Scientific Justification for the Workshop
The information provided below is intended to be a starting point that will be the basis for further discussion during the Workshop.
Histology in genital schistosomiasis
The tissue around both viable and dead S. haematobium eggs portrays increased vascularity and a high density of cells such as macrophages, lymphocytes, foreign body giant cells, eosinophils, neutrophils, plasma cells, Langerhans cells, fibroblasts, and multinucleate histiocytes. Even calcified eggs may induce the influx of immune cells and blood vessel proliferation, local bleeding and oedema. The exact natural history of the local immune reaction to S. haematobium eggs in different phases is not known, but should be explored as it will have implications on treatment schedules and in choosing the best target populations for costly interventions.
The mucosal remains of childhood infection
Female genital schistosomiasis (FGS) has been defined as having sandy patches and / or microscopically proven S. haematobium eggs in genital tissue. The largest clinical studies in adult women living in endemic areas have found that the prevalences of women with sandy patches, contact bleeding, or eggs in genital tissue seem to be fairly constant in adulthood. Mucosal and stromal lesion severities do not follow the same characteristic decline with age as urinary egg excretion. It is well known that urinary S. haematobium egg excretion rises steadily to a peak in the early teenage years, falling to relatively low levels in adulthood. The trend is almost independent of duration of exposure, fuelling the theory that the onsets of phenomena around puberty offer some protection against the worm. Urinary egg excretion is significantly correlated with urinary tract morbidity in the young, but there is no such correlation in adults. While egg count in urine (currently interpreted as intensity of infection) is used as an overall proxy for S. haematobium worm burden, the genital involvement seems to be associated with the presence of eggs in urine but not with the intensity of infection. Lesions have been found to be more persistent in adults, possibly because many lesions now constitute calcified, dead eggs and chronic immunological reactions. In clinical practice, the cervix, the Fallopian tubes, and the vagina are the most common gynaecological sites found to contain Schistosoma eggs. However, eggs seem to be almost equally distributed in the pathophysiologically vital areas in the pelvis, indicating that identification of disease on the cervix may reflect upper genital tract disease.
Age and genital schistosomiasis
One community-based study has shown that almost 50% of children who had urinary ova excretion in a high-endemic school had genital symptoms this last week. Urinary ova and symptoms (ulcers, tumours, burning genital sensation, bloody, malodorous discharge) could hence be indicators of childhood FGS. However, these findings should be triangulated with genital examination. Adolescents are often too shy to come for gynaecological investigations the first few years after sexual debut. Hence case reports have been our only source of information on pathogenesis and most of these manifestations are reported from the vulval regions. Since intravaginal inspection in virgins is undertaken only in exceptional circumstances, one cannot know what these sites look like. However, a vaginal polyp was found in a 3-year old, a 4 cm by 4 cm ‘raised, reddened area’ in the upper third of the vagina was found in a 16-year old, and sandy patches have been found in the cervix of a 15-year old. Collectively this points towards a much greater burden of disease than presently acknowledged.
Genital schistosomiasis and the susceptibility to HIV
The cervix is the site of most HIV acquisition, and the relative frequencies of the mucosal immune cells are critical determinants of HIV transmission. Calcified S. haematobium eggs in genital tissue have been found to increase the density of HIV receptive CD4 cells and treatment has been found to decrease HIV receptors in genital tissue and blood. Compared with healthy tissue, ulcers caused by sexually transmitted infections (STIs) such as Herpes simplex virus, primary or secondary syphilis, had significantly higher numbers of neutrophils and macrophages expressing HIV co-receptors on the cell surfaces, critical for primary HIV transmission. Yet STI treatment studies have been marred with a lack of effect on HIV incidence, all of which have been performed in schistosomiasis endemic areas without taking genital schistosomiasis into consideration. Peripheral blood mononuclear cells in S. mansoni infected individuals also express higher levels of HIV co-receptors. This may indicate that the lesion(s) around the eggs in genital mucosa provide an entry point for the HIV.
