed between two slides While one slide is kept stationary, the other is moved in a circular direction at the same time as firm pressure is applied An evenly spread smear is obtained on both slides ? Leishman. or Giemsa stain may be used to stain the “ spreads ", for routine diagnostic use we have found Leishman stain very satisfactory The dye should be allowed to remain in contact with the smear for one minute and a half Leishman stain 11 One of the modifications of Romanowsky stain und Gutes to what American workers call Wr ght stain ·ETIOLOGY 17 before being diluted with distilled water The diluted stain should be allowed to remain for five minutes Another simple and satisfactory method of staining for Donovan organisms recently recommended by Greenblatt et al * is the use of 1% pisacyanole (CasH25N,1) dye with methyl alcohol The dye is allowed to act for one and a half to two minutes before it is diluted with distilled water The diluted staja is allowed to remain for a further ope-and-a-half to two minutes. The capsulated Donovan bodies stain a purplish pink and the chromatin inclusions a dark blue The two characteristic features of the organism observed in tissue spreads are (a) the extreme pleomorphism, and (b) intracellular parasitism in the mononuclear tessue-cells in cultures of D granulomatis in the yolk of living chick embryos all the morphological variations observed in tissue smcars from human lessons occur The morphology of the organism, based upon the examination of tissue smears from human lesions, is described below Examination of a stained tissue smear shows red blood cells, neutrophil and cosinophile leukocytes, plasma cells, and lymphocytes The most characteristic feature in the sytological picture, however, is the presence of scattered large mononuclear cells with round, oval, or bean shaped aucle: The size of the macrophages varies from 2014 to 60je The Donovan organisms are found inside these large cells and docur in two forms, the capsulated and the noncapsulated The capsulated organism is an ovoid or bean shaped body, varying in size from la to 1 Su in length, and from 0 5p to 07 10 thickness, and consisting of a well-defined dense pinkish material surrounding a blue bacillary body with dark blue or black chromatia toclusions These maipute inclusions in the body of the organism may be rounded or rod shaped, and disposed centrally, penpherally, or in bipolar fashion The older capsulated forms take the stain so deeply, assuming an almost homogeneous purplish pink, that the minute inclusions are scarcely recognizable It is probable that they are the degenerating forms. The Boncapsulated forms occur as minute deeply stained bodies of varyiog morphology-Coccoid, bacillary, diplococcold-with or without a closed safety-pin appearance, and surrounded by a halo of unstained area The size of these immature young forms vanes from 0 to 1 Both the mature capsulated and the young noncapsulated forras of the organism may occur scattered in thick clusters or in cystlike spaces inside the mononuclear cell, and both the forms may occur in the sume cyst In acute, rapidly spreading lesions the young forms predominate and are found both snside and outside the mononuclear cells In chronic lesions the capsulated forms prevail and are sometimes found 10 single or muluple morula like masses inside the mononuclear cells, often overlying and obscuring the nucleus of the cell. Occasionally the organisms are found laside polymorphonuclear leukocytes When the mononuclear cell us heanly parasitized, the cytoplasm either disappears or has a faidily a ·18 DONOVANOSIS vacuolated appearance Besides these organisms, certain inclusion bodies are observed inside the mononuclear cells The most frequently observed type of inclusion is one or more sharply defined globular masses staining homogeneously a deep pink, or less often a deep blue, and lying away from the intact nucleus of the cell A second type of inclusion seen is a mass of deeply staining spherical bodies almost filling the cell and obscuring the nucleus The inclusions do not appear to be of puclear origin because the nucleus of these cells is intact The Donovan organisms can be demonstrated in 90% 95% of lesions of donovanosis They may be absent, or with difficulty demonstrable, in (1) acute destructive lesions caused by a superimposed fusospırıllary infection, (2) the cicatricial or sclerotic type of granuloma, and (3) very early cases It cannot be too strongly emphasized that the demonstration of the organism is often difficult, particularly in very early lesions of less than a week's duration and diligent and protracted search may be necessary, involving the taking of more than one smear It has been our experience that in early lesions the organisms are atypical, few in number, and extracellular, requiring for their identifica tion a trained eye and patient search Pathology The disease has a predilection for moist stratified epithelium Through some breach of the surface of the skin or mucous membrane the Donovan organism gains entrance and sets up an inflammatory cellular reaction in the corium and, to a lesser extent, in the subcutaneous tissue The earliest macroscopic lesion is a small raised flat topped nodule, the size of a pea, and covered by skin The epithelium overlying the nodule becomes doggy and macerated and in a few days excoriates In other cases a subcutaneous swelling of varying size is the initial lesion The swelling softens and becomes a small abscess In either case an ulcer is formed by the loss of the over lying skin The ulcer is indolent looking, with a raised soft bright pink velvety vascular base and a crenated or wavy bluish edge The further evolution of the disease process will be dealt with in Chapter 5 (see page 24) Histology The histological characteristics of donovanosis have been described by many students of the subject over the past 40 years The chief features are (1) the massiveness of the cellular reaction in the corium, resulting in the growth of an exuberaot granulation tissue, and (2) an associated hyperplasia of the marginal epidermis (see fig 3) The real specific diagnostic feature of the disease is the condition of the corium, although there is a ·ETIOLOGY 19 tendency on the part of pathologists to lay special stress on the epithelial changes, which are copion to many other chronic r&flammations of the integumentary system Histological examiation of an early podule shows & dense cellulat infiltration of the corum, together with desquamation of the superficial layers, and ocdema of the deeper layers, of the epidermus With the increase in the cellular infiltration of the corium at the papellae, the epidermal layers become attenuated and ultimately disappear The deruded vicerated area consists of a loturiant granulation tissue The type of celular reaction on the surface of the ulcer es predominantly poly morphonuclear, with a few scattered cosinophile leukocytes, Wononuclear and plasma cells, and fast cells The outstaodmg features of the margoal cpithelium are (a) a remark able degree of acanthosis , (6) regular elongation of the rete pegs forming an interlactog detwork enclosing islands of exudate comprising plasma cells, 2 smaller number of polymorphonuclear leukocytes, cosmophils, monocytes, and occasional lymphocytes (see fig 4), collections of poly morpbonuclear leukocytes are also observed in some of the spaces dearer the surface, resemblag bulary abscesses (see fig 5), (c) pseudo-epithelion matovs hyperplasia may be a prominent feature (see page 37) The excessive, uregular, epithelia) proliferation in some cases is so suggestive of early malignancy that the literature on the subject-even from seasoned pathologists contains much confusion and doubt Below the surface, at the papillae and at the spreading edge of the ulcer, the granulation tissue is rich is plasma cells, lymphocytes, and scattered large mononuclear cels (sec fig Running through the dense plasma-cell 19filtraron a network of capillaries can be seen, with marked hyperplasca of the endothelum, often giving the appearance of solid cords of large pale starring cells (see hg 7) Proliferation of fibroblasts us well marked ja the deeper layers Ipold cases, and in the bypertropluc type of granuloma, an extensive fibrous assue reaction is observed with collections of plasma cells, lymphocytes, and mononuclear cells here and there in the crevices of the interlacing strands of fibrous tissue (see fg 8) in the sclerotic or cicatrizal type of granuloma, thick buddles of a hyalnized collagenous fibrous tissue dominate the histological picture Giant cells, cascation, and suppuration are conspicuous by their absence from the lessons At tbc periphery of the ulcer the cellular infiltration extends for a variable distance into the normal skin, showing that she infection spreads centnfugally from the infected corium The presence of the large mononuclear celis A sections of donovagost was first dentified by Goldweber & Peck 45 and was subsequently described in detall by Puad & Greepblatt." The latter workers claimed that the mononuclear cells they described are specific fos donavanosis and are as significant as the Sternberg Reid cell is no Hodgkin's disease, they have termed the cell the pathogoononc cell of granuloma vedereyra" These cells are scattered la varmble Auribers ·18 DONOVANOSIS vacuolated appearance Besides these organisms, certain inclusion bodies are observed inside the mononuclear cells The most frequently observed type of inclusion is one or more sharply defined globular masses staining homogeneously a deep pink, or less often a deep blue, and lying away from the intact nucleus of the cell A second type of inclusion seen is a mass of deeply staining spherical bodies almost filling the cell and obscuring the nucleus The inclusions do not appear to be of nuclear origin because the nucleus of these cells is intact The Donovan organisms can be demonstrated in 90%-95% of lesions of donovanosis They may be absent, or with difficulty demonstrable, in (1) acute destructive lesions caused by a superimposed fusospirillary infection, (2) the cicatricial or sclerotic type of granuloma, and (3) very early cases It cannot be too strongly emphasized that the demonstration of the organism is often difficult, particularly in very early lesions of less than a week's duration, and diligent and protracted search may be necessary, involving the taking of more than one smear It has been our experience that in early lesions the organisms are atypical, few in number, and extracellular, requiring for their identifica tion a trained eye and patient search Pathology The disease has a predilection for morst stratified epithelium Through some breach of the surface of the skin or mucous membrane the Donovan organism gains entrance and sets up an inflammatory cellular reaction in the corium and, to a lesser extent, in the subcutaneous tissue The earliest macroscopic lesion is a small raised flat topped nodule, the size of a pea, and covered by skin The epithelium overlying the nodule becomes boggy and macerated and in a few days excoriates In other cases a subcutaneous swelling of varying size is the initial lesion The swelling softens and becomes a small abscess In either case an ulcer is formed by the loss of the overlying skin The ulcer is indolent looking, with a raised soft bright pink velvety vascular base and a crenated or wavy bluish edge The further evolution of the disease process will be dealt with in Chapter 5 (see page 24) Histology The histological characteristics of donovanosis have been described by many students of the subject over the past 40 years The chief features are (1) the massiveness of the cellular reaction in the corium, resulting in the growth of an exuberant granulation tissue, and (2) an associated hyperplasia of the marginal epidermis (see fig 3) The real specific diagnostic feature of the disease is the condition of the corium, although there is a ·ETIOLOGY 19 tendency on the part of pathologists to lay special stress on the cpitheliat changes, which are common to many other chronic inilammations of the integumentary system Histological eramination of an early nodule shows a dense cellular infiltration of the corium, together with desquamation of the superficial layers, and oedema of the deeper layers, of the epidermis With the increase in the cellular infiltration of the corium at the papıllae, the epidermal layers become attenuated and ultimately disappear The denuded ulcerated area consists of a luxuriant granulation tissue The type of cellular reaction on the surface of the ulcer is predominantly poly morpbonuclear, with a few scattered cosinophile leukocytes, mononuclear and plasma cells, and mast cells The outstanding features of the marginal epithelium are (a) a remarkable degree of acanthosis , (b) irregular elongation of the rete pegs forming an interlacing network enclosing islands of exudate comprising plasma cells, a smaller number of polymorphonuclear leukocytes, eosinophils, monocytes and occasional lymphocytes (see fig 4), collections of poly morphonuclear leukocytes are also observed in some of the spaces nearer the surface, resembling miliary abscesses (see fig 5), (c) pseudo-epitheliomatous hyperplasia may be a prominent feature (see page 37) The excessive, irregular, epithelial proliferation in some cases is so suggestive of early malignancy that the literature on the subject-even from seasoned pathologists-contains much confusion and doubt Below the surface, at the papillae and at the spreading edge of the ulcer, the granulation tissue is rich in plasma cells, lymphocytes, and scattered large mononuclear cells (see fig) Running through the dense plasma-cell infiltration a network of capillaries can be seen, with marked hyperplasia of the endothelium, often giving the appearance of solid cords of large pale stanıng cells (see fig 7) Proliferation of fibroblasts as well marked in the deeper layers In old cases, and in the hypertrophic type of granuloma, an extensive fibrous tissue reaction is observed with collections of plasma cells, lymphocytes, and mononuclear cells here and there in the crevices of the interlacing strands of fibrous tissue (see fig 8) In the sclerotic or cicatricial type of granuloma thick bundles of a hyalınızed collagenous fibrous tissue dominate the histological picture Giant cells, caseation, and suppuration are conspicuous by their absence from the lesions At the periphery of the ulcer the cellular infiltration extends for a variable distance into the normal skin, showing that the infection spreads centrifugally from the infected corium The presence of the large mononuclear