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Cervical schistosomiasis, human papilloma virus (HPV), and human immunodeficiency virus (HIV): a dangerous coexistence or coincidence?
Available online at www.sciencedirect.com R
Gynecologic Oncology 90 (2003) 211–214
www.elsevier.com/locate/ygyno
Case Report
Cervical schistosomiasis, human papilloma virus (HPV), and human immunodeficiency virus (HIV): a dangerous coexistence or coincidence? M.B. Mosunjac,* T. Tadros, R. Beach, and B. Majmudar Department of Pathology and Laboratory Medicine, Emory University, Grady Memorial Hospital, Atlanta, GA 30303 USA Received 28 August 2002
Abstract Background. Female genitourinary schistosomiasis (FGS) is widespread in endemic areas causing significant morbidity and mortality. Recent data suggest that FGS of the cervix not only is considered a risk factor for contracting different sexually transmitted diseases (STD), but also plays a significant role in modifying the natural history and immunological response to those infections, in particular HIV and HPV. Case report. A 32-year-old female from Zambia, who was recently diagnosed with HIV and high-grade dysplasia with koilocytosis on cervical Pap smear, underwent cervical conization which confirmed moderate cervical dysplasia and also revealed the presence of viable and nonviable schistosoma eggs in cervical stroma. Four different HPV types were isolated by PCR, including one “low-risk” (type 6) and three “high-risk” types (types 45,56, and 58). Conclusion. The presence of HPV, HIV infection, and cervical schistosomiasis in our patient is likely more than coexistence of multiple agents in the same milieu as cervical schistosomiasis increase susceptibility for other STDs including HIV and HPV. Therefore, in patients with schistosomiasis, immediate treatment for schistosomiasis and additional testing for HIV and HPV is warranted. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Female genital schistosomiasis; Human papilloma virus (HPV); Human immunodeficiency virus (HIV)
Introduction Schistosomiasis is endemic in 43 African countries where it affects up to 40 million people. An estimated 9 –13 million people may have genitourinary schistosomiasis [1] which was first described by Madden in Egypt in 1899 [2]. Female genital schistosomiasis (FGS) is defined as the presence of ova and/or a characteristic pathology in reproductive organs [1]. Approximately 75% of women in endemic areas may have uterine, cervical, vaginal, or vulvar schistosomiasis. Since schistosomiasis is generally confined to its endemic areas, it is exceedingly rare to see cervical schistosomiasis in the USA. New evidence indicates an interaction between HIV infec* Corresponding author. Department of Pathology, Grady Memorial Hospital, 80 Jesse Hill Jr. Dr., Atlanta, GA 30303, USA. Fax: ⫹1-404616-9084. E-mail address: [email protected] (M.B. Mosunjac).
tion and genital schistosomiasis. Possible interference of schistosomiasis with the natural history of HIV infection at different levels including impaired barrier of genital mucosa and modulation of immune responses has been investigated. Therefore, we describe a case of cervical schistosomiasis coexisting with severe squamous dysplasia, HPV, and HIV infection.
Case report A 32-year-old female that recently emigrated from Zambia had a high-grade squamous intraepithelial lesion (moderate squamous dysplasia) on routine Pap smears. On colposcopy a large acetowhite lesion from 3 to 6 o’clock was seen. Cervical biopsy and consecutive cone biopsy of the cervix confirmed moderate squamous dysplasia. Multiple calcified nonviable and viable schistosoma eggs were also identified in the cervical stroma. Past medical history is significant for treatment of pulmonary tuberculosis, malaria,
0090-8258/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0090-8258(03)00191-4
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M.B. Mosunjac et al. / Gynecologic Oncology 90 (2003) 211–214
Fig. 1. (A) PAP smear showing superficial squamous cells containing hyperchromatic enlarged nuclei with coarse chromatin consistent with high-grade dysplasia (1000⫻). (B) Characteristic perinuclear koilocytic halos and binucleation is present which is indicative of viral HPV changes (1000⫻). (C) A single nonspecific round calcification was identified in the PAP smear (1000⫻).
