RESUMO
In this article the present recommendations for immunization of adult patients who received hematopoietic stem cell transplantation -a common procedure in therapy of many types of hematological diseases and serious inborn defects of the immune system- are reviewed and discussed. Patients that undergo this kind of transplantation procedure exhibit, compared to the general population, an elevated susceptibility of immune-preventable infections, due to loss of the humoral and cellular protective immunity. A revaccination strategy for transplanted patients can result in a significant diminution of morbidity and mortality related to the treatment of these diseases. Few data are published about the duration and magnitude of the vaccination response in this specific population of patients. Moreover, deviation from international guidelines recommendations for post-transplant immune prophylaxis can be observed frequently, partly as a result of the absence of specific vaccines in some countries. Multiple factors as intensity of the pharmacologic immune suppression, myeloablative regimen, administration of monoclonal and polyclonal antibodies, duration of the post-transplant period or the presence of graft-versus-host disease (GVHD), can influence the immune response and establish special considerations for certain biological agents, as observed in case of living attenuated virus composed vaccines. This conditions are responsible for the fact that an optimal time point for vaccination of transplanted patients remains not clearly defined. More specific studies about the underlying immunological mechanisms during immunocompromised periods are necessary to understand better the immunogenicity and security of existing vaccines. The development of innovative vaccines as well can induce certain advances in the post-transplant therapy.
El presente artículo revisa las recomendaciones actuales para la inmunización de pacientes adultos que han recibido trasplante de células madre hematopoyéticas, procedimiento común en la terapia de muchas patologías hematológicas y defectos congénitos del sistema inmune. Los pacientes que reciben este tipo de tratamiento son más susceptibles a infecciones inmunoprevenibles que la población general debido a la pérdida de la inmunidad protectora tanto humoral como celular con posterioridad al trasplante. De esta manera, la revacunación de los receptores de trasplante representa una estrategia importante para reducir la morbilidad y mortalidad asociadas con esas enfermedades. Sin embargo, se conoce poco sobre la duración y magnitud de la respuesta inmunológica generada por las vacunas en esta población. Además, aunque existen guías internacionales consensuadas en inmunoprofilaxis post-trasplante, frecuentemente ocurren desviaciones en las prácticas recomendadas por múltiples motivos, incluyendo la no disponibilidad de ciertas vacunas en algunos sistemas de salud. Factores como la intensidad de la inmunosupresión farmacológica, el régimen mieloablativo empleado, la administración de anticuerpos monoclonales y policlonales, la duración de la fase neutropénica en el período posterior al trasplante y la presencia de enfermedad injerto versus hospedero (graft-versus-host disease, GVHD) pueden influenciar la respuesta inmunitaria y establecer consideraciones especiales para ciertos agentes como es el caso de las vacunas compuestas por virus vivos atenuados. Estas condiciones contribuyen a que el momento oportuno de inicio de las inmunizaciones en los receptores de trasplante aún no se encuentre bien definido. Se requieren más estudios específicos acerca de los mecanismos inmunológicos subyacentes durante los estados de inmunocompromiso para entender mejor la inmunogenicidad y seguridad de las vacunas existentes en dichos contextos. El desarrollo de vacunas innovadoras puede también inducir avances en la terapia post-trasplante.
Assuntos
Humanos , Feminino , Adulto , Vacinas Bacterianas/administração & dosagem , Vacinas Virais/administração & dosagem , Esquemas de Imunização , Vacinação/métodos , Transplante de Células-Tronco Hematopoéticas , Costa RicaRESUMO
In this article the present recommendations for immunization of adult patients who received hematopoietic stem cell transplantation -a common procedure in therapy of many types of hematological diseases and serious inborn defects of the immune system- are reviewed and discussed. Patients that undergo this kind of transplantation procedure exhibit, compared to the general population, an elevated susceptibility of immune-preventable infections, due to loss of the humoral and cellular protective immunity. A revaccination strategy for transplanted patients can result in a significant diminution of morbidity and mortality related to the treatment of these diseases. Few data are published about the duration and magnitude of the vaccination response in this specific population of patients. Moreover, deviation from international guidelines recommendations for post-transplant immune prophylaxis can be observed frequently, partly as a result of the absence of specific vaccines in some countries. Multiple factors as intensity of the pharmacologic immune suppression, myeloablative regimen, administration of monoclonal and polyclonal antibodies, duration of the post-transplant period or the presence of graft-versus-host disease (GVHD), can influence the immune response and establish special considerations for certain biological agents, as observed in case of living attenuated virus composed vaccines. This conditions are responsible for the fact that an optimal time point for vaccination of transplanted patients remains not clearly defined. More specific studies about the underlying immunological mechanisms during immunocompromised periods are necessary to understand better the immunogenicity and security of existing vaccines. The development of innovative vaccines as well can induce certain advances in the post-transplant therapy.