cells 10 sections of donovanosis was first identified by Goldzıcher & Peck ** and was subsequently described in detail by Pund & Greenblatt" The latter workers claimed that the mononuclear cells they described are specific for donovanosis and are as significant as the Sternberg Reid cell 13 in Hodgkin's disease, they have termed the cell the "pathognomonic cell of granuloma vencreum" These cells are scattered in variable numbers ·22 DONOVANOSIS The parasite, and the host and his environment, should be subjected to organized, detailed, and adequate study to find completely satisfactory answers to some of the problems posed above The Donovan organism is a signal example of a parasite which is pathogenic only to man and has its growth and multiplication jaside mononuclear cells None of the labora tory animals is susceptible to infection In human beings, clinical observa tion suggests that individual susceptibility to infection plays a significant role The organism seems to have a low grade of infectivity, and in this the disease resembles leprosy The degree of morphological variation which the microorganism exhibits, both in human tissues and in cultures in chick embryo, is another notable characteristic Individual host susceptibility, a rigidly restricted parasitism, and the pleomorphism of the organism, may explain the low percentage of disease as compared with syphilis, and the infrequency of infections in the sexual partners It may be that the disease infectious only during a brief phase of its evolution Racial differences in the incidence of the disease may be explained by social conditions and sex habits, as has already been pointed out The difference in the sex distribution of the disease, as reported by different workers, seems to vary from clinic to clinic In our study the number of male patients with donovanosis who attended the clinic during a ten year period was more than twice the number of female patients The same male preponderance is observed even in the case of syphilis and gonorrhoca Hence, the hospital figures do not convey an idea of the real extent of prevalence of the disease among the population The majority view of the sexual transmission of the disease is based on the following grounds (1) In the vast majority of the male patients with donovanosis a definite history of sexual exposure before the appearance of the ulcer could be elicited For obvious reasons such a history is not obtainable in women (2) The initial lesion of donovanosis occurs on the external genitalia in 90% of the cases studied The spread of the disease to adjacent regions such as the groin or the cruro scrotal fold is secondary to the genital lesion (3) The greatest incidence of the disease falls during the age period of maximum sexual activity In our study 86% of patients suffering from the disease were between 15 and 40 years old (4) The relative incidence of primary peri apal and anal donovanosis in men and women is 4 I, and the quadruple predominance in the male can be attributed only to the practice of pederasty In our study we have verified this to be true of almost all male patients with the anal lesion (5) The occurrence of extragenital lesions, far from being a point T the analyse against of our disease ·EPIDEMIOLOGY 23 genital granuloma, and the fact that the disease us occasionally seen in children or sexually soactive persons, prove nothing (5) The disease is more often found in persons who are sexually promis cuous, although cases not associated with promiscuuty occasionally occur (7) The main argument cited by some clinicians agaiast the venereal origin of the disease is the rarity of afection among partners in sexual relationships Clarke, in an illuminatiog discussion on the subject, has quoted eleven cases of partner infections reported in the Americaa literature. Dunag the past three years (1950-3) 30 cases of partner infections among 250 cases of donovanosis were observed at the venereal-diseases clinic at Madras The epidemiological investigation of the partner who is not seeking treatment is a matter of great difficulty The infected person of either sex is often unable or unwilling to bring the partaer for examination, in many cases, however, by careful history taking the presence of the disease may be saferred From the many case histories it would appear that the disease was mild and healed spontaneously, while in the other partner, the disease became established It is also our observation that in conjugal or partaer afections the topographical extent of the disease in the male was limited and stationary, although chronologically older by many months, while the disease in the female case was much more extensive, although of more recent origia For example, an unmarried male had been suffenog for over a year from a ssaall, paraiess, stationary ulcer on the ventro-lateral aspect of the coropal suſcus as a result of sexual exposure with an unknown woman As the ulcer was small and paroless, and did pot trouble him, he had not sought medical advice or treatment. He marned, and four months after the marriage the young wife developed extensive ulceration of both labia majora with pseudo-elephantiasis of the coloris, it was at this stage that both reported for treatment at the clinic It is our considered opinion that partnet infections are not so rare as is made out, and that with detailed painstaking epidemiological investigation many more cases will be brought 10 lgbt ·CHAPTER 5 CLINICAL FEATURES Appearance of Lesions The incubation period of donovanosis shows extreme variations, from a few days to as long as four to five months In many patients who present themselves with fully developed lesions, it has been difficult to find out when the disease actually started In the experimentally induced infec tion in human volunteers, McIntosh, and Greenblatt and co workers 82 have separately reported an incubation period varying from 42 to 50 days for the development of a typical granuloma In our study of a limited series of early disease of less than four months' duration, the incubation period, as elicited from the patient, varied from two weeks to one month In the disease experimentally induced in a human volunteer by the transplantation of tissue from a streptomycia resistant case of granuloma, we found the incubation period to be 17 days Early or inal lesions Some writers, including the senior author (R VR) at one time believed that there was a primary lesion in donovanosis comparable with the primary lesion of syphilis or lymphogranuloma venereum Careful observation and study of a large number of patients with early lessons has shown, however, that the early initial lesion does not differ qualitatively from the typical granuloma Before describing the clinical features of the disease it may be worth while to emphasize two points (1) The initial and primary site of the disease is genital in the majority of cases The occurrence of the disease in other parts of the body such as the inguinal, peri anal, and oral regions, is secondary to the genital infection in a very large proportion of cases In the past, undue stress has been laid on the inguinal location of the disease Even in patients presenting them selves with inguinal granuloma with no active lesion of the genitalia, there is a history of a genital lesion or depigmented scar of past ulcer in the genitala in about 75% of cases (2) The disease has a predilection for moist stratified surface epithelium of the cutaneous, mucocutaneous, and mucous surfaces of the genital, inguinal, anal, and oral regions of the body 24 - ·CLINICAL FEATURES 2_ The earliest lesion may be a button like papule, a subcutaneous nodule, or an ulcer The papule, a quarter of an inch to half an inch 1a size, is firm. raised above the surface, flat topped, and covered by skin or mucous mem brane in a few days the overlyrag epithelium exconates and an ulcer is formed The papule may represent the initial lesion as well as a means of propagation in long standing cases (see fig 10 aod 11) The subcutaneous podule or swelling seems to be much less commoa and is frequently mistaken for a bubo when it occurs in the inguinal region The nodule, at first firm and of varying size, slowly softens and becomes an abscess which may burst of its own accord or, more often, is opened by the surgeon A typical granulomatous ulcer is formed in exther case Green blatt and co workers have termed it "pseudo bubo in contra-distinction to the real bubo or lymphadents (see fig 12) la spite of the fairly large aumber of patients with donovanosis who have been examined and treated at the venereal-diseases chnic in Madras during the past two decades, we have only infrequently encountered this early type of subcutaneous unruptured granuloma (see fig 13) The ulcer is the commonest early fesion of the disease it varies 19 size, Is soft, velvety, apd bright piok in colour, with a wavy or serpiginous outline, it is comparatively painless and is covered with a film of sero sanguineous exudate or a thin transluceat parchment hike crust (see fig 14) In the male, the prepuce, frenum and glans penis are the usual sites In the female, the labsa minora moas veneris, and fourchet are the common sites (see fig 15, 16, and 17) From the initial lesion the disease spreads slowly along the vanous moist folds of the genitalia, taking months to savolve a fair sized area The disease spreads in various ways (1) by direct continuity of Lissue along the corium of the skro (2) by auto inoculation of adjacent or opposing surfaces (contact infection), (3) by mediate transmussion through infected clothes or finger nails Greenblatt and co-workers clasm that the disease may spread through the lymphatics, and etplain the occurrence of pseudo-bubo in the groin by postulaung the spread of infection from a genital lesion via the lym phatics to the regional lymph node and from there to the subcutaneous fissue and corum of the overlying skin It is difficult to conceive of such a lymphatic spread of infection without chapical and pathological involvement of the lymph nodes and the intervening tissues The finding of endothelial byperplasia and focal collection of mononuclear cells, without the presence of Dodovan organism in the regional lymph nodes, appears to be a non specific seaction to the secondary bacterial contamination of the lesions The absence of sqvolvement of the lymph nodes, cvca za extensive Jong standing cases or dodovanosis, is one of the diagnostic hall marks of the disease Our histopathological studies of lymph nodes, botb la genital ·26 DONOVANOSIS and inguinal granuloma, and in oral lesions, have revealed no histological change in the nodes which might suggest infection by Donovan organisms The presence of palpable or enlarged lymph nodes in association with genital granuloma may be due to one of four coexisting causes (a) superadded secondary infection with non specific organisms, (b) lymphogranuloma of the lymph nodes, (c) early latent syphilis, (d) malignant metastasis Table II gives the various sites of infection in 858 patients who attended the venereal diseases clinic at Madras over a ten year period TABLE 11 TOPOGRAPHICAL DISTRIBUTION OF DONOVANOSIS IN 838 PERSONS S te of nfect on Number of ma e cases Number of fema e cases Total number of cases 312 160 472 4 4 2 2 127 22 149 14 10 24 10 68 78 30 9 39 38 1 39 External gentas only External and Internal gen tal a Inte nal gen tal a onty Gen to nou na! Gen to nou no anal Gen to per neo anal Gen to o al Ingu nal only Ingu no ana) Ingu no o al Ingu no cru al Peri anal and anal only Ana) oral Gen tal-oral cery cal Oral only Buttock 3 1 4 4 4 1 1 29 34 2 2 3 3 2 2 1 1 Total 575 283 858 An analysis of the table reveals (1) The overwhelming predominance of genital lesions and secondary spread to neighbouring areas (90% (2) The greater tendency of the genital lesion in the male to extend upwards and outwards towards the inguinal regions (see fig 18), as con ·CLINICAL FEATURES 27 trasted with the frequency of genital lesions in the female tending to spread downwards and backwards towards the perineum and peri-anal regions (see fig 19) (3) Donovadosis confined to the peri anal and anal regions shows a marked preponderance in the male, for the obvious reason that the practice of pederasty is almost invariably confined to males (4) Extragenital lesions are almost exclusively confined to the oral lesions in our series and are invariably secondary to long-standing genital granuloma Only two patients with primary oral granuloma were encountered in the study An extension of the disease to the skin of the cervical region from lesions in the mouth was observed in a dozen cases (see fig 20 and 21) (5) The occurrence of the disease in the deeper parts of the vagina and cervix was observed in 18 cases, either in association with vulval lesions, or as primary solitary lesions It is our impression that primary dodovanosis in the inguinal region, as well as extension of the infection to the neighbouring areas, was observed in 5% of the patients The evolution of the disease, as has already been stated, is very slow In the male, from the initial lesion on the prepuce or glans pedis the infection may extend to the stem of the penis, encircle the root, involve the peno scrotal junction, and spread upwards and outwards along the inguinal regions or downwards and laterally along the cruro-scrotal folds or round the root of the scrotum In the female, the ulcer starting in the labia minora may spread laterally to the labrum majus, and upwards to involve the crura of the clitoris and the mons veneris, or downwards to the fourchet, perineum, and peri anal region In long standing cases the disease may extend inwards to the vaginal introitus, the vagina, and the cervix The disease has not been known to affect the rectum or the urethra, although some writers have loosely described the extension of the disease to these parts It is true that the stratified epithelium of the urethral orfice and the anus are frequently infected by an extension of the disease from the glans penis of the male and the vestabule of the female in the former, and from the peri anal region of both sexes in the latter However, the columnar epithelium lining the urethra and the rectum seems to be resistant to invasion by the organisms of donovanosis The extension of the disease to the uterus, tubes, and ovaries is exceedingly rare, although Pund & Gotcher 6 reported a case in 1938 Extragenital lesions Next to the involvement of the genitalia and their environs, the oropharyngeal cavity is most frequently the site of the disease Extragenital granuloma has been reported by a number of workers, but it would seem