and herpes zoster and genital herpes infection. The patient was recently diagnosed with HIV, contracted through unprotected sex. Clinical examination and pelvic sonography findings were unremarkable. Significant laboratory findings were CD4 count of 208, viral load of 1.26 ⫻ 1000 copies per ml, and WBC counts of 5.0 with 15% of eosinophils. Urine and stool microscopic examinations were negative for ova and parasites. Cytologic findings Pap smear showed high-grade squamous intraepithelial lesion (moderate squamous dysplasia) with numerous single cells showing high nuclear to cytoplasmic ratio and hyperchromatic coarse chromatin (Fig. 1A). Multinucleation and koilocytic change consistent with HPV infection were also identified (Fig. 1B). Single large amorphous calcification was present (Fig. 1C). Histologic findings Cervical biopsies as well as consecutive therapeutic cervical cone biopsy confirmed the Pap smear diagnosis of
moderate squamous dysplasia. The cervical stroma had multiple seemingly unimpressive and nonspecific clusters of microcalcifications. However, on closer microscopic examination, the microcalcifications appeared to be intravenular deposits of calcified nonviable and viable parasitic eggs (Fig. 2A and B). Inside intact shells of viable parasitic eggs, mature miracidia (Fig. 2C) were identified. Occasional foreign-body granulomas were scattered in the stroma around the fragmented calcified eggshells. Sparse inflammatory infiltrate, mainly mononuclear, with occasional eosinophils was present around the granulomas and viable eggs (Fig. 3). Ova were exclusively situated within stroma and the overlying epithelium was spared of parasitic colonization (Fig. 2A). Additional investigation DNA was extracted from two unstained 5-m sections of paraffin embedded tissue block. HPV was detected using L1 consensus PCR and typed using the line blot assay [3]. Four different HPV types were isolated, including one “low-risk” (type 6) and three “high-risk” types (types 45,56, and 58).
Fig. 2. (A) Low power of multiple clustered calcifications in the cervical stroma (200⫻). (B) Calcified nonviable schistosoma egg adjacent to the viable egg with intact shell filled with round regular purple bodies consistent with miracidia (400⫻). (C) High power of two viable schistosoma eggs filled with miracidia (1000⫻).
M.B. Mosunjac et al. / Gynecologic Oncology 90 (2003) 211–214
Fig. 3. Foreign-body giant cell engulfing schistosoma egg particle (1000⫻).
Discussion Schistosomiasis is caused when free-swimming schistosoma embryos or cercarie penetrate skin, travel through pelvic or mesenteric vascular plexus, mature into trematodes, mate, and deposit ova. Most commonly this occurs in the bladder where half of the ova are excreted, develop into miracidia, which infect the fresh water snail, and thus, complete the cycle. The remainder of the eggs die and elicit granulomatous tissue reaction with subsequent fibrosis [1]. Systematic autopsy studies have shown that FGS has been widespread in endemic areas and can affect any genital organ with the cervix being the most common site followed by the vagina and fallopian tubes [3]. Every third case of FGS will affect the cervix. Symptoms associated with cervical schistosomiasis are nonspecific and consist of dysmenorrhea, menorrhagia, leukorrhea, lower abdominal pain, and postcoital bleeding, intermenstrual bleeding, and dyspareunia [4]. Schistosomiasis of the cervix has a heterogeneous appearance colposcopically and can appear as cauliflower-like growths, nodular hypertrophy, ulcerative and polypoid lesions, and so called “sandy patches,” a pathognomonic finding. Schistosoma may exist on a colposcopically normal cervix, but often is found in the vicinity of ulcerations or erosions [3]. Histomorphologically, two distinct patterns of cervical schistosomiasis can be recognized. The type A pattern has an intense inflammatory reaction of plasma cells, lymphocytes, eosinophils, and macrophages around sites of viable egg deposition. The type B pattern consists of a fibrous connective tissue reaction with a minimal cellular infiltrate. This pattern is found in the majority of cases around nonviable eggs or calcified shell fragments, as in our case. In
213
