Female genital schistosomiasis: facts and hypotheses

Acta Tropica 79 (2001) 193– 210 www.parasitology-online.com

Review Article

Female genital schistosomiasis: facts and hypotheses Gabriele Poggensee a,*, Hermann Feldmeier b a

Institute of Tropical Medicine and Medical Faculty Charite´, Humboldt-Uni6ersity, Berlin, Germany b Epidemiology Working Group, Faculty of Medicine, Freie Uni6ersita¨t Berlin, Berlin, Germany Received 15 October 2000; received in revised form 11 January 2001; accepted 17 January 2001

Abstract In this paper we summarise the parasitological, clinical and epidemiological characteristics of female genital schistosomiasis (FGS), a frequent manifestation of the infection with Schistosoma haematobium. Means to diagnose and treat lesions in the lower and upper genital tract are discussed. Based on clinical findings and available pathophysiological as well as immunological data it is conceivable that FGS of the cervix and vagina not only facilitates the infection with agents of sexually transmitted diseases, but presumably also alters the natural history of such infections. Two infectious agents are of particular concern: the Human Immunodeficiency Virus and the oncogenic Human Papilloma Viruses. Possible interactions and their consequences are discussed and research areas which should be addressed are outlined. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Schistosomiasis; Genital disease; Women; HIV; HPV; Cervical cancer; Infertility

1. Introduction Female genital schistosomiasis (FGS) is defined as the presence of ova and/or a characteristic pathology in reproductive organs. Genital schistosomiasis as a clinical feature of the infection with schistosomes was already described in 1899 when Madden reported a case of vaginal and Petrides a case of uterine schistosomiasis (Madden, 1899; Petrides, 1899). As in S. haematobium infection * Corresponding author. Fax: + 49-30-30116888. E-mail address: [email protected] (G. Poggensee).

urinary and genital schistosomiasis frequently coincided the term urogenital schistosomiasis was coined (Mu¨hlens et al., 1942). In 1949 examining the records of the South African Institute of Medical Research, Charlewood came to the conclusion ‘‘that practically all gynaecologists who have been practising in Johannesburg or Durban for any length of time, have encountered gynaecological manifestations of Bilharzia’’ (Charlewood et al., 1949). In 1953, Gelfand and Ross, based on extensive gynaecological and pathological studies in South Africa, remarked that ‘‘if a patient has urinary bilharziasis, the probability is that she will have ova of S. haematobium in some portion of

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the genital tract’’ (Gelfand and Ross, 1953). Later Gentilini stated that in S. haematobium infection ‘‘female genital schistosomiasis is clinically a frequent and anatomically a constant condition’’ (Gentilini et al., 1986). It is therefore surprising that until recently the scientific literature on this disease entity offered more questions than answers. In this paper we summarise the parasitological, clinical and epidemiological characteristics of female genital schistosomiasis caused by S. haematobium and its presumptive interactions with other infectious diseases. Furthermore we outline priority areas for research in order to better understand the public health impact of FGS. Reviews on FGS caused by the intestinal schistosomes have been published previously (Feldmeier et al., 1995, 1998).

2. Anatomical and pathophysiological basis When after maturation in the liver adult schistosomes leave the portal vein against the blood stream the first obstacle to overcome is the anorectal plexus (Fig. 1). Once this plexus is passed, worms gain easy access to the perivesical plexus, as well as to the plexus utero-vaginalis, either by traversing the recto-vaginal septum or through vascular links between the bladder and the reproductive organs. The abundant anastomoses between the different venous plexus of the small pelvis, the veins of which are almost without valves and allow blood to flow in either direction, offer a network of routes for the migration of worms to any genital organ. Adaptive changes in pelvic vascularisation and changes in the direction of blood flow during

Fig. 1. Female pelvis venous vasculature (from Poggensee et al., 1999).

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pregnancy further increase the chances of adult worms to settle in genital organs during the reproductive age (Moore and Smith, 1989; Netter, 1987; Waldeyer and Mayet, 1980; Magdi, 1974). Furthermore, S. haematobium worms do not stay at a certain anatomic site their whole life span, but tend to explore the adjacent vascular beds, making multiple organ lesions due to sequestered eggs likely (Smith and Christie, 1986). In fact, copulating worms and/or sequestered eggs have been observed in any of the internal and external genital organs of women (Arora et al., 1986; Attia, 1962; Badawy, 1962; Koller, 1975; van Raalte et al., 1981; Wright et al., 1982; Youssef and Fayad, 1970). Eggs deposited at the ‘wrong’ site find themselves in an anatomical impasse and induce the formation of a peri-oval granuloma the accumulation of which eventually leads to destruction of soft tissue, fibrosis and the formation of scars. The ensuing pathology is presumably independent of the way eggs have reached the genital tissue, i. e. through direct oviposition at the anatomic site or passive transport with the blood flow from a topographically distant location. The various types of lesions and the broad spectrum of clinical manifestations are assumably expressions of a complex delayedtype hypersensitivity response to sequestered viable, dying or dead ova. The heterogenicity in macroscopic and microcopic appearance of lesions in the vulva, vagina and cervix is not surprising taken into account intrinsic tissue difference as well as the dynamics of granuloma formation and resolution, as well as the fact that S. haematobium worms may induce granulomas encompassing a single ovum to a cluster of eggs (Smith and Christie, 1986). In histological sections of the cervix two major patterns of tissue reaction have been observed: a strong inflammatory response frequently around a cluster of viable eggs and the presence of only few mononuclear cells around non-viable or calcified eggs (Berry, 1966; Helling-Giese et al., 1996).