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·CLINICAL FEATURES 31 and 29) Its cause is mechanical, being pressure of scar tissue on the lymphatics, and it is not dependent on the duration or chronicity of the disease Particularly in women, early localized lesions of a few months' duration tend to cause elephantiasis of the vulva and clitoris Stenosis of the urethral, vaginal, and anal orfices may result from the sclerotic type of donovanosis, and cause difficulty in mictuntion, defaeca tion, and partuntion In the process of healing of extensive vulva lesions, the lips may become adherent along the entire extent, causing occlusion of the vaginal introitus and resulting in a sort of pathological infibulation (see fig 30) Various deformities follow long standing ulceration in the various regions Adhesions of the penis to the scrotum, incarceration of the organ into the skin of the scrotum, partial or total amputation of the penis (see fg 31) lateral and backward deformity of the phallus, are the chief, obvious sequelae of venereal granuloma in the male In the female the normal anatomical architecture of the external genitalia may be destroyed by ulceration and scar tissue In oral donovanosis, adhesions of the lip and cheek to the gums cause microstomia and difficulty in opening the mouth Difficulty in swallowing and regurgitation of food through the nose, occur, seriously inconveniencing the patient A depigmented scar 13 left when the ulcer heals The scar may be soft and supple or hard and unyielding in the course of time the white scar gradually becomes pigmented 10 patches Epidermoid carcinoma may occur as a complication of, or a sequel to, long standing donovanosis, but the complication seems very infrequent as only o 25% in 2,000 cases were discovered with cancer ·30 DONOVANOSIS reveals an abundance of bacterial flora, the fusospinillary group of organisms being the most numerous, but Donovan organisms disappear from the surface exudate The inflammation rapidly spreads both superficially and deeply, destroying the tissues in its wake In the female, the vulva, perineum, and peri anal region may be completely destroyed, and the recto-vaginal septum represented by a gaping cloacal pus filled cavity In the male, necrosis of the genitalia, particularly of the penis, may occur and partial or complete amputation of the organ is a not uncommon result of virulent fusospıcıllosis The patient with a severe infection has fever, displays toxic symptoms, and suffers from an acute secondary anaemia The condition occasionally proves fatal (see fig 27) Course and Termination The disease is chronic and its course is slow in our study its duration, from the time when the patient presented himself for treatment, varied from a fortnight to 35 years, the most usual period being about two and a half years The tendency to recurrence of ulceration in apparently healed cases is great The general health remains unaffected for a long time Some patients complain of pain over the ulceration, others, especially women, suffer from intolerable itching of the genitalia lo many patients, the disease is so advanced that sexual function is difficult or impossible Others with earlier lesions are able to lead a normal sex life for some time Infected women may become pregnant and give birth to healthy children who do not suffer from the disease, but very often the pregnancy ends in miscarriage or abortion The discase may cause mechanical difficulty in micturition, defaecation, sexual intercourse, and parturition, and in extensive disease of the genito-inguino-anal regions in walking as well The plight of patients with advanced granuloma is very distressing the disease in its late stages is as incurable as advanced cancer or leprosy They seek relief at differeat hospitals, are deserted by their partners and relatives, become derelicts of society, and often commit suicide in despair Patients rarely die of the disease itself Progressive secondary anaemia, a fulminating septic infection, tuberculosis of the lungs and sntestines, and, in a few cases, the development of epidermoid carcinoma, may be the Cerrutaal causes of death Eight fatalities occurred among the patients JD the series under review, in five of whom tuberculosis of the lungs was the cause of death Two died suddenly after an injection of an antimonial compound The eighth patient died of a fulminating fusospirillary infection Complications and Sequelae Pseudo-elephantiasis of the genitalia Occurs in 15% 20% of patients with donovanosis, and is more common in women than in men (see fig 28 ·CLINICAL FEATURES 31 and 29) Its cause is mechanical, being pressure of scar tissue on the Iymphatics, and it is not dependent on the duration or chronicity of the disease Particularly in women, early localized lesions of a few months' duration tend to cause elephantiasis of the vulva and clitons Stenosis of the urethral, vaginal, and anal orifices may result from the sclerotic type of donovanosis, and cause difficulty in micturition, defaecation, and parturition In the process of healing of extensive vulva lesions, the lips may become adherent along the entire extent, causing occlusion of the vagnal introitus and resulting in a sort of patbological infibulation (see fig 30) Various deformities follow long standing ulceration in the various regions Adhesions of the penis to the scrotum, incarceration of the organ into the skin of the scrotum, partial or total amputation of the penis (see fig 31), lateral and backward deformity of the phallus, are the chief, obvious sequelae of venereal granuloma in the male In the female the normal anatomical architecture of the external genitalia may be destroyed by ulceration and scar tissue In oral donovanosis, adhesions of the lip and cheek to the guns cause sucrostomia and difficulty is opening the mouth Difficulty in swallowing, and regurgitation of food through the nose, occur, seriously inconveniencing the patient A depigraented scar is left when the ulcer heals The scar may be soft and supple or hard and unyielding in the course of time the white scar gradually becomes pigmented in patches Epidermoid carcinoma may occur as a complication of, or a sequel to, long standing donovanosis, but the complication seems very infrequent as only 0 25% in 2,000 cases were discovered with cancer ·CHAPTER 6 DIAGNOSIS Methods It should be constantly borne in mind by the medical practitioner in the tropics that mere dependance upon clinical methods of diagnosis of anogenital lesions is frequently unreliable and may trip even the trained, seasoned specialist into a wrong diagnosis It is not uncommon to find the association of two or more disease entities in the same individual, with a consequent change in the clinical picture Our studies show that donovanosis is associated with chancroids, syphilis, or lymphogranuloma venereum either alone or in combination, in about 10% 20% of the cases On rare occasions, penile cancer and donovanosis, and cutaneous amoebiasis and donovanosis, are encountered in the same patient Accurate diagnosis of ano genital lesion requires the performance of a battery of laboratory tests It has been our routine practice to subject every ulcerating ano genital Jesion to the following tests (a) expressed serum for darkfield examination of Treponema pallidum, (6) smear stained with Gram stain for the streptobacillus of Ducrey, (c) tissue smear stained with Leishman stain for D granulomatis Clinically, the occurrence of an indolent soft granulomatous ulcer with a homogeneous velvety bright pink base and a wavy edge, in the genital, inguinal, or peri anal regions, with a history of antecedent sexual exposure, should be looked upon with suspicion as a probable case of donovanosis The suspicion is strengthened if the vicer shows no tendency to heal, and is not associated with enlargement of the regional lymph nodes Tissue smear The diagnosis should be based on the finding of D granulomatis in tissue smears taken from the lesion The morphological and tinctorial characteristics of the organism are so typical that it is easily demonstrable 10 tissue smears in the large majonty of cases, provided the technique described elsewhere (see pages 16 17) is carefully followed in the necrotic grossly infected lesion D granulomatis is not easily revealed In such cases a preliminary injection of 600 000 units of penıcıllın will rapidly clear the -32 – ·DIAGNOSIS 33 les on of the contaminants, and Donovan organisms can be successfully demogstrated 10 tissue smears In the long standing, partially healed, cicatricial type of lesion, it may be necessary to perform a biopsy and obtain smears from the cut surface of the specimen for finding the organisms The diagnosis of an early lesion of donovanosis, of one or two weeks' duration is often missed by the general practitioner and even by trained specialists in venereal diseases clinics The reasons for this state of affairs are many There may be a certain lack of awareness of the disease on the part of the physician when it occurs as a small ulcer in the external genitalia, a physician encountering a genital lesion often thinks in terms of syphilis and chancroids and tries the bit or miss therapy of sulfonamides followed by penicillin The still persisting name of "granuloma inguinale" for the diseasc has empbasized the inguinal regions as the primary anatomical sites and is responsible for the low threshold of suspicion among clinicians when a genital sore 13 encountered Hence, no attempt is made to examine tissue smcars for Donovan organisms, which in very carly