Dually infected women and men, with schistosomiasis and HIV, may pose an additional risk of HIV transmission to their partners. Increased levels of HIV virus have been demonstrated in genital ulcers, compared with neighbouring normal tissue in the same women, and this may hold true for schistosomal lesions as well. Genital HIV-RNA excretion increases in the presence of reproductive tract diseases in women and men alike. Similarly, S. haematobium infection has been hypothesized to cause increased viral shedding into the semen of HIV infected men as a result of egg-induced inflammation in the seminal vesicles and the prostate. This meeting will therefore call on the participation by experts in male genital schistosomiasis, immunology, STIs and pathology.
Diagnosis of genital S. haematobium
Wet smears and PAP smears may contribute to the diagnosis of FGS, but their sensitivity is low. Tanzanian and Zimbabwean studies have shown that 23-41% of the women with negative urine tests had FGS. The crushed biopsy of genital tissue was previously deemed to be the gold standard for the parasitological diagnosis of genital S. haematobium. However, the eggs are located in highly focal clusters and one may miss them in histological sectioning of a biopsy. Moreover, taking a biopsy for the diagnosis of genital S. haematobium remains an HIV transmission risk for the patient and her partner until the inflicted wound has healed, raising due ethical concern. Where funds are available, an alternative to the biopsy is the Schistosoma real-time polymerase chain reaction (PCR). However, in a pilot study on FGS, the sensitivity in vaginal lavage was only 53%. The sensitivity was better in younger women (67%), suggesting that Schistosoma DNA from eggs (that have a limited life span) is maybe more likely present in recent lesions. Increased levels of eosinophil cationic protein, Neopterin or IgA in cervico-vaginal lavage have only limited value in the diagnosis of female gynaecological schistosomiasis. Furthermore, S. haematobium eggs may be found in almost every organ of the body and there may sometimes be no inflammatory reaction. Hence, the presence of S. haematobium eggs in a lesion or discharge may not always be the cause. A consensus meeting it has been concluded that, in patients from S. haematobium endemic areas visual inspection is the best diagnostic tool. However, it requires training, good light and magnification and, if a colposcope is available, an unusual way of using it. This meeting will call upon experts in diagnosis to define the new research agenda in this increasingly important topic.
The possible impact of treatment
Of parasitic infections schistosomiasis is second only to malaria in terms of public health impact and has been estimated to affect at least 250 million people, which means that worldwide an equivalent of one in 30 people are affected. Urogenital schistosomiasis is endemic in 53 countries in Africa and the Middle East. The control groups in all studies to date are women who had been exposed to the same water sources. Hence the differences between exposed and unexposed groups are likely larger than the reported figures. It has been estimated that 16 million women will acquire the genital manifestations of S. haematobium infection and that, if cured, 120 000 new cases of HIV could be averted through regular praziquantel treatments in the next decade.
In the urinary tract, the effect of praziquantel has largely been determined by resolution of lesions detectable by ultra sound scan and decreased egg excretion in urine. Praziquantel kills the egg-laying worms; however, lesions may remain and develop around eggs already deposited in the tissues. Once egg deposition has induced lesions in the genital tract the egg excretion and lesion development are two independent processes, with praziquantel affecting the former almost immediately, but not the latter. Only one study has followed gynaecological lesions after treatment. It showed no significant change in the adult sandy patches and contact bleeding over a 12-month period, even though urinary egg excretion ceased. The outcome of treatment in the urinary tract has been found to be variable, depending on four factors: (1) the age of patient, (2) the pre-treatment intensity of infection, (3) the degree of fibrosis or calcification, and (4) the site of the lesion.
In younger patients the urinary tract lesions are more responsive to treatment; this may be so in the genital tract as well. Furthermore, the fact that children have symptoms of FGS indicates that it must start early, possibly already in infanthood. However, the optimal timing for curative treatment for girls and novel treatment of adults must still be explored.