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3. Clinical features and pathological findings The clinical picture of genital schistosomiasis and the pathological findings vary according to the organ affected.

3.1. O6aries and fallopian tubes Whether lesions in the ovaries and the Fallopian tubes are consistenty associated with clinical findings is not kown. Cases reported were diagnosed through laparascopy (Ekoukou et al., 1995; Bac et al., 1987). In a prospective clinical and histopathological study of surgically removed genital specimens Bland and Gelfand (1970) found schistosome eggs in 10/104 (9.6%) Fallopian tube samples. Out of 38 cases with ectopic pregnancies in five schistosomiasis of the Fallopian tube was diagnosed. Furthermore, women with ectopic pregnancy and FGS were younger than patients without schistosomiasis. Between 1946 to 1955 8.2% of all pathological findings in sections from Fallopian tubes and ovaries removed from Egyptian patients were due to schistosomiasis (Shafeek, 1961). There is no doubt that the involvement of the Fallopian tubes and/or the ovaries may cause primary or secondary infertility (Bland and Gelfand, 1970; Badawy, 1962; Ekoudou et al., 1995; Zolotar and Sandbank, 1962; Scheller, 1974). If granulomas are located in the proximity to the mucosa they induce a sterile salpingitis followed by local fibrosis eventually leading to fibrotic scars and tubal occlusion. Granulomatous reactions near the hilus may cause hilar obstruction and parovarian adhesions may result in anovulation (Berry, 1966). Schistosome eggs have been detected in the stroma of the ovaries (Berry, 1966) as well as in the corpus luteum (Mouktar, 1966). In histological sections of the Fallopian tubes eggs have been found in all layers of the tube wall accompanied by generalised salpingitis or fibrosis (Arora et al., 1986; Okonofua et al., 1990; Vass and Lucey, 1982; Carayon et al., 1968). Menstrual disturbances, lower abdominal pain with varying intensity and duration, abdominal masses and delayed puberty may occur in women

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with schistosomiasis of the Fallopian tubes and/or ovaries (Charlewood et al., 1949; Vass and Lucey, 1982). Nodular lesions of the mesosalpinx (Crump et al., 2000; Harouny and Pedersen, 1988), adhesions (Mouktar, 1966; el-Mahgoub, 1972), haematosalpinx (Bland and Gelfand, 1970) and hydrosalpinx (Ekoukou et al., 1995) have been described. FGS of the Fallopian tubes is often combined with FGS of the ovaries (Diouf et al., 1973; el-Mahgoub, 1972; Charlewood et al., 1949).

3.2. Uterus and placenta S. haematobium ova and adult worms have been found in endometrial tissue and in diagnostic or therapeutic curretage material (Mouktar, 1966; Berry, 1966; Attia, 1962). A causal relationship between bilharzial endometritis and abortion has been hypothesised (Attia, 1962). Leutscher et al. (1998) have shown in Madagascar that spontaneous abortion is more frequently in a S. haematobium endemic village as compared to a non-endemic village. Furthermore, it has been observed that FGS occurs together with uterine fibroids (Adeleye, 1975; Arora et al., 1986). Clinically, FGS of the uterus translates to metrorrhagia and lower abdominal pain. Renaud et al. (1972) investigated the frequency of placental involvement in 322 placentas from women with normal deliveries, premature deliveries and women giving birth to small-for-date babies. In pregnancy terminating during the second trimenon 32% of the placentas contained schistosome eggs whereas in only 3% of pregnancies terminating in the first trimenon eggs were detected.

3.3. Cer6ix Schistosomiasis of the cervix shows a polymorphous picture. Cauliflower-like growth, nodular hypertrophy, ulcerative and polypoid lesions have been reported (Badawy, 1962; Bland and Gelfand, 1970; Diouf et al., 1973; Koller, 1975; Bellingham, 1972; Coulanges et al., 1975). Such lesions closely resemble a malignancy (Gibson, 1925; Charlewood et al., 1949). Sandy patches are

pathognomic findings; they may exist on a macroscopically normal cervix, but are often in the vicinity of ulcer and erosions (Poggensee et al., 2000; Schwartz, 1984). The ova are predominantly located at the ectoendocervical junction (Berry, 1966). Granuloma vary in size and contain from a single degenerated ovum to numerous viable ova with or without the presence of adult worms. Pathological changes can occur in the epithelium as well as in the stroma sometime related to ova and other times not apparently so (Berry, 1966). In Tanzania the proportion of women with moderate to severe cervical inflammation — assessed by histological sectioning of a biopsy — was significantly higher in patients with FGS than in women without genital schistosomiasis. Even in women with a macroscopically normal cervix significantly more women with FGS showed moderate to severe inflammation in histological sections than uninfected women (Poggensee et al., in press). Symptoms associated with cervical schistosomiasis are dysmenorrhoea, menorrhagia, leukorrhoea, lower abdominal pain, post-coital bleeding, intermenstrual bleeding and dyspareunia (Bland and Gelfand, 1970; Camain, 1953; Badawy, 1962; Bellingham, 1972; Sharma and Trussell, 1970). None of these symptoms are specific.