Assuntos
Vacinas Bacterianas/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Esquemas de Imunização , Vacinação/métodos , Vacinas Virais/administração & dosagem , Adulto , Costa Rica , Feminino , HumanosRESUMO
Driven by findings that human papillomavirus (HPV)-induced degradation of p53 differs by a TP53 polymorphism at codon 72 (Pro72Arg), past studies of TP53 genetic variants and cervical cancer have focused on this nonsynonymous polymorphism, with mixed results. We analyzed common single nucleotide polymorphisms (SNP) across the TP53 locus in a population-based nested case-control study in Guanacaste, Costa Rica. We evaluated 11 SNPs, including Pro72Arg (rs1042522), among 1,281 women: 465 with cervical intraepithelial neoplasia grade 3/cancer (CIN3+), 380 with HPV persistence (median, 25 months), and 436 random population controls. We combined HPV persistence and CIN3+ into one case group because they did not differ in TP53 genotypic frequencies and calculated odds ratios and 95% confidence intervals (CI) for individual SNPs and inferred haplotypes. We observed that proline at codon 72 was associated with increased risk of CIN3+/persistence compared with population controls. Relative to GG (Arg), the CG (Pro/Arg) and CC (Pro) genotypes had a 1.3-fold (95% CI, 0.99-1.6) and 1.8-fold (95% CI, 1.2-2.7) increased risk, respectively (P(trend) < 0.01). rs12951053 and rs1642785 were also associated with CIN3+/persistence (P (trend), 0.05 and 0.04, respectively), as was a haplotype containing the codon 72 variant (rs1042522), rs12951053, rs1642785, and rs12947788 (odds ratio, 1.6; 95% CI, 1.1-2.3 versus the most common haplotype, which comprised the major alleles for all 11 SNPs). Although genetic variation in TP53 might affect the natural history of HPV and cervical cancer, further work is needed to elucidate the possible mechanism.
Assuntos
Variação Genética , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Polimorfismo de Nucleotídeo Único , Proteína Supressora de Tumor p53/genética , Displasia do Colo do Útero/genética , Adulto , Alelos , Estudos de Casos e Controles , Códon , Costa Rica , Progressão da Doença , Feminino , Genótipo , Humanos , Modelos Logísticos , RiscoRESUMO
BACKGROUND: We examined host genetic factors to identify those more common in individuals whose human papillomavirus (HPV) infections were most likely to persist and progress to cervical intraepithelial neoplasia grade 3 (CIN3) and cancer. METHODS: We genotyped 92 single-nucleotide polymorphisms (SNPs) from 49 candidate immune response and DNA repair genes obtained from 469 women with CIN3 or cancer, 390 women with persistent HPV infections (median duration, 25 months), and 452 random control subjects from the 10,049-woman Guanacaste Costa Rica Natural History Study. We calculated odds ratios and 95% confidence intervals (CIs) for the association of SNP and haplotypes in women with CIN3 or cancer and HPV persistence, compared with random control subjects. RESULTS: A SNP in the Fanconi anemia complementation group A gene (FANCA) (G501S) was associated with increased risk of CIN3 or cancer. The AG and GG genotypes had a 1.3-fold (95% CI, 0.95-1.8-fold) and 1.7-fold (95% CI, 1.1-2.6-fold) increased risk for CIN3 or cancer, respectively (P(trend) = .008; referent, AA). The FANCA haplotype that included G501S also conferred increased risk of CIN3 or cancer, as did a different haplotype that included 2 other FANCA SNPs (G809A and T266A). A SNP in the innate immune gene IRF3 (S427T) was associated with increased risk for HPV persistence (P(trend) = .009). CONCLUSIONS: Our results require replication but support the role of FANCA variants in cervical cancer susceptibility and of IRF3 in HPV persistence.
Assuntos
Reparo do DNA/genética , Infecções por Papillomavirus/epidemiologia , Polimorfismo de Nucleotídeo Único , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/genética , Estudos de Coortes , Costa Rica/epidemiologia , Sondas de DNA de HPV , DNA Viral/isolamento & purificação , Proteínas de Ligação a DNA/genética , Progressão da Doença , Exodesoxirribonucleases/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , NADPH Oxidases/genética , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/fisiopatologia , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
The objective of this analysis was to compare the performance characteristics of two human papillomavirus (HPV) DNA detections assays, the Hybrid Capture 2 assay (HC2) and the SPF(10) assay, for the detection of carcinogenic HPV. Data are from the enrollment visits of women who participated in the randomized, double-blind, placebo-controlled phase III HPV16/18 Vaccine Trial in Guanacaste, Costa Rica. We compared the results of HC2 and SPF(10) testing of cervical specimens. Since the line probe assay (LiPA) detection system does not distinguish between HPV type 68 (HPV68; which is targeted by HC2) and HPV73 (which is not targeted by HC2), for SPF(10)-LiPA, we defined the carcinogenic HPV types as the 12 HC2-targeted types (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59), HPV68/73, and the HC2-cross-reactive, carcinogenic type HPV66. The kappa values and the performance characteristics for the detection of cervical abnormalities were ascertained. Paired observations were available for 5,683 sexually active, young women (median age, 21 years). The prevalence of carcinogenic HPV types was 35% (n=1,962) by HC2 and 35% (n=2,003) by SPF(10)-LiPA. There were no differences in the prevalence of carcinogenic HPV types by HC2 and SPF(10)-LiPA among women with normal, atypical squamous cells of undetermined significance and high-grade squamous intraepithelial lesion cytology. Among women with low-grade squamous intraepithelial lesion cytology, HC2 was more likely to test positive than SPF(10)-LiPA for the carcinogenic HPV types (87% and 79%, respectively; P=0.001) as a result of HC2 cross-reactivity with HPV types 40, 43, 44, 53, 54, 60, 70, and 74. The crude agreement between the two assays was 88%, with a kappa value of 0.75 (95% confidence limits, 0.73 to 0.76). We observed very good agreement between HC2 and SPF(10)-LiPA for carcinogenic HPV type detection.