both types, ova are predominantly located at the ecto– endocervical junction [4]. In our patient there was an unusual coexistence of schistosoma, HIV, HPV infection, and cervical dysplasia. Based on clinical, pathophysiological, and immunological studies it has been established that FGS of the cervix can facilitate the infection with other sexually transmitted diseases, and also alter the natural history of such disease including HIV and the oncogenic HPV virus. Several theories are supporting the hypothesis that cervical schistosomiasis may play a pivotal role in HPV-induced cervical carcinoma. It has been postulated that FGS facilitates the implantation of HPV though FGS-associated erosions and ulcerations of the cervical mucosa. There is also evidence that FGS interferes with the physiological mechanisms of HPV clearance and participates in rapid propagation of the virus augmenting the viral load and ultimately aiding in the development of cervical carcinoma [5]. These findings were supported by studies on mice, which indicate that down-regulation of virusspecific cytotoxic lymphocytes may play an important role. However, in the large retrospective study of 4520 cervical carcinomas in Tanzania only 1.7% of all cases revealed an association with schistosoma [6]. The same authors investigated the HPV typing and schistosoma, to show that in the absence of HPV, schistosomiasis is not the oncogenic causative agent for cervical carcinoma [7]. However, the association between schistosomiasis and bladder carcinoma have been well established. A specific model for bladder carcinoma involves not only the presence of schistosoma with fibrosis around the egg deposition but also an additional carcinogen such as nitrosamine [1]. Schistosomiasis of the lower reproductive tract may interfere with the natural history of HIV infection at various levels. Similar to HPV infection, the barrier function of the genital epithelium is impaired, thus allowing the facilitated penetration of HIV virus. Activated inflammatory cells which express CD4 antigen on their surface including Thelper lymphocytes, macrophages, and Langerhans cells provide ample opportunity for HIV virus to bind and initiate infection [8]. Secretion of interferon-␥, IL-2, and TNF-␣ by activated T cells can not only enhance the susceptibility to HIV infection but also increase the permeability between epithelial junctions [9]. In addition, the initial protective effect of cytotoxic T cells and NK cells in early HIV infections may be compromised by schistosoma by its ability to reduce the number and efficacy of NK cells [10,11]. Taken together, genital schistosomiasis facilitates virus adhesion, replication, and systemic spread. Therefore mucosal transmission is more likely to be efficient in FGS as well as faster progression of HIV infection and disease. Clinical history including the emigration from endemic areas should prompt the cytopathologist for a diligent search for egg particles or whole eggs in the Pap smear [12]. The presence of calcifications in the cervix with or without inflammatory and granulomatous reaction should raise the possibility of parasitic infection by schistosoma. Additional
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M.B. Mosunjac et al. / Gynecologic Oncology 90 (2003) 211–214
and serial sectioning is recommended in the search of viable and nonviable eggs. A thorough history about country of origin or even recent travel should be investigated. Once the diagnosis of schistosomiasis is made, the presence of other STDs should be investigated, especially HPV, chlamydia, and Neisseria gonorrhoeae. It has been shown that schistosomiasis of the lower reproductive tract interferes with the natural history of HIV and that women with FGB are at higher risk of contracting HIV. Testing for HIV is therefore recommended, even with the lack of significant risk factors.
Acknowledgment We thank Mr. Brian Allen, fellow at the Centers for Disease Control and Prevention, Atlanta, GA, for performing the HPV assays.
References [1] Poggeensee G, Feldmeier H. Female genital schistosomiasis: facts and hypothesis. Acta Trop 2001;22:193–210. [2] Madden FC. A case of bilharzia of the vagina. Lancet 1899;1:1716. [3] Gelfand M, Ross MD, Blair DM, Weber MC. Distribution and extend of schistosomiasis in female pelvic organs, with special reference to the genital tract, as determined at autopsy. Am J Trop Med Hyg 1971;20:864 –9.