3.4. Vagina Similar to the cervix lesions vary in the clinical presentation. Lesions may be fibroid-like polypoid, ulcerative or have the aspect of coarsegrained sandpaper (Berry, 1966). Pruritus, leukorrhea and dyspareunia are reported by patients (Lu¨ ttges and Koransky, 1985; Desmond et al., 1994). Recto-vaginal and vesico-vaginal fistula seem to be possible extremely delibilitating sequel of vaginal schistosomiasis (Diouf et al., 1973). Based on empirical observations surgeons working in schistosomiasis endemic areas recommend to first treat patients with praziquantel before repairing a vesico-vaginal fistula in order to ensure a successful operation (Magdi and El Hefnawi, 1951).

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3.5. Vul6a and clitoris Again lesions vary in size and presentation. Progressive and relapsing swelling, painful or painless ulceration, nodular surface, pruritus and a hypertrophic clitoris with an eroded granular surface have been described (Crump et al. 2000; Ba et al., 1959; Carmona, 1993; El-Zawahry, 1975; Goldsmith et al., 1993; Laven et al., 1998; Mawad et al., 1992; Attili et al., 1983; Farrell et al., 1996). In a few women the development of lesions has been monitored. Genital schistosmiasis started with an irritation of the skin, followed by oedema and hyperaemia. Later small nodules developed under the skin and papillomatous lesions appeared forming masses resembling condylomata (Attili et al., 1983; Desmond et al., 1994). Schistosomiasis induced vulval growth has been observed in girls as young as three years (El-Adnani and Saleh, 1982). In travellers returning from the tropics, due to the unspecific nature of gynaecological findings, delays of more than 24 months in diagnosis have been reported (Crump et al., 2000) the lesions being misdiagnosed as e.g. vulval warts (Goldsmith et al., 1993; Desmond et al., 1994).

3.6. Breast Only a few cases of breast involvement have been reported (Nkanza, 1989; Varin et al., 1989; Gorman et al., 1992.) The mammographic appearance of the calcified eggs can lead to confusion with breast cancer. The diagnosis requires a biopsy and histological examination (Gorman et al., 1992).

4. Occurrence and risk factors FGS due to S. haematobium has been reported from almost all countries where the parasite occurs (Fig. 2). So far, the frequency of genital involvement can only be inferred from histopathological, post-mortem and a few populationbased studies. Systematic autopsies have shown, that FGS can affect any genital organ the cervix being the most common site followed by the

Fig. 2. Geographic distribution of FGS in Africa (dotted area: S. haematobium endemic countries with FGS case reports; stripped areas: S. haematobium endemic countries (prevalence\ 10%).

vagina and the Fallopian tubes (Table 1). The frequencies vary widely in these studies. This can be explained by the fact that the studies have been carried out in different endemic situations using different methodological approaches. Histological sectioning and the digestion of tissue with KOH gave incongruent results. Whereas in severe, moderate and mild infection — defined by the number of eggs in bladder tissue — the digestion method detected in 100%, 50% and 30% of the samples eggs in the cervix, only 66%, 10% and 20% of the specimens were positive in the corresponding histological sections (Edington et al., 1975). Another good example for the underestimation of the true occurence of FGS when a technique with low sensitivity is used is provided by Renaud et al. (1972) who analysed the frequency of placental schistosomiasis. Using a digestion method in 22% of the placenta eggs were discovered whereas only in a single case (0.3%) eggs were dected in the histological section. Comparing the performance of three different diagnostic approaches to detect ova in cervical tissue the quan-

198

Organ

Iraqa

Egyptb

Nigeriac

Ivory Coastd

Vulva Vagina Cervix Uterus Fallopian tubes Ovaries Not specified/other Total

3 (10) 4 (14) 7( 24) 1 (4)

13 (40) 14 (41) 7 (21) 4 (11) 11 (31)

46 (78)

14 (48)

68 (17) 103 (26) 121 (31) 14 (4) 28 (7) 63 (16)

29

397

34

a

Tanzaniae

Malawif

4 (7) 8 (13) 1 (2)

22 (14) 22 (14) 101 (62) 1 (1) 15 (9) 1 (1)

16 (9) 17 (10) 106 (60) 1 (0.1) 28 (16) 17 (10)

59

162

176

Zimbabweg

12 (32) 23 (62) 4 (11) 8 (22) 7 (19) 7 (10) 37

Mozambiqueh

South Africai

9 (6)

18 (9) 7 (3) 137 (67) 8 (4) 21 (10) 10 (5) 4 (2)j 205

11 (7) 19 (13) 48 (32)

150

Retrospective histopathological study; al-Adnani and Saleh (1982). Retrospective histopathological study; Youssef and Fayad (1970). c Prospective post-mortem study (digestion method); only cases with concomittant urinary schistosomiasis; Edington et al. (1975). d Retrospective histopathological study; Renaud et al. (1972). e Retrospective histopathological study; van Raalte et al. (1981). f Retrospective histopathological study; Wright et al. (1982). g Prospective post-mortem study (digestion method); Gelfand et al. (1971). h Prospective histopathological study, Elling et al. (1967). i Retrospective histopathological study; Berry (1966). j Placenta, 1; round ligament, 3. b

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Table 1 Anatomical distribution of FGS according to histopathological and post-mortem studies in various endemic areas (percentages are given in brackets; multiple mentioning of organs possible)