Assuntos
DNA Viral/isolamento & purificação , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Hibridização de Ácido Nucleico/métodos , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/virologia , Adolescente , Adulto , Costa Rica/epidemiologia , Feminino , Genótipo , Humanos , Infecções por Papillomavirus/epidemiologia , Sensibilidade e Especificidade , Neoplasias do Colo do Útero/epidemiologiaRESUMO
Persistent cervical infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical cancer. Cytologic abnormalities are the manifestations of HPV infections used to identify women at risk. To compare the potential of the full range of anogenital HPV genotypes to induce cytopathic effects, we examined the influences of HPV type, viral load, and age on cytopathology among 1,222 women having a single HPV type at enrollment into a 10,000-woman population-based study in Costa Rica. Cervical specimens were tested for approximately 40 HPV types by MY09/MY11 L1 primer PCR and type-specific dot blot hybridization. Types were organized by phylogenetic species and cancer risk. PCR signal strength served as a qualitative surrogate for viral load. Overall, 24.8% [95% confidence interval (95% CI), 22.4-27.3] of single prevalent HPV infections had concurrent abnormalities (atypical squamous cells or worse) ranging from 0.0% to 80.0% based on HPV type. Noncarcinogenic alpha3/alpha15 types, although highly prevalent, uncommonly caused cytologic abnormalities (13.1%; 95% CI, 9.8-17.0). In contrast, one quarter to nearly one half of infections with a single major carcinogenic species type (alpha9/alpha11/alpha7/alpha5/alpha6) produced abnormalities. Greater abnormalities were observed with increasing qualitative viral load of carcinogenic types; fewer abnormalities were observed among older women (>54 years). A high percentage (46.2%) of detected abnormalities in women infected with HPV16 or related alpha9 types were high grade or worse, consistent with strong carcinogenicity, compared with 10.7% in women infected with alpha7 types, including HPV18, a major cause of adenocarcinoma. The lack of evident severe abnormalities associated with HPV18 and related HPV types might have implications for screening for poorly detected glandular and alpha7-related lesions.
Assuntos
Papillomaviridae/classificação , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Doenças do Colo do Útero/patologia , Doenças do Colo do Útero/virologia , Adulto , Fatores Etários , Colo do Útero/patologia , Colo do Útero/virologia , Estudos de Coortes , Costa Rica/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Doenças do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Carga Viral , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologiaRESUMO
Approximately 15 human papillomavirus (HPV) types cause virtually all cervical cancer whereas other HPV types are unrelated to cancer. We were interested in whether some noncarcinogenic types differ from carcinogenic in their affinity for the cervical transformation zone, where nearly all HPV-induced cancers occur. To examine this possibility, we tested cervical specimens from 8,374 women without cervical precancer and cancer participating in a population-based study in Guanacaste for >40 HPV types using PCR. We compared age-group specific prevalences of HPV types of the alpha9 species, which are mainly carcinogenic and include HPV16, to the genetically distinct types of the alpha3/alpha15 species (e.g., HPV71), which are noncarcinogenic and common in vaginal specimens from hysterectomized women. We related HPV detection of each group to the location of the junction between the squamous epithelium of the ectocervix and vagina and the columnar epithelium of the endocervical canal. Models evaluated the independent effects of amount of exposed columnar epithelium (ectopy) and age on the presence of alpha9 or alpha3/alpha15 types. Prevalence of alpha9 types (7.6%) peaked in the youngest women, declined in middle-aged women, and then increased slightly in older women. By contrast, prevalence of alpha3/alpha15 types (7.6%) tended to remain invariant or to increase with increasing age. Detection of alpha9 infections increased (P(trend) < 0.0005) but alpha3/alpha15 infections decreased (P(trend) < 0.0005) with increasing exposure of the columnar epithelia. Older age and decreasing cervical ectopy were independently positively associated with having an alpha3/alpha15 infection compared with having an alpha9 infection. These patterns need to be confirmed in other studies and populations. We suggest that these genetically distinct groups of HPV types may differ in tissue preferences, which may contribute to their differences in carcinogenic potential.
Assuntos
Papillomaviridae/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Neoplasias do Colo do