[4] Helling-Giese G, Sjaastad A, Poggensee G, Kjetland EF, Richter J, Chitsulo L, Kumwenda N, Racz P, Roald B, Gundersen SG, Krantz I, Feldmeier H. Female genital schistosomiasis (FGS): relationship between gynecological and histopathological findings. Acta Trop 1996;62:257– 67. [5] Shattock R, Griffin GE, Gorodeski GI. In vitro models of mucosal transmission. Nat Med 2000;6:607. [6] Moubayed P, Lepere JF, Mawakyoma H, Neuvians D. Carcinoma of the uterine cervix and schistosomiasis. Int J Gynecol Obstet 1994;45: 133–9. [7] Moubayed P, Ziehe A, Peters J, Mwakyoma H, Schmidt D. Carcinoma of the uterine cervix associated with schistosomiasis and induced by human papilloma viruses. Int J Gynaecol Obstet 1995;49: 175–9. [8] Mabey D. Interaction between HIV infection and other sexually transmitted disease. Trop Med Int Health 2000;5:A32– 6. [9] Actor JK, Shirai M, Kullberg MC, Buller RM, Sher A, Berzofsky JA. Helminth infection results in decreased virus specific CD8⫹ cytotoxic T-cell and Th 1 cytokine responses as well as delayed virus clearance. Proc Natl Acad Sci USA 1993;90:948 –52. [10] Feldmeier H, Poggensee G, Rohrbach C, de Aguiar Patricio MI, Noguiera Queiroz A. Female genital schistosomiasis and human papilloma virus (HPV) infection: a dangerous relationship. Virus Rev Res 1998;2:119 –21. [11] Mwinzi PNM, Karanja DMS, Colley DG, Orago ASS, Secor WE. Cellular immune responses of schistosomiasis patients are altered by Human Immunodeficiency Virus type-1 co-infection. J Infect Dis 2001;184:488 –96. [12] De Mille PA, Bourquin P, Sun CJ, Kauffman L. Cytologic diagnosis of Schistosoma haematobium in routine cervicovaginal smears. Diagn Cytopathol 1995;13:181–2.
Gynecologic Oncology 90 (2003) 211–214
www.elsevier.com/locate/ygyno
Case Report
Cervical schistosomiasis, human papilloma virus (HPV), and human immunodeficiency virus (HIV): a dangerous coexistence or coincidence? M.B. Mosunjac,* T. Tadros, R. Beach, and B. Majmudar Department of Pathology and Laboratory Medicine, Emory University, Grady Memorial Hospital, Atlanta, GA 30303 USA Received 28 August 2002
Abstract Background. Female genitourinary schistosomiasis (FGS) is widespread in endemic areas causing significant morbidity and mortality. Recent data suggest that FGS of the cervix not only is considered a risk factor for contracting different sexually transmitted diseases (STD), but also plays a significant role in modifying the natural history and immunological response to those infections, in particular HIV and HPV. Case report. A 32-year-old female from Zambia, who was recently diagnosed with HIV and high-grade dysplasia with koilocytosis on cervical Pap smear, underwent cervical conization which confirmed moderate cervical dysplasia and also revealed the presence of viable and nonviable schistosoma eggs in cervical stroma. Four different HPV types were isolated by PCR, including one “low-risk” (type 6) and three “high-risk” types (types 45,56, and 58). Conclusion. The presence of HPV, HIV infection, and cervical schistosomiasis in our patient is likely more than coexistence of multiple agents in the same milieu as cervical schistosomiasis increase susceptibility for other STDs including HIV and HPV. Therefore, in patients with schistosomiasis, immediate treatment for schistosomiasis and additional testing for HIV and HPV is warranted. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Female genital schistosomiasis; Human papilloma virus (HPV); Human immunodeficiency virus (HIV)
Introduction Schistosomiasis is endemic in 43 African countries where it affects up to 40 million people. An estimated 9 –13 million people may have genitourinary schistosomiasis [1] which was first described by Madden in Egypt in 1899 [2]. Female genital schistosomiasis (FGS) is defined as the presence of ova and/or a characteristic pathology in reproductive organs [1]. Approximately 75% of women in endemic areas may have uterine, cervical, vaginal, or vulvar schistosomiasis. Since schistosomiasis is generally confined to its endemic areas, it is exceedingly rare to see cervical schistosomiasis in the USA. New evidence indicates an interaction between HIV infec* Corresponding author. Department of Pathology, Grady Memorial Hospital, 80 Jesse Hill Jr. Dr., Atlanta, GA 30303, USA. Fax: ⫹1-404616-9084. E-mail address: [email protected] (M.B. Mosunjac).