lesions are scarce, atypical, and extracellular Prolonged diligent search, with repeat smears if necessary, must be carried out before the organism can be identified Bropsy Histological examination of biopsy obtained from the lesion is recommuended by the workers of the University of Georgia School of Medicine as an additional and more reliable method in the diagnosis of donovanosis It has been our experience, as it is of other workers, that the organisms are not easily identified in sections prepared with haematoxyun and cosia Pund & Greenblatt" recordmended the use of Delafield's haematoxylın and cosin or Dieterle's silver impregnation method for a satisfactory and unfailing recognition of the intracellular inclusions la the routine day to day work of a busy venereal-diseases clinic, the cxamination of a properly obtained tissue smear stained with Leishman stain 15 simple, rapid, and reliable in the diagnosis of a suspect lesion, and any physician with a microscope and a bottle of Leishman stain will be able to perform the test. We do not recommend as a routine procedure on which to base the diagnosis of donovanosis the time-consuming histological examination of sections obtained from the lesion The section method us, however, indicated in two cases (1) wben repeated examination of tissue Imears in a clinically suspect lesion is negative to D granulomatis, and/or (2) ahes there is a strong suspicion of malignancy in the clinical appearance of the lesion Immunological Tests Complement fireson tert Anderson and Areason, Goodpasture & Devonbreun," followed by Dunham & Raket ud Dularey, Gro & Packer.se bave successfully ·34 DONOVANOSIS established a specific immunological relationship of D granulomatis to donovanosis by demonstrating that the sera of patients with donovanosis contain complement fixing antibodies against D granulomatis The com plement fixation test is claimed as an additional tool in the diagnosis of the disease Skin test Kornblth, using an antigen prepared from the superficial tissue of a lesion of donovanosis, tested proved cases the disease with a series of controls and reported positive intracutaneous reaction in all but two of the cases of donovanosis Anderson and her associates, with the antigen prepared from the embryonic yolk culture, reported positive reactions in all the cases tested Likewise, Chen et al, 10 and Packer & Dulaney 6 have reported similar results A critical study of the several publications on the value of immunological tests (both serological and cutaneous) reveals the following facts (1) Both the complement fixation and skin tests have satisfactorily established the immunological relationship of D granulomans to dono vano$1$ (2) The tests seem to be much more subject to limitations of sensitivity and specificity than similar tests for syphilis and lymphogranuloma vene reum (3) The demonstration of D granulomatis in tissue smears from active lesions has the highest and most reliable, direct, and specific diagnostic value Hence, the employment of the immunological tests in laboratory proved cases of donovanosis seems superfluous, and wasteful of time and labour (4) The value of the immunological tests has not been proved in the asymptomatic sexual partners of patients with overt disease and positive tissue smear Hence it is very doubtful whether the tests will help to un ravel some of the unsolved problems in the epidemiology of donovanosis (5) The existence of latent asymptomatic syphilis and lymphogranuloma venereum has been established by both serological tests and epidemiolo gical investigation, whereas donovanosis, as far as present knowledge goes, does not exist in a latent form, and a positive complement fixation test has never been observed in sexual contacts showing no clinical evidence of the disease ( A negative complement fixation or skin test may help to rule out donovanosis in patients suffering from chronic ano genital ulceration who are repeatedly negative to D granulomatis (7) The immunological tests will be useful in studying the antigenic behaviour of different strains of the Donovan organisms, and the similarity of antigenic pattern between D granulomatis and other allied organisms ·DLAGOSES 35 (8) It would seem that the sensitivity of the complement fixation test in carly lesions of donovanosis is inadequate for diagnostic purposes The skin test lacks the clear-cut pattern observed with a similar test in lymphogranuloma venereum, and gives false positive reactions in many chronic infections other than donovadosis (9) Information is lacking as to whether a change in the titre of the complement fixation test after treatment with streptomycin or antimony occurs 10 the sera of patients with donovanosis Differential Diagnosis Syphilus Primary syphils The primary sore is easily distinguished by its indura tion, absence of bleeding. built up base, shelving edge with a red areola, the associated indiarubbery painless enlargement of the regional lymph glands, and the presence of T pallıda in the serum expressed from the lesion Secondary syphilis The hypertrophic moist button like papules occurring in the genitalia may have a superficial resemblance to the buttonlike papule or nodule of early donovanosis The moist papule of syphilts, however, has a greyish white colour and even when it is eroded it lacks the bright pink casily bleeding characteristic of donovanosis The history of a primary sore, the occurrence of the secondary lesions in other parts of the body, and the finding of T pallıda to the scrapings from the moist lesions help in the diagnosis Tertiary syphilis A gummatous ulcer has a punched-out appearance, with clean-cut vertical edges and a slough-covered base Nodulocutaneous ulcerating syphilides have the same appearance, with a tendency to central healing and peripheral spread in an arciform, gyrate, or serpiginous fashion Other evidences of syphilis will be found A positive scrological reaction, and response of syphilitic lesions to antisyphilitic drugs, are other points in the differenual diagnosis Chancroid or soft sore A short incubation period of two or three days, the acuteness of the lesion, its multiplicity, the painful angry looking pus-covered ulcer with irregular "mouse-eaten" undermined edge, the acute painful lymphadentis with a tendency to suppuration, a positive Ito-Recostierna test, and the presence of Ducrey's streptobacilla in deep scrapings from the lesions, help to distinguish chancroid from donovaRosis Lymphogranuloma senereum Although this disease is quite distinct from donovanosis, the two condi tions are so frequently confused that it is proposed to frst the points of distinction in a tabular form ·36 DONOVANOSIS Donovanosis (granuloma venereum) (1) The disease has a predilection for most stratified epithelium of the genital and oral regions of the body (2) It is generally accepted that Donovan organisms are the causal agents of the disease, they are easily demonstrated in the exudate or scrapings from the ulcer (3) There is no primary lesion distinct from the typical granulomatous ulcer (4) Constitutional manifestations are absent neither preceding nor accompanyog the disease (5) The typical lesion is an indolent granulomatous ulcer, very slowly spreading and involving the skin of the gerutal, inguinal and anal regions Lymphogranuloma venereum The disease affects primarily the lyn phatic tissue of the inguinal genital, and rectal regions of the body Caused by a filterable virus, bacteria logical demonstration of the organisms is difficult but can be achieved by animal transmission The primary inoculatory sore is usually a small superficial evanescent herpetiform lesion—it precedes the other manifesta tions Constitutional symptoms such as fever, malarse, or arthralgia invariably proc or accompany the onset of the local man festation of the discase The manifestations vary in the setes, inguinal adenitis with tendency to suppuration and formation of multiple fistulae in the male, hyperplastic and uloer ative changes of the genito-ano-rectal regions in the female Pseudo elephantiasis of the genitalia, particularly in the female is more frequent and is caused by a virus lymphangitus and lymphostasis The ulceration of the geri talia is secondary to the elephantiases The ulceration is superficial with irregular serrated edge and a yellowish anaemiclooking base devoid of the raised pink granulations seen in donovanoses Inflammatory structure of the rectum with polyposis and ulceration of the mucous membrane is common and typical of lymphogranuloma vedereum. Donovan organisms are absent in ulcer. ation due to lymphogranuloma. Freis atradermal lest 28 posure The disease is widely prevalent all over the world All races are susceptible (6) Pseudo-elephantasis of the genitalia occurs secondary to the ulceration, the ulcer is granulomatous pink, and velvety (7) Inflammatory structure of the rectum is unknown in donovanosis The ulcera tion stops short of the anus and anal stricture is common. (8) Donovan organisms can be demont strated from the ulcers of donovanosis (9) Freis madradermal test is negative (10) The disease is sparsely distributed, even in endemic areas There is a marked individual susceptibility (11) No changes in blood chemistry. hypoproteinac ua in chronic donovanosis 101 some cases (12) Serum fixes complement in the presence of antigen prepared from prenulomatis Hyperproteinaemia with reversal of albu min globulia ratio is a characteristic feature of the disease. Serum fixes complement in the presence of antigen prepared from cultured virus of the disease.