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titative compressed biopsy technique (QCBT, see below) detected significantly more cases than histological sectioning (49% vs 18%; Poggensee et al., in press). Therefore, frequency estimations based on histopathological studies tend to be systematically biased. The same helds true for frequencies reported from routine histopathological examinations or screening procedures. In Madagascar and Gabon, 0.7% and 2.5% of all genital specimens examined showed FGS (Brygoo, 1968; Ville et al., 1991). In Malawi between 1976 and 1980 12% out of 1617 cervical specimens and 15% out of 110 vaginal specimens were found egg-positive in a histopathological examination (Wright et al., 1982). Even in this highly selected population the true frequency of FGS should be considerable higher (Table 2). As schistosome ova have accidentally been observed in cervical smears this method has also been used to assess the frequency of FGS in endemic areas. In Zimbabwe Shennan et al. (1971) have analysed the PAP smears of women attending a gynaecological outpatient clinic during a period of 6 months. In 2.3% (44/1901) of the samples ova were detected. However, in a com-

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munity-based study in Tanzania the sensitivity of the PAP smear was as low as of 2.5% (Poggensee et al., in press). It is therefore conceivable that this method largely underestimates of the numbers of FGS cases. Another cause for the underestimation of the occurrence of FGS are false diagnoses. This is related to the unspecific nature of symptoms and signs making false diagnosis highly probable. As to the differential diagnosis between cervical schistosomiasis and cancer this assumption is supported by a histopathological study of cervical specimens in Tanzania. Whereas cervical cancer and FGS were detected in 1.9% of the histological sections, eggs were encountered in 6% of the biopsies without a histopathological diagnosis of cervical cancer (Riffenburgh et al., 1997). As the clinical features of FGS resemble cervical cancer very closly the high percentage of FGS cases in the non-cancer group is easily explained by problems in differential diagnosis by the gynecologists when examining the patients. Indeed, there are numerous case reports of unnecessary surgery carried out in women with clinical schistosomiasis mistaken for malignancy (Camain, 1953; Nosny, 1963).

Table 2 Occurrence of FGS detected in surgically removed specimens and cervical smears Specimen

n

FGS (%)

Study design/country

Author

Surgically removed specimens Surgically removed genital tissue Surgically removed genital tissuea Surgically removed genital tissue Fallopian tubes (ectopic pregnancies only) Fallopian tubes (ectopic pregnancies only) Placenta Cervical specimens

38 400 n.g.d 8755 513 331

170 (0.4) n.g. (2.5) 62 (0.7) 150 (29) 12 (3.6)

Retrospective study/Tanzania Retrospective study/Gabun Retrospective study/Madagascar Prospective study/Mozambique Retrospective study/Cote d’Ivoire

van Raalte et al. (1981) Ville et al. (1991) Brygoo (1968) Elling et al. (1988) Loubie`re (1977)

n.g.

n.g. (1.8)

Retrospective study/Gabun

Ville et al. (1991)

322 8082

72 (22.3)b 266 (3.3)c

PAP smears

1901

44 (2.3)

Prospective study/Ivory coast Retrospective study/Malawi and Tanzania Prospective study/Zimbabwe

Renaud et al. (1972) Riffenburgh et al. (1997) Shennan et al. (1971)

a

Number includes specimens of the breast; genital specimens represent 33% of all schistosomiasis haematobium cases. Digestion method; prevalence of urinary schistosomiasis: 3.4%. c Results pooled; FGS without cervical cancer: 165/2769 (6.0%); FGS with cervical cancer: 101/5313 (1.9%). d n.g.= data not given. b

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Table 3 Prevalence studies on FGS of the lower genital tract based on biopsies Organ

n

FGS

Country

Author

Vagina Cervix Cervixf Cervix Cervixf

61 24 51 36 372

46 (75%)a 11 (46%)b 33 (65%)c 12 (33%)d 139 (37%)e

Niger Ghana Malawi Madagascar Tanzania

Renaud et al. (1989) Szela et al. (1993) Kjetland et al. (1994) Leutscher et al. (1998) Poggensee et al. (2000)

a

Prevalence of urinary schistosomiasis: 86%. Women living in an endemic village with past or present haematuria. c Prevalence of urinary schistosomiasis: 100% (hospital-based study). d Prevalence of urinary schistosomiasis: 76%. e Prevalence of urinary schistosomiasis: 42%. f Method: histological sectioning/QCBT. b

Until now, there are only few populationbased studies providing reliable data on the frequency of FGS of the lower genital tract (Table 3), while estimates of FGS of the upper genital tract still do not exist. On a population level the point prevalences for FGS of the cervix/vagina range between 33– 75%. The prevalence of FGS in women with diagnosed urinary schistosomiasis lies between 55– 65% (Kjetland et al., 1996; Poggensee et al., 1998). In Tanzania, in a population with a rather low egg excretion in urine (median: 2.1 eggs/ 10 ml urine), the intensity of infection in the urine increased the risk for FGS. The age adjusted OR increased from 1.86 (95% CI: 1.03– 3.38) for an egg excretion of 0.1 eggs/10 ml urine (P B 0.05) to 2.28 (95% CI: 1.32–4.65) for 1– 10 eggs/10 ml urine (P B0.01) (Poggensee, manuscript in preparation). Women with cervical schistosomiasis showed a higher proportion of macroscopically overt cervical lesions (75% vs 48%, Poggensee et al., 2000). In women without sexually transmitted diseases but with FGS 38% of the clinically detected inflammatory lesions, 42% of histopathologically assessed moderate to severe cervical inflammation and 28% of cytologically determined moderate to severe inflammation could be attributed to FGS. On the population level 26%, 16% and 11%, respectively, of the inflammatory reactions could be attributed to FGS (Poggensee et al., manuscript in preparation).