tion and genital schistosomiasis. Possible interference of schistosomiasis with the natural history of HIV infection at different levels including impaired barrier of genital mucosa and modulation of immune responses has been investigated. Therefore, we describe a case of cervical schistosomiasis coexisting with severe squamous dysplasia, HPV, and HIV infection.
Case report A 32-year-old female that recently emigrated from Zambia had a high-grade squamous intraepithelial lesion (moderate squamous dysplasia) on routine Pap smears. On colposcopy a large acetowhite lesion from 3 to 6 o’clock was seen. Cervical biopsy and consecutive cone biopsy of the cervix confirmed moderate squamous dysplasia. Multiple calcified nonviable and viable schistosoma eggs were also identified in the cervical stroma. Past medical history is significant for treatment of pulmonary tuberculosis, malaria,
0090-8258/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0090-8258(03)00191-4
212
M.B. Mosunjac et al. / Gynecologic Oncology 90 (2003) 211–214
Fig. 1. (A) PAP smear showing superficial squamous cells containing hyperchromatic enlarged nuclei with coarse chromatin consistent with high-grade dysplasia (1000⫻). (B) Characteristic perinuclear koilocytic halos and binucleation is present which is indicative of viral HPV changes (1000⫻). (C) A single nonspecific round calcification was identified in the PAP smear (1000⫻).
and herpes zoster and genital herpes infection. The patient was recently diagnosed with HIV, contracted through unprotected sex. Clinical examination and pelvic sonography findings were unremarkable. Significant laboratory findings were CD4 count of 208, viral load of 1.26 ⫻ 1000 copies per ml, and WBC counts of 5.0 with 15% of eosinophils. Urine and stool microscopic examinations were negative for ova and parasites. Cytologic findings Pap smear showed high-grade squamous intraepithelial lesion (moderate squamous dysplasia) with numerous single cells showing high nuclear to cytoplasmic ratio and hyperchromatic coarse chromatin (Fig. 1A). Multinucleation and koilocytic change consistent with HPV infection were also identified (Fig. 1B). Single large amorphous calcification was present (Fig. 1C). Histologic findings Cervical biopsies as well as consecutive therapeutic cervical cone biopsy confirmed the Pap smear diagnosis of
moderate squamous dysplasia. The cervical stroma had multiple seemingly unimpressive and nonspecific clusters of microcalcifications. However, on closer microscopic examination, the microcalcifications appeared to be intravenular deposits of calcified nonviable and viable parasitic eggs (Fig. 2A and B). Inside intact shells of viable parasitic eggs, mature miracidia (Fig. 2C) were identified. Occasional foreign-body granulomas were scattered in the stroma around the fragmented calcified eggshells. Sparse inflammatory infiltrate, mainly mononuclear, with occasional eosinophils was present around the granulomas and viable eggs (Fig. 3). Ova were exclusively situated within stroma and the overlying epithelium was spared of parasitic colonization (Fig. 2A). Additional investigation DNA was extracted from two unstained 5-m sections of paraffin embedded tissue block. HPV was detected using L1 consensus PCR and typed using the line blot assay [3]. Four different HPV types were isolated, including one “low-risk” (type 6) and three “high-risk” types (types 45,56, and 58).