·DIAGNOSIS 37 Epithelioma When studying the literature, fargely American, on the relationship of donovanosis to epithelioma, the authors have noted the frequency with which the former 15 mistaken for the latter and, less frequently, the latter for the former Beerman & Sonck, in a paper read before the Tenth International Congress of Dermatology, London, 21 26 July 1952, on the epithelial changes in granuloma inguinale, have posed three questions on the subject and have tried to answer them by both a review of the existing literature and the histological examination of a series of cases of granuloma with a case report (1) Does granuloma simulate cancer ? (2) Does cancer develop as a complication on a pre-existing granuloma ? (3) Do cancer and granuloma occur independently in the same patient at the same Our own views on this aspect of the disease have been stated elsewhere 6 but we feel it desirable to outline them once more in this paper "A study of the literature and our experience suggest that the resemblance between the two lesions may be close both on clinical and histological grounds. Granuloma venereum has been mistaken for cancer more frequently than cancer for granuloma venereum The threshold of suspicion for granuloma venereum on the part of the average surgeon and gynaecologist is rather low even in eademuc areas and it is not uncommon for mutilating operations (to be) performed on patients the mistaken diagnosis of the lesion for cancer Kern 31") report of three cases where squamous-cell carcinoma simulated granuloma vepereum even in the presence of Donovan organisms in two of the cases is an example of the reverse rustake in diagnosis The cladical appearance of a chronic long standing granuloma venereum may closely mimic that of an epidermoid carcinoma in the exuberant fleshy growth or in an ulcer with nodular base and everted edge * In common with other chronic granulomas of the integumentary system such as syphilis tuberculosis, yaws roycotic infection eta, a pseudoepitheliomatous hyper plasia of the marginal epithelium is a characteristic histological feature of grapuloma Yenereur Fig (32 and 33) arc photo-micrographs of various grades of pseudo- ? L cells with or without the Donovan organisms The predominance of polymorpho nuclear leukocytes in the superficial part of the ulceration along with the invasion of the prickle cell layer by the same leukocytes is another feature of granuloma veoertum which is not usually the case in squamous-cell epithelioma "In some cases of granuloma vencreum of long standing, there may be an extreme hyperplasus and proliferation of the epidermis in an irregular manner with Darrow strands ·38 DONOVANOSIS of prickle cells reachucg deep into the cutis, with even pearl formation, bustologically resembling Grade I squamous-cell epithelioma and the final diagnosis depends on the clinical outcome to antibiotic therapy. With a multiplicity of effective therapeutic agents, such as streptomycin, aurcomycin, etc, failure to achieve cure must cast serious doubt on the validity of diagnosis of granuloma venereum "On the second and third questions whether epidermoid carcinoma occurs as a complication of or sequel to granuloma vedereum and whether the two conditions may occur independently in the same patient, opinions are not unanimous "The incidence of epithelioma arising from other conditions which include syphilitic, tuberculous and varicose ulcers, ano-rectal lymphogranuloma, scar of burns and certain precancerous dermatoses, varies from a fraction of 1% to a maximum of 6% according to Orsmby & Montgomery [68] It is likewise conceivable that carcinoma may supervene on a lesion of long standing granuloma venereum for the same reason that at occurs in other chronic cutaneous granulomatous conditions It is also pertinent to point out that both granuloma venereum and epithelioma of the external genitalia, particularly L. wth in 13 about 88% among Negroes and 12% among the poor Whites of America (USA) endemic reservoir for granuloma venereum "The study of the titles of the case reports that have appeared in the American Literature, such as "Granuloma inguinale sunulating carcinoma", "Granuloma inguinale ? carcinoma".["“Granuloma inguinale chaically diagnosed as carcinoma".["] * Carcinoma simulating granuloma inguinale", (") reveals the difficulty, doubt and the mistakes that have occurred in the differential diagnosis of the two conditions Chen, - loma neram renarted (that) en the rigid criteria of correct diagnosis of an earlier granuloma, a response tu ueau icon and subsequent development of cancer venfied clinically and histologically We consider that a true epitheliomatous change may occur as a late complication of or sequel to long-standing granuloma venereum, but this seems an infrequent current "The association of cancer and granuloma vedereum occurring in the same patient has been recognized by us as affecting the penis in the male and cery in the female The occurrence in our opinion seems to be merely sequential without any implication of causality In some of the reported cases and also in two patients in our study ... it would seem that cancer was the earlier lesioa chronologically and that granuloma oms ·Filariasis DLAGNOSIS Elephantiasis of the genitalia is a common sequel of flanasis in the tropics, and the pseudo-elephantiasis occuring in donovanosis may be mistaken for the former la filariasis there 18 BO ulceration, the history of frequent attacks of fever and swelling and the preseace of microfilaria in the blood belp in the diagnosis 39 Tuberculous ulceration This is rare in the genito inguinal region and has no resemblance to donovanosis Biopsy shows cascation grant cells, and tubercfc bacıl Cutaneous amoebiasis (aro-genital) In tropical practice amoebic ulceration of the ano genital region is not uncommon, it bears a superficial resemblance to donovanosis and may be a superimposed infection on a pre-existing lesion of this disease Examidation of the unstained exudate from the lesion will reveal active vegetative forms of Endamoeba histolynca ·CHAPTER 7 TREATMENT Antimony Compounds The antimonial compounds such as tartar emetic, urea subamine (sodium amino phenyl stıbinate), Fuadın (sodium antimony III biscatechol 2,4 disulfonate), Anthiomaline (Lithium antimony thiomalate), Duramın, and Fantorin, have been used with varying degrees of success in the treatment of donovadosis during a period of nearly 35 years from 1913 to 1947 The success of treatment with antimonial compounds is in inverse propor tion to the duration and extent of the disease, the tendency to recurrences after treatment and apparent healing is a marked feature of the disease Such recurrent lesions develop an insusceptibility to further antimonial therapy-antimony fastness Toxic intolerance to repeated therapy with antimony is another serious drawback, and a few sudden deaths have occurred during treatment with the drug Further, it is our impression that antimony is an activator of latent tuberculous infection, the patients in our series who died ultimately of galloping tuberculosis had received interrupted therapy with antimony over a period of years Antibiotics In the pre antibiotic era, the sulfonamides were tried without success The initial hope that penicillin, the first of the antibiotics, might prove effective in donovanosis was not fulfilled, although it has a place in clearing up the secondary contamipants in lesions of the disease it was only logical that the other antibiotics, as they were discovered and became available for therapeutic evaluation, should be tried Barton and his associates in the USA were the first to report, in 1947, on the therapeutic effects of streptomycin on donovanosis Since tben a number of additional reports have appeared in American medical literature 91 42 43 76 Greenblatt and co workers *1 have made a detailed study on the largest group of cases (142 patients) treated so that country and, as a result of their experience of treatment with varying schedules, have recommended 4 g of streptomycin dally in divided doses at fourhour intervals for a period of five days An example of response of extra- - 40 - ·TREATMENT genital granuloma inguinale to antibiotic therapy is illustrated in fig 34 About 10% of the patients relapsed and all but four of these responded to a second course of therapy We shouid like to record our experience with streptomycin in the largest number of cases of donovaposis ever treated a one clinic during a period of three years * ** 227 patients--146 males and 81 fernales -- were treated with strepto mycin from August 1948 to September 1951 All the patients were hospi talized and the diagaosis was estabushed by the demonstrauon of typical intracellular Donovan bodies in tissue smears obtained from the lesions Both streptomycin and dihydrostreptomycia were used in the treatment according to the availabıuty of the drug and no appreciable difference between them was discovered, in either therapeutic effect or toxicity The total dosage of the drug employed vaned from 5 g to 70 g, but the largest bumber of patients received 20 & The indindual dose varied from 18 10 2 8 per day, and the duration of treatment extended from 5 to 20 days Best therapeutic results were obtained with 10-20 g of streptomycia admi nistered over a minimum period of 10 days The immediate results were excellent (see fig 35) All but four cases had bealed satisfactonly at the time of discharge from the hospital Three of the four refractory cases were treated with either aurcomycia or chloramphenicol The fourth streptomycin resistant palient suffered from a concomitant tuberculous infection of the lungs and ultimately died of it in spite of the administra txoa of 70 g of streptomycia Nectopsy revealed an advanced disease of the lungs with teemog tubercle bacilli in the tissues This is an example of streptomycin resistance of two chronic ofections in the same patient Totic reaction 208 of the 227 patients in our series did not calubit any toxic reaction to the drug Among the remaining 19, vestibular dysfunctioa occurred In 4, urticaria in 4, beadache in 3. fever sa 3, conjunctival haemorrhage ID 2, dysphagia in 1, diarrhoea in 1, and pain ia the abdomen in 1 The reactions were all temporary and did not necessitate discontinuance of treatment. The Donovan organism, the causative agent or donovanosis, 13 a fastidious tissue-parasite revealog marked pleomorphism This being the case, the organism may be expected to develop an ocreasing resistance 10 streptomycia on the analogous experience with antimony in the treat ment of the disease In vitro experiments seem to indicate that micto organisms in general develop resistance to streptomycia much more castly and quickly than to other anubiotics The chemoresistance of Dodovan organisms to streptomycin was Successfully transferred to a human volunteer by Dienst and workers 19 of the Georgia School of Medicine, by the transplantation of Donovan body nich granulation tissue from a donos with resistant disease, the ·CHAPTER 7 TREATMENT Antimony Compounds The antimonial compounds such as tartar emetic, urea-stibamine (sodium amino phenyl strbinate), Fuadın (sodium antimony III catechol- 2,4 disulfonate), Anthiomaline (lithium antimony thiomalate), Duramın, and Fantorin, have been used with varying degrees of success in the treatment of donovanosis during a period of nearly 35 years from 1913 to 1947 The success of treatment with antimonial compounds is in inverse proportion to the duration and extent of the disease, the tendency to recurrences after treatment and apparent healing is a marked feature of the disease Such recurrent lesions develop an insusceptibility to further antimonial therapy-antimony fastness Toxic intolerance to repeated therapy with antimony is another serious drawback, and a few sudden deaths have occurred during treatment with the drug Further, it is our impression that antimony is an activator of latent tuberculous infection, the patients in our series who died ultimately of galloping tuberculosis had received interrupted therapy with antimony over a period of years Antibiotics In the pre-antibiotic era, the sulfonamides were tried without success The initial hope that penicillin, the first of the antibiotics, might prove effective in donovanosis was not fulfilled, although it has a place in clearing up the secondary contaminants in lesions of the disease it was only logical that the other antibiotics, as they were discovered and became available for therapeutic evaluation, should be tried Barton and his associates in the USA were the first to report, in 1947, on the therapeutic effects of streptomycin on donovanosis then a number of additional