5. Diagnosis The diagnosis of schistosomiasis of the reproductive tract is usually made through the incidental observation of schistosome eggs in histological sections made from biopsies routinely taken during gynecological examination or laparoscopy (Williams, 1967; Bland and Gelfand, 1970). Due to their visible nature vulval lesions have been diagnosed less randomly (Wright et al., 1982). This is a matter of concern since in the endemic area FGS is a common disease and untreated genital schistosomiasis has to be considered as a significant health hazard for the affected women (see below). The random nature of diagnosis parallels the fact that the value of most diagnostic procedures is unknown.

5.1. Schistosomiasis of the lower reproducti6e tract There are four catogories of approaches for the diagnosis of schistosomiasis in the lower reproductive tract: symptoms, macroscopically observable alteration of the genital epithelium, demonstration of eggs in tissue, and immunological disease markers presumably released during the development of egg-related lesions. Whereas in previous reports symptoms like dyspareunia, intermenstrual bleeding and bloody vaginal charge have been considered as reliable indicators of vulval, vaginal or cervical lesions, a

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recent community-based study in Tanzania showed that, perhaps, except post-coital bleeding, self-reported symptoms are neither sensitive nor specific for FGS (Poggensee et al., 2000). Macroscopically, the lesions in the lower reproductive tract may mimic almost any type of infectious or malignant condition found in the vagina or cervix, and therefore can not be pathognomonic. However, on a population level sandy patches, leukoplakia, and erosion are alterations significantly associated with the presence of eggs in epithelial tissue (Poggensee et al., 2000). The use of a colposcope considerably enhances the diagnostic value of a routine gynecological examination as lesions can be examined more clearly and disrupted areas of the epithelium, another suspicious finding, become visible (Poggensee et al., 2000). The gold standard for the diagnosis of FGS remains the quantitative compressed biopsy technique (QCBT), in which a forceps biopsy is taken from a suspicious lesion, or if absent from the anterior lip of the cervix, and the material is compressed between two glass slides (Kjetland et al., 1996). If in individual patients with the presumptive diagnosis of FGS, but a macroscopically normal cervix and vagina several biopsies are taken and examined by the QCBT, the likelihood to confirm the presence of eggs becomes very high. The sensitivity of the QCBT compares favourably with that of histological sections made from a biopsy and its specificity is near to 100% (Poggensee et al., in press). Two alternative diagnostic methods have been tried to replace the QCBT: the examination of routinely obtained cervical smears and the wet examination of tissue scraping, e.g. obtained with the corner of a glass slide. Whereas the former technique has a disappointing low sensitivity (Feldmeier et al., 2001) and cannot be recommended, the latter method is a valid alternative, though it is only suitable for vulval lesions (Swart and van der Merwe, 1987; Savioli et al., 1990). Unfortunately, the examination of urine for the presence of eggs does not substitute the gynecological examination. FGS frequently has been reported in women with scanty or even no

201

egg excretion in urine (Attili et al., 1983; Camain, 1953; Bland and Gelfand, 1970; Gloor et al., 1979; Vass and Lucey, 1982; Goldsmith et al., 1993). This assumption was comfirmed in a population based study which showed that if urine examination is limited to a single specimen 31% of all FGS cases will be missed. Even if a highly sensitive urine examination technique is applied on three consecutive days 23% of women with FGS will be classified as being uninfected (Poggensee et al., 1998). As in rural Africa, except in teaching hospitals, a colposcope is rarely at hand and taking a biopsy is wholly inappropriate at the tertiary health care level, and even impossible during screening, the development of assays for the detection of indirect disease markers in vaginal fluid is of utmost importance. Various putatively useful marker molecules have been identified, but only a few have been validated (Feldmeier et al., 1995). A promising candidate is eosinophil cationic protein (ECP), a cytotoxic granule protein released by activated eosinophils (Poggensee et al., 1996). Investigations into the usefulness of antigen detection in vaginal fluid are under way. Using a dip-stick-like technology, such marker molecules could be detected in elutions of tampons or hygiene pads designed for this special purpose thus enabling the diagnosis of FGS at the primary health care level.

5.2. Schistosomiasis of the upper reproducti6e tract Until now, the diagnosis of FGS of the upper reproductive tract is made through the histological examination of material taken during laparoscopy or abrasion (el-Mahgoub, 1972; Smith and Christie, 1986; Scully et al., 1994). Using transabdominal ultrasound Richter et al. (1995) in Malawi and Leutscher et al. (1998) in Madagascar observed enlargement of the corpus uteri, focal hyperechogenicities inside the uterine parenchyma, ovarial enlargement combined with hyperechogenicity and hyperechoic masses palpable involving the tubes and ovaries. The specificity of these findings, though, remains unclear.