Fig. 2. (A) Low power of multiple clustered calcifications in the cervical stroma (200⫻). (B) Calcified nonviable schistosoma egg adjacent to the viable egg with intact shell filled with round regular purple bodies consistent with miracidia (400⫻). (C) High power of two viable schistosoma eggs filled with miracidia (1000⫻).
M.B. Mosunjac et al. / Gynecologic Oncology 90 (2003) 211–214
Fig. 3. Foreign-body giant cell engulfing schistosoma egg particle (1000⫻).
Discussion Schistosomiasis is caused when free-swimming schistosoma embryos or cercarie penetrate skin, travel through pelvic or mesenteric vascular plexus, mature into trematodes, mate, and deposit ova. Most commonly this occurs in the bladder where half of the ova are excreted, develop into miracidia, which infect the fresh water snail, and thus, complete the cycle. The remainder of the eggs die and elicit granulomatous tissue reaction with subsequent fibrosis [1]. Systematic autopsy studies have shown that FGS has been widespread in endemic areas and can affect any genital organ with the cervix being the most common site followed by the vagina and fallopian tubes [3]. Every third case of FGS will affect the cervix. Symptoms associated with cervical schistosomiasis are nonspecific and consist of dysmenorrhea, menorrhagia, leukorrhea, lower abdominal pain, and postcoital bleeding, intermenstrual bleeding, and dyspareunia [4]. Schistosomiasis of the cervix has a heterogeneous appearance colposcopically and can appear as cauliflower-like growths, nodular hypertrophy, ulcerative and polypoid lesions, and so called “sandy patches,” a pathognomonic finding. Schistosoma may exist on a colposcopically normal cervix, but often is found in the vicinity of ulcerations or erosions [3]. Histomorphologically, two distinct patterns of cervical schistosomiasis can be recognized. The type A pattern has an intense inflammatory reaction of plasma cells, lymphocytes, eosinophils, and macrophages around sites of viable egg deposition. The type B pattern consists of a fibrous connective tissue reaction with a minimal cellular infiltrate. This pattern is found in the majority of cases around nonviable eggs or calcified shell fragments, as in our case. In
213
both types, ova are predominantly located at the ecto– endocervical junction [4]. In our patient there was an unusual coexistence of schistosoma, HIV, HPV infection, and cervical dysplasia. Based on clinical, pathophysiological, and immunological studies it has been established that FGS of the cervix can facilitate the infection with other sexually transmitted diseases, and also alter the natural history of such disease including HIV and the oncogenic HPV virus. Several theories are supporting the hypothesis that cervical schistosomiasis may play a pivotal role in HPV-induced cervical carcinoma. It has been postulated that FGS facilitates the implantation of HPV though FGS-associated erosions and ulcerations of the cervical mucosa. There is also evidence that FGS interferes with the physiological mechanisms of HPV clearance and participates in rapid propagation of the virus augmenting the viral load and ultimately aiding in the development of cervical carcinoma [5]. These findings were supported by studies on mice, which indicate that down-regulation of virusspecific cytotoxic lymphocytes may play an important role. However, in the large retrospective study of 4520 cervical carcinomas in Tanzania only 1.7% of all cases revealed an association with schistosoma [6]. The same authors investigated the HPV typing and schistosoma, to show that in the absence of HPV, schistosomiasis is not the oncogenic causative agent for cervical carcinoma [7]. However, the association between schistosomiasis and bladder carcinoma have been well established. A specific model for bladder carcinoma involves not only the presence of schistosoma with fibrosis around the egg deposition but also an additional carcinogen such as nitrosamine [1]. Schistosomiasis of the lower reproductive tract may interfere with the natural history of HIV infection at various levels. Similar to HPV infection, the barrier function of the genital