reports have appeared in American medical literature 41 42 43 76 Greenblatt and co-workers s1 have made a detailed study on the largest group of cases (142 patients) treated in that country and, as a result of their experience of treatment with varying schedules, have recommended 4 8 of streptomycin daily in divided doses at four hour intervals for a period of five days An example of response of extra- Since -40 ·TREATMENT 41 genital granuloma inguinale to antibiotic therapy is illustrated in fig 34 About 10% of the patients relapsed and all but four of these responded to a second course of therapy We should like to record our experience with streptomycin in the largest number of cases of donovanosis ever treated in one clinic during a period of three years 68 69 227 patients-146 males and 81 females-were treated with streptomycin from August 1948 to September 1951 All the patients were hospi talized and the diagnosis was established by the demonstration of typical intracellular Donovan bodies in tissue smears obtained from the lesions Both streptomycin and dihydrostreptomycin were used in the treatment, according to the availability of the drug, and no appreciable difference between them was discovered, in either therapeutic effect or toricity The total dosage of the drug employed varied from 5 g to 70 g, but the largest number of patients received 20 g The individual dose varied from 18 to 2 $ per day, and the duration of treatment extended from 5 to 20 days Best therapeutic results were obtained with 10 20 g of streptomycin admi nistered over a minimum period of 10 days The immediate results were excellent (see fig 35) All but four cases bad healed satisfactorily at the time of discharge from the hospital Three of the four refractory cases were treated with either aureomycin or chloramphenicol The fourth streptomycia resistant patient suffered from a concomitant tuberculous infection of the lungs and ultimately died of it in spite of the administra tion of 70 g of streptomycin Necropsy revealed an advanced disease of the lungs with teeming tubercle bacılls in the tissues This is an example of streptomycin resistance of two chronic infections in the same patient Toxic reaction 207 of the 227 patients in our series did not exhibit any toxic reaction to the drug Among the remaining 19, vestibular dysfunction occurred 104, urticaria in 4, headache in 3, fever in 3, conjunctival haemorrhage 2a 2, dysphagia in 1, diarrhoea un 1, and pain in the abdomen in 1 The reactions were all temporary and did not necessitate discontinuance of treatment The Donovan organism, the causative agent of donovanosis, is a fastidious tissue-parasite revealing marked pleomorphism This being the case, the organism may be expected to develop an increasing resistance to streptomycin on the analogous experience with antimony in the treatment of the disease in vitro experiments seem to indicate that microorganistus in several develop itsistance 10 streptomycin moth mort easily and quickly than to other antibiotics The chemoresistance of Donovan organisms to streptomycin was successfully tracsferred to a human volunteer by Dienst and workers" of the Georgia School of Medicine, by the transplantation of Donovan body rich granulation tissue from a donor with resistant disease, the ·42 DONOVANOSIS volunteer, after developing the disease, exhibited a similar resistance to streptomycin This observation was confirmed by us 67 by carrying out a similar experiment on a volunteer at the vencreal diseases clinic, Madras General Hospital (see fig 36) The latest additions to our therapeutic armament in the treatment of donovanosis are aureomycin, chloramphenicol, and oxytetracycline A number of favourable reports on the subject have been appearing in American medical Lterature £$ 30 35-38 10 a 72 73 82 Fig 37 and 38 illustrate the effect of chloramphenicol on a case of granuloma inguinale of the cervix On account of their high cost, a large-scale trial of the antibiotics was not practicable in our laboratory In a small series of 32 cases, 19 were treated with chloramphenicol and 13 with aureomycin 17 of the former and 9 of the latter series were cured Recently, 3 cases of strepto mycin resistant donovanosis were cured by oral administration of oxytetra cycline The initial farſures from one drug were cured by a change to one or other of the untried antibiotics The optimum total dosage is 20 g of the antibiotic administered orally at the rate of 500 mg every six hours Donovan organisms disappeared from the lesion in 3 15 days, and the time taken for the lesions to heal vaned from 14 to 40 days, depending upon the extent and duration of the disease No uptoward reactions are reported except pausea and vomit ing, occurring with orally administered aureomycin Parenteral adminis. tration of the antibiotics is very painful, has no advantage over the oral therapy, and is not recommended Resistance and recurrence A statistically insignuficant number of cases of donovanosis are chemoresistant to initial therapy, irrespective of the type of antibiotic used in other cases, the lesions heal satisfactorily during the period erva tion in the hospital, only to relapse and break down after a period ranging from a few months to two years Such recurreat lesions become resistant to the drug which resulted in the initial healing, however, the physician now has at his disposal a multiplicity of specific drugs with which treat ment resistance can be circumvented, by the combination of two or more drugs administered simultaneously or successively The well known tendency of the disease to relapse after ifitial healag should be kept in mind, and a long post treatment observation of about two years is essential to assess the permanence of the initial cure General Measures In the majonty of cases hospitalization is necessary to ensure satisfactory response to specific therapy The general health must be main- ·TREATMENT 43 turned and improved by nutritious food, vitamins, etc Concurrent venereal afections, either recept or latent, should receive attention Secondary sofecuon should be treated by penicillin, and surgical cleanliness should be maintained before specific treatment is started Minor surgical measures, such as crcision of elephaptoid masses and occlusive deforming scars, aod ska grafting, may be necessary in healed cases with deformity and distortion ·42 DONOVANOSIS volunteer, after developing the disease, exhibited a similar resistance to streptomycin This observation was confirmed by us 67 by carrying out a similar experiment on a volunteer at the venereal-diseases clinic, Madras General Hospital (see fig 36) The latest additions to our therapeutic armament in the treatment of donovanosis are aureomycin, chloramphenicol, and oxytetracycline A number of favourable reports on the subject have been appearing in American medical literature 29 80 85-29 40 41 72 73 82 Fig 37 and 38 illustrate the effect of chloramphenicol on a case of granuloma inguinale of the cervix On account of their high cost, a large scale trial of the antibiotics was not practicable in our laboratory In a small series of 32 cases, 19 were treated with chloramphenicol and 13 with aureomycin 17 of the former and 9 of the latter series were cured Recently, 3 cases of streptomycin resistant donovanosis were cured by oral administration of oxytetra cyclinc The artial failures from one drug were cured by a change to one or other of the untried antibiotics The optimum total dosage is 20 g of the antibiotic administered orally at the rate of 500 mg every six hours Donovan organisms disappeared from the lesion in 3 15 days, and the time taken for the lesions to beal varied from 14 to 40 days, depending upon the extent and duration of the disease No untoward reactions are reported except nausea and vomiting, occurring with orally administered aureomycin Parenteral administration of the antibiotics is very paipful, has no advantage over the oral therapy, and is not recommended Resistance and recurrence A statistically insignificant number of cases of donovanosis are chemoresistant to initial therapy, irrespective of the type of antibiotic used in other cases, the lesions heal satisfactorily during the period of observa tron in the hospital, only to relapse and break down after a period ranging from a few months to two years Such recurrent lesions become resistant to the drug which resulted in the initial healing, however, the physician now has at his disposal a multiplicity of specific drugs with which treatment resistance can be circumvented, by the combination of two or more drugs administered simultaneously or successively The well known tendency of the disease to relapse after initial healing should be kept in mind, and a long post treatment observation of about two years is essential to assess the permanence of the martial cure General Measures In the majonty of cases hospitalization is necessary to ensure satis factory response to specific therapy The general health must be main ·TREATMENT 43 tained and improved by nutritious food, vitamins, etc Concurrent venereal infections, either recent or latent, should receive attention Secondary infection should be treated by penicillin, and surgical cleanliness should be maintained before specific treatment is started Minor sargical measures, such as etcision of elephantoid masses and occlusive deforming scars, and skin grafting, may be necessary in healed cases with deformity and distortion ·UR 44 DONOVANOSIS CONCLUSION It is true that the hospital incidence of donovanosis is negligible in comparison with that of syphilis or gonorrhoea in southern India, and the disease is not a major public health problem It is, however, a signal example of the close interrelation between poverty and disease As Winslow Bl has so admirably put it, a man becomes sick because he is poor-he becomes poorer because he is sicker, and sicker because he is poorer This aphorism is particularly true in the case of patients suffering from donovanosis The disease 28 is a terrible affliction which slowly and inexorably ravages its victim Poorly understood, and poorly handled, it becomes so loathsome that the patient is shunned like a leper, there are sanatoria for the tuberculous, and leprosana for lepers, but the patient with donovanosis goes from hospital to hospital for admission Few general practitioners are interested in the disease Its victims, as has already been pointed out, come from the poverty stricken, under privileged sections of the population, with poor personal hygiene and debased sexual standards Thanks to the low infectivity of the organism, the disease is prevalent only in a small percentage In view of the limited nature of the incidence of donovanosis, it should be possible to control and eradicate the reservoirs of infection by an organized public health drive Early diagnosis and adequate therapy with the antibiotics are the answers to the problem of control REFERENCES 1 Anderson, K. 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Gaz 11 113 ·46 DONOVANOSIS 51 Mackay, CR & Bunch, W L (1952) Amer Syph 36, 511 52 Manson Bahr, P H (1950) Ed, Manson's tropical diseases, 13th ed, London, Toronto, Melbourne, Sydney, Wellington 33 Margolis, G (1945) Amer J Path 21, 543 54 Marmell, M (1948) Granuloma inguinale donovanosis (Thesis, Brooklyn College, New York) 55 Marmell, M & Santora, E (1950) Amer ) Syph 34, 83 56 Menon, T B (1933) Indian med Gaz 68, 15 $7 Nair, VG & Pandalai, N G (1934) Indian med Gaz 69, 361 58 U (1049) ก - DL adalah. 59 60 n S P. IX L 18 t 61 Packer, H Turner, H B & Dulaney, A D (1948) v Amer med Ass 136, 327 62 Pariser, H & Beerman H (1944) Amer med Sci 208, 547 63 Pund ER & Gotcher, V A (1938) Surgery, 3, 34 64 Pund, E R & Greenblatt, R B (1937) Arch Path Lab Med 23, 224 65 Pund, E R., Greenblatt, R B & Huie, G B (1938) Amer Syph 22, 495 66 Rajam, R > Jine- 67 Rajam, R 68 Rajam R 69 Rajam, R. 70 Rake, G (1943) Amer 1 Syph 32 150 71 Rhinepast, WJ & Bauer, J T (1947) Amer Roentgenol 57, 563 72 Robinson, R. C, V (1950) Amer J Syph 34, 273 73 Robinson, R CV, Elmendorf, D F, , & Zheutlin, H E C. (1949) Amer Syph 33, 389 74 Schildkraut, JM (1951) Arch Derm Syph (Chicago), 63, 399 75 Speiser, MD (1948) Amer J Obstet Gynec 56, 1181 76 Stewart, JJ & Laur, WE (1949) Amer 1 Syph 33, 65 77 Symmers, D & Frost, A D (1920) Amer med Ass 74, 1304 78 Thierfelder MU (1925) Arch Schiffs- u Tropenhyg 29, 690 79 Vogel W T de (1928) Bull Soc Path exor 21, 354 80 Walker, E L (1918) J med Res 37, 427 81 Winslow, CEA (1951) The cost of sickness and the price of health (wid Hith Org monogr Ser 7), Geneva 82 Wright, L. T, Sanders, M, Logan, MA, Pngot, A & HUI, L M (1948) Ann. NY Acad Sci 51, 318 ·ILLUSTRATIONS

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·FIG 1
DONOVAN DODIES
Magnification X 970
Aded al Celree of Georfu LS4
By Wy of b
RB Grebka
FIG 2
TECHNIQUE
FOR ORTAINING SMEARS FOR DONOVAN BODIES
As establ shed at the Med cal College of Georgia Auguole, Coorgia, USA
8 w wyn Greate Wada al College of Correia ise
19 -

·FIG 3
HYPERPLASIA OF MARGINAL EPITHELIUM WITH MASSIVE
CELLULAR REACTION IN CORIUM
Magnification > 320
FIG 4
ACANTHOSIS WITH IRREGULAR ELONGATION OF RETE PEGS
FORMING AN INTERLACING NETWORK ENCLOSING
ISLANDS OF CELLULAR EXUDATES
Magnification 120
- 50 -

·FIG 3
HISTOLOGICAL SECTION, SHOWING INTRADERMAL ABSCESSES
Magnification 160
FIG 8 GRANULATION TISSUE SHOWING PLASMA CELLS,
LYMPHOCYTES, AND SCATTERED LARGE MONONUCLEAR CELLS
Mononuclear cells containing Donovan organisms In cytoplasm indicated
by anons
Magnification 1440
- S1

·FIG. 7.
GRANULATION TISSUE WITH MARKED HYPERPLASIA
OF ENDOTHELIAL CELLS OF THE CAPILLARIES
Magnification X 320
FIG 8
EXTENSIVE FIBROUS TISSUE REACTION WITH COLLECTIONS
OF CELLS IN CREVICES OF INTERLACING STRANDS
OF FIBROUS TISSUE
Magnification X 320
- 52 -

·F1G 9
HISTOLOGICAL SECTION OF GRANULOMA INGUINALE
SHOWING PATHOGNOMONIC CELL STAINED
WITH DELA FIELD S HAEMATOXYLIN
• Indicated by arrow
Magnification 1440
By courry of Dr ER Pund and DR B Greenbior Med al College of Georgia LS4
FIG 10
EARLY GRANULOMA INGUINALE WITH DAUGHTER LESIONS
OFTEN MISTAKEN FOR CONDYLOMA LATA
De L Garabiare Art College of Grorth, ISI

·FIG 11
MULTIPLE UNBROKEN BUTTOR LIKE NODULES ON GLANS PENIS
AND NNER LINING OF RETRACTED PAPUCE
Positive for Donovan organisms , duration one month
FIG 12
GRANULOMA INGUINALE OF LARIA
Duration several months w th recently enlarging and fiuctuatsng senin teftinguinal
region (pseudo bubo) on aspiration Donovan organismi found to the exclusion
of other organiem
By coure of Dr RB Grecidia ? Nied cal College e Georgia USA

·PSEUDO BUBO IN GROIN
FIG 13
Aspi ated mate tal positiya to Donovan organlams

·FIG 14
EARLY GRANULOMATOUS ULCER ON LEFT SIDE OF PREPUCE
7-
Positive for Donovan organisms , duration 15 days
FIG 15
EARLY GRANULOMATOUS LESIONAT FRENULUM
- 56 -

·FIG 10
EXTENSIVE ULCERATION ON DORSAL ASPECT
OF PREPUCE AND GLANS PENIS
FG 17
ULCERATION OF LABIA MINORA FOURCHET AND CLITORIS
57

·FIG 18
EXTENSIVE GRANULOMA OF PREPUCE AND GLANS PENIS
EXTENDING UPWARDS TO BOTH GROINS
FIG 19 TENDENCY OF ULCERATION IN FEMALE TO SPREAD DOWNWARDS
AND BACKWARDS TOWARDS PERINEUM AND PERI ANAL REGIONS
- 58 -

·FIG 20
GRANULOMA OF INNER SIDE OF LIPS AND CHEEK
SECONDARY TO GENITAL DISEASE
59

·FIG 21 FLESHY TYPE OF GRANULOMA OF NECK SECONDARY TO GENITAL AND BUCCAL GRANULOMA

·FIG 72 HISTOLOGICAL SECTION OF LIVER BIOPSY SHOWING LIVER
PARENCHYMA CELLS CONTAINING DONOVAN ORGANISMS
IN VARYING NUMBERS DIETERLE STAIN
Magnification * 720
FIG HISTOLOGICAL SECTION OF LIVER BIOPSY SHOWING
CAPSULATED ORGANISMS IN THE LIVER PARENCHYMA CELLS
GIEMSA STAIN
Magnification *77
61

·FIG 24
HYPERTROPHIC TYPE OF GRANULOMA INVOLVING PREPUCE,
RIGHT GROIN, AND UPPER PART OF THIGH IN MALE
FIG 25 HYPERTROPHIC TYPE OF GRANULOMA INVOLVING MAJOR LABIA,
CLITORIS, PERINEUM, AND PERI-ANAL REGION IN FEMALE
- 62 -

·FIG 26 SCLEROTIC TYPE OF GRANULOMA IN MALE INVOLVING PENIS
PENILE SHAFT AND INNER ASPECT OF BOTH GROINS
FIG 17
DESTRUCTIVE NECROTIC TYPE OF GRANULOMA INVOLVING
EXTERNAL GENITALIA PERINEUM AND PERI ANAL REGION IN FEMALE

·FIG 28 PSEUDO ELEPHANTIASIS OF PENIS
SECONDARY TO HEALED DONOVANOSIS
- 64 -

·FIG 25 PSEUDO ELEPHANTIASIS OF EXTERNAL GENITALIA
IN FEMALE WITH LONG STANDING DONOVANOSIS
7
65

·FIG 30
ALMOST COMPLETE OBLITERATION OF PUDENDAL CLEFT
FIG 31 COMPLETE DESTRUCTION OF PENIS
SECONDARY TO DONOVANOSIS
- 66

·FIG
PSEUDO EPITHELIOMATOUS HYPERPLASIA GRADE II
IN A CASE OF DONOVANOSIS
Low power photomicrog aph: marked acanthotts with tendency to pearl
formation in spite of Iregular epithelial down-growth the Integrity of basal layer
is ma ntained abundant subepidermal In Rammatory cells
FIG 33
PSEUDO EPITHELIOMATOUS HYPERPLASIA GRADE III
IN A CASE OF DONOVANOSIS
Low power photomicrograph Banthosis but with me hrdly trogutar and rolova
down to the old thel um with ind it net and pasal layu
moderate tubepide mal colest ont of inflammatory cel.

·FIG 34.
EXTRAGENITAL GRANULOMA INGUINALE OF NECK
Note excellent response to antibiotics
By courtesy of Dr RB Greenblate Medical College of Georgia, USA
- 68 -

·FIG 25 EXTENSIVE GRANULOMA OF GROINS AND OF INGU NAL
AND PUB CREG ONS WITH DEFORMITY OF PENIS
(A) BEFORE AND (8) AFTER TREATMENT WITH STREPTOMYCIN
A
69

·FIG 36 SUCCESSFUL TRANSPLANTATION OF CHEMORESISTANT
DONOVANOSIS IN GROIN AND FORE ARM OF A VOLUNTEER
- 70 -

·FIG 37
GRANULOMA INGUINALE OF CERVIX (OFTEN MISTAKEN
FOR CERVICAL CARCINOMA) BEFORE TREATMENT
WITH CHLORAMPHENICOL
Ar cowtry of Dr X. Correur
Aset wirer of Cow

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