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6. Therapy As FGS is not systematically diagnosed it is not surprising that knowledge on treatment is scanty. Lesions of the ovaries and tubes, but also of the cervix have been treated by aggressive surgery, such as ovarectomy and hysterectomy (Camain, 1953; Charlewood et al., 1949). While such an approach may be justified when during laparoscopy an enlarged ovary or a tubal mass are seen which look like a malignancy and rapid-section histopathology can not be performed, irreversible surgery is by no means warranted for lesions in the lower reproductive tract. If, for example the differential diagnosis of a lesion of the cervix is cervical cancer, the application of the QCBT will usually confirm FGS within minutes. A conservative approach to various forms of FGS using anti-schistosomal drugs is supported by a number of case reports, which showed regression or disappearance of lesions after treatment. A small clinical study in Malawi confirmed that after a single-dose treatment with praziquantel (40 mg/ kg) symptoms disappeared in most patients within 9 weeks (Richter et al., 1996). The regression and complete disappearance of macroscopic lesions in the cervix, vagina or vulva, though, apparently needed even more time. This is corroborated by findings of a longitudinal study in Tanzania in which women were followed up for a period of 12 months (Poggensee et al., in press). The rationale to use praziquantel is based on the observation that, although the drug acts only against (very young) schistosomulae and mature worms, the elimination of the latter enhances the resolution of egg induced granulomas and tissue fibrosis. This has been demonstrated in patients with hepatosplenic schistosomiasis mansoni in whom sensitive markers of liver fibrosis decreased to normal values within 2– 6 six months after repeated treatment with praziquantel (Zwingenberger et al., 1990). Similarly, granulomatous lesions in the urinary tract involuted after praziquantel as assessed by ultrasonography. As complete resolution of egg induced pathology presumably requires the elimination of all worms and since the cure-rate after a single dose of praziquantel is rather low, a repeated administration of

the drug, four to five doses of 40 mg/kg each spaced 48 h, seems to be warranted in moderately to heavily infected women.

7. Interaction with other infectious diseases Based on clinical findings and available pathophysiological as well as immunological data it is conceivable that FGS of the cervix not only facilitates the infection with agents of sexually transmitted diseases (STDs), but presumably also alters the natural history of such infections. Two infectious agents are of particular concern: the Human Immunodeficiency Virus (HIV) and the oncogenic Human Papilloma Viruses (HPV).

7.1. FGS and HPV, FGS and cer6ical cancer Besides Herpes simplex virus (HSV-2) HPV is the most prevalent sexually transmitted infectious agent in women and without any doubt HPV plays a central role in the aetiology of cervical neoplasia (Bosch et al., 1995). Therefore any evidence pointing to an association between FGS and HPV warrants careful consideration. Several reasons give credit to the hypothesis that cervical schistosomiasis may play a pivotal role in HPV induced cervical cancer (Fig. 3). Firstly, there is convincing evidence that FGS develops — and also occurs — during puberty (Poggensee et al., 2000). Hence, egg-induced lesions, particularly at the cervix, may be present at the very beginning of sexual activity. Thinning, erosion and ulceration of the cervix epithelium due to egg-associated pathology, though, should ease the penetration and implantation of HPV. In this way, FGS could facilitate the infection with HPV at very young age, which in turn would favour the development of cervical malignancy at a younger age than normal. In fact, in sub-Saharan Africa women with cervical cancer are surprisingly young (Moubayed et al., 1995). In a study in Tanzania Moubayed et al. (1994) found that 18% of the women with FGS and cervical cancer were younger than 25 years. In contrast in women with cervical cancer in the absence of genital schistosomiasis only 5% were in this age group.

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Secondly, the propensity of HPV induced lesions to either spontaneously regress or progress to invasive carcinoma suggest that virus infections alone is not sufficient and that other factors are necessary to stimulate the development of malignancy (zur Hausen et al., 1981). In fact the natural history of genital HPV infection is characterised by a high rate of acquisition and clearance of HPV types. FGS could interfere with the physiological mechanisms of HPV clearance or alternatively favour a rapid propagation of the virus, thereby augmenting local viral load which in turn would aid the development of cervical cancer (Ylitalo et al., 2000). This assumption is supported by findings of Moubayed et al. (1995). The authors observed that in all cancer cases in which FGS was also present the lesions were co-infected with HPV. However, in cancer patients without FGS only half of the women showed the presence of HPV by in situ hybridisation. Although the mechanism by which FGS may impede normal viral clearance is not known, an experimental study in S. mansoni infected mice indicates that down-regulation of virus-specific cy-

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totoxic lymphocytes may play an important role (Actor et al., 1993). A decrease in the number and efficiency of NK cell could also contribute to an inefficient control of HPV infection (Feldmeier et al., 1985). As there is overwhelming evidence of the cancerogenic potential of S. haematobium eggs for bladder tissue (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 1994) one might assume that in analogy to the pathogenesis of bladder cancer in urinary schistosomiasis the epithelium of the cervix could also be susceptible for neoplastic transformation induced by sequestered eggs (Feldmeier et al., 1998; Badawi et al., 1995). Finally, disrupted blood vessels and neo-vascularisation, clinical features frequently observed around egg-associated lesions of the cervix (Kjetland et al., 1996) may ease the local spread of malignant cells when occurring within or near a site of HPV induced cell transformation. This, together with a presumably young age at infection with oncogenic HPV, could explain why in many African women cervical cancer is observed already at an age of 30 years or less.

Fig. 3. Putative relationships between female genital schistosomiasis and HPV infection in the natural history of cervical cancer.

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7.2. Female genital schistosomiasis and HIV/AIDS Schistosomiasis of the lower reproductive tract may interfere with the natural history of HIV infection at various levels starting from an impaired barrier function of genital epithelium to the deleterious modulation of protective immune responses. It is generally assumed that the intact genital epithelium forms a tight and effective barrier preventing access of HIV — either cell-associated or free — to subepithelilal mononuclear cells (Shattock et al., 2000). Disruption of the epithelial surface, however, is likely to enhance HIV transmission from a man to a woman by allowing access of cell free virus or HIV-infected cells to CD4 receptor expressing subepithelial cells. In fact, it has been convincingly demonstrated that breaks in the integrity of the mucosal barrier, due to either trauma or sexually transmitted ulcerative diseases, are associated with an increased risk of HIV transmission (for review: Mabey, 2000). Thinning, erosion and ulceration of the epithelium is a typical finding of genital schistosomiasis (Kjetland et al., 1996; Poggensee et al., 2000; Badawy, 1962; Diouf et al., 1973; Koller, 1975). Moreover, in the lower reproductive tract FGS usually is not restricted to a single localised sore leaving the rest of vulval, vaginal or cervical epithelium intact — as this is usually the case in sexually transmitted ulcerative diseases — instead various lesions coexist surrounded by an altered epithelium. Histological sectioning indicates that the epithelium is frequently atrophic (Berry, 1966). Since there is anecdotal and circumstantial evidence that egg-associated lesions already develop during puberty, assumably such a pathologically altered epithelium is present when women reach sexual maturity. Hence, as in sub-Saharan Africa sexual relationships are frequently initiated shortly after menarche (Matasha et al., 1998), the presence of FGS should facilitate the infection with HIV at very young age. Similar to the situation in infections with Neisseria gonorrhoea or Chlamydia trachomatis disruption of the epithelial integrity may facilitate

transmission of HIV in yet another way (Mabey, 2000). Inflammation around egg-associated lesions will recruit activated immune cells expressing the CD4 and the chemokine receptor CCR5 into the epithelium providing HIV with ample opportunity to bind. Furthermore, egg granulomas are likely to change the pattern of the cytokines released locally during the inflammatory response: Secretion of pro-inflammatory cytokines such as interferon-gamma, IL-2 and TNFa could enhance the susceptibility of different cell populations to HIV infection and may also increase the permeability between epithelial junction (Shattock and Griffin, 1996). These cytokines are released in high concentrations when new granulomas build up (Rumbley and Phillips, 2000; Stadecker, 1999; Boros, 1999). Inflammation also increases HLAexpression on epithelial cells which potentially enhances the ability of such cells to bind HIV infected CD4+ cells (Shattock and Griffin, 1996). The events occurring after exposure of female mucosal surface to HIV and the initial phase of infection in the subepithelial cell layers are still relatively poorly understood. The primary cellular targets of HIV are believed to be T helper cells, macrophages and Langerhans cells, all of which express the CD4 antigen on their surface (Weiss, 2000). Peri-oval granulomas are frequently formed near to the basal layer of the epithelium. Within the egg-granulomas, but also in adjacent areas, T cells, macrophages and Langerhans cells are abundant (Helling-Giese et al., 1996). In animal models CD4 + ab T cells represent 8–10% of granuloma cells (Weinstock et al., 1999). There is also some evidence that eosinophils express the CD4+ receptor and may constitute a compartment susceptible for HIV infection (Fincham et al., 1999). Eosinophils represent almost 50% of the granuloma cells (Weinstock et al., 1999). Taken together, the abundance of CD4 receptor-bearing cells within the confines of the granuloma and in adjacent areas make a rapid binding of virus after penetration through the friable and eroded epithelium very likely. The immunological sequence after the integration of HIV into appropriate cells in sub-epithelial tissue, in part determine the latter clinical course

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of the infection. The picture that emerges is one of a battle during the initial weeks after HIV infection between the virus trying to replicate in CD4 cells and CD4 cells trying to respond to sites of viral replication. Losing this essential battle in the early phase of HIV infection results in a rapid propagation of HIV (Desrosiers, 1999). Conceivably, the early burst of viral replication as well as the attempt of the immune system to control the infection are both altered in the presence of genital schistosomiasis. This is based on the assumption that induction of the transcription factor NFkappaB through cytokines released from the granuloma may augment the early viral burst (Feldmeier et al., 1995). Due to identical binding sites for NFkappaB in host DNA and the enhancer region of HIV, increase in the transcription will augment the replication rate of HIV considerably (Jamieson et al., 1991). Hydrogen peroxide and oxygen radicals, molecules that are involved in the immune response against schistosomes, also have the potential to trigger the replication of HIV by stimulating the production of NFkappaB. In the initial phase of HIV infection protective immune mechanisms assumably are mediated by cytotoxic T cells (CTL) and NK cells (Freedman and Groopman, 1996). However, there is experimental evidence that schistosomiasis impairs CTL response to retrovirus infection (Actor et al., 1993) and that it reduces the number of circulating NK cells as well as their efficacy to kill (Feldmeier et al., 1985). After HIV has spread to the systemic circulation its replication is limited by the fact that usually few activated lymphocytes and differentiated macrophages are present in the blood stream and that resting T cells and undifferentiated monocytes are not susceptible to HIV infection (Shaunak and Teo, 1996). However, in patients infected with schistosomes (and/or intestinal helminths) a panel of immunological alterations have been observed that may facilitate rapid replication of HIV in the systemic circulation (Bentwich et al., 1995). Firstly, the number of activated T cells expressing HLA-DR and HIV coreceptors is elevated (Kalinkovich et al., 1998). Secondly, HIV replicates preferentially in TH2 −

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and TH0 type clones, and TH2 cells are usually abundant in individuals infected with helminths (Bentwich et al., 1999). Thirdly, peripheral blood mononuclear cells of patients with helminthic infection are significantly more susceptible to infection with HIV than those of uninfected controls (Shapira-Nahor et al., 1998). Finally, elevated IL-4 levels, characteristic for the TH2 type of immune response in helminthic infection downregulate TH1 differentiation and function (Bentwich et al., 1995). The assumption that immune dysregulation associated with chronic helminthic infections alters the course of HIV infection is also sustained by a field study from Ethiopia: HIV viral load was significantly higher in individuals with various helminthic infection including schistosomiasis than in individuals without and correlated positively to the parasite load (Bentwich, 2000). Furthermore, the viral load decreased after elimination of the worms by antiparasitic treatment (Bentwich, 2000). Taken together, whereas usually mucosal transmission is a relatively inefficient mode of HIV transmission compared with intravenous inoculation, it is likely to be much more efficient in FGS. Therefore women with FGS should have a higher per episode risk. The immunological characteristics of schistosomiasis in general and genital schistosomiasis in particular seem to favour the initiation of virus replication in sub-epithelial tissue, to increase the initial viral burst, and to facilitate rapid local as well as systemic viral replication. Hence, a faster progression from symptomless HIV infection to full-blown AIDS becomes very likely in women with FGS (Table 4). It comes therefore not as a surprise that in a recent commentary on the natural history of HIV1 infection in Africa the authors suggested to evaluate the impact of anthelminthic mass treatment on the progression of HIV infection (Morgan et al., 2001).

8. Control In the past decades schistosomiasis control has switched from disease control to morbidity control. Numerous studies have been carried out to

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Table 4 Presumable enhancing effects of FGS on HIV infection Type of risk factor

Consequence

Development of FGS of the cervix during puberty

Increased risk for HIV transmission at young age

Barrier function of genital Penetration of HIV epithelium impaired facilitated - Intrinsic characteristics of FGS lesions - Additional trauma during sexual intercourse - Increased permeability due to release of inflammatory cytokines - Simultaneous presence of otherSTDs Easy binding of HIV

HIV infection becomes easily established

- CD4 cells, macrophages, Langerhans cells in the granuloma and adjacent tissue - Granuloma frequently present in transformation zone

9. Research needs

Early rapid replication of Increased initial viral burst HIV - Favourable micro-environment of the granuloma - Function of CTL and NK cells impaired Uncontrolled replication of HIV

assumably plays through interacting with other infectious diseases make it essential to include genital morbidity into control measures aimed at morbidity reduction. At present diagnostic means to identify girls and women with FGS of the upper and/or lower genital tract suitable at the community level are not at hand. The only option to reduce schistosomiasis-associated morbidity of the reproductive tract is to treat the whole female population in an endemic area, irrespective whether girls and women excrete ova in the urine or not. Although praziquantel is not considered to be teratogenic or mutagenic, the drug is not recommended in pregnancy or in lactating women. This means that a certain proportion of women will not be treated in a running control programme. Operational problems to reduce schistosomiasisassociated genital morbidity on population level are summarised in Table 5.

High viral load; rapid progression from HIV infection to AIDS

- Increased number of susceptible cells in the systemic circulation - TH2 cells predominate - Downregulation of TH1 response - Function of CTL and NK cells impaired

identify schistosomiasis-associated disease markers in order to assess the impact of treatment on morbidity. Not surprisingly, assessment of morbidity in genital schistosomiasis has been completely neglected. However, documented sequels of genital schistosomiasis such as infertility or ectopic pregnancy and the important role FGS

With several community-based studies documenting the high prevalence of FGS and the increasing evidence for excess morbidity it is timely to address crucial issues of this disease entity. Priority areas for research are summarised in Table 6. Table 5 Operational contraints in FGS control measures Operational contraints

Factors

Identification of women at risk

Lack of tracer signs Unreliability of urine examination to identify genital disease Unreliability of self-reported symptoms to identify genital disease

Restricted use of praziquantel

Pregnant women Lactating women

Assessment of control measures

Lack of easily determinable disease markers

G. Poggensee, H. Feldmeier / Acta Tropica 79 (2001) 193–210 Table 6 Research needed Problem area

Research topic

Assessment of the impact of FGS on the reproductive health of women

Prevalence of FGS of the upper and lower genital tract in different endemic areas in girls and women; Proportion of ectopic pregnancies and infertility attributable to FGS; Pregnancy complications (abortion, still-birth, premature delivery) in women with FGS; FGS as a co-factor for the transmission of HIV and the progression to AIDS; FGS as co-factor in the natural history of HPV-infection; FGS as co-factor for the development of cervical cancer Assessment of the diagnostic value of indirect disease markers; Development of diagnostic means suitable for control measures Optimal dosage of praziquantel

Impact of FGS on other infections

Appropriate diagnostics

Treatment of FGS

Acknowledgements Gabriele Poggensee gratefully acknowledges the support by the Rachel Hirsch scholarship, Medical Faculty Charite´ , Humboldt-University, Berlin.

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