epithelium is impaired, thus allowing the facilitated penetration of HIV virus. Activated inflammatory cells which express CD4 antigen on their surface including Thelper lymphocytes, macrophages, and Langerhans cells provide ample opportunity for HIV virus to bind and initiate infection [8]. Secretion of interferon-␥, IL-2, and TNF-␣ by activated T cells can not only enhance the susceptibility to HIV infection but also increase the permeability between epithelial junctions [9]. In addition, the initial protective effect of cytotoxic T cells and NK cells in early HIV infections may be compromised by schistosoma by its ability to reduce the number and efficacy of NK cells [10,11]. Taken together, genital schistosomiasis facilitates virus adhesion, replication, and systemic spread. Therefore mucosal transmission is more likely to be efficient in FGS as well as faster progression of HIV infection and disease. Clinical history including the emigration from endemic areas should prompt the cytopathologist for a diligent search for egg particles or whole eggs in the Pap smear [12]. The presence of calcifications in the cervix with or without inflammatory and granulomatous reaction should raise the possibility of parasitic infection by schistosoma. Additional
214
M.B. Mosunjac et al. / Gynecologic Oncology 90 (2003) 211–214
and serial sectioning is recommended in the search of viable and nonviable eggs. A thorough history about country of origin or even recent travel should be investigated. Once the diagnosis of schistosomiasis is made, the presence of other STDs should be investigated, especially HPV, chlamydia, and Neisseria gonorrhoeae. It has been shown that schistosomiasis of the lower reproductive tract interferes with the natural history of HIV and that women with FGB are at higher risk of contracting HIV. Testing for HIV is therefore recommended, even with the lack of significant risk factors.
Acknowledgment We thank Mr. Brian Allen, fellow at the Centers for Disease Control and Prevention, Atlanta, GA, for performing the HPV assays.
References [1] Poggeensee G, Feldmeier H. Female genital schistosomiasis: facts and hypothesis. Acta Trop 2001;22:193–210. [2] Madden FC. A case of bilharzia of the vagina. Lancet 1899;1:1716. [3] Gelfand M, Ross MD, Blair DM, Weber MC. Distribution and extend of schistosomiasis in female pelvic organs, with special reference to the genital tract, as determined at autopsy. Am J Trop Med Hyg 1971;20:864 –9.
[4] Helling-Giese G, Sjaastad A, Poggensee G, Kjetland EF, Richter J, Chitsulo L, Kumwenda N, Racz P, Roald B, Gundersen SG, Krantz I, Feldmeier H. Female genital schistosomiasis (FGS): relationship between gynecological and histopathological findings. Acta Trop 1996;62:257– 67. [5] Shattock R, Griffin GE, Gorodeski GI. In vitro models of mucosal transmission. Nat Med 2000;6:607. [6] Moubayed P, Lepere JF, Mawakyoma H, Neuvians D. Carcinoma of the uterine cervix and schistosomiasis. Int J Gynecol Obstet 1994;45: 133–9. [7] Moubayed P, Ziehe A, Peters J, Mwakyoma H, Schmidt D. Carcinoma of the uterine cervix associated with schistosomiasis and induced by human papilloma viruses. Int J Gynaecol Obstet 1995;49: 175–9. [8] Mabey D. Interaction between HIV infection and other sexually transmitted disease. Trop Med Int Health 2000;5:A32– 6. [9] Actor JK, Shirai M, Kullberg MC, Buller RM, Sher A, Berzofsky JA. Helminth infection results in decreased virus specific CD8⫹ cytotoxic T-cell and Th 1 cytokine responses as well as delayed virus clearance. Proc Natl Acad Sci USA 1993;90:948 –52. [10] Feldmeier H, Poggensee G, Rohrbach C, de Aguiar Patricio MI, Noguiera Queiroz A. Female genital schistosomiasis and human papilloma virus (HPV) infection: a dangerous relationship. Virus Rev Res 1998;2:119 –21. [11] Mwinzi PNM, Karanja DMS, Colley DG, Orago ASS, Secor WE. Cellular immune responses of schistosomiasis patients are altered by Human Immunodeficiency Virus type-1 co-infection. J Infect Dis 2001;184:488 –96. [12] De Mille PA, Bourquin P, Sun CJ, Kauffman L. Cytologic diagnosis of Schistosoma haematobium in routine cervicovaginal smears. Diagn Cytopathol 1995;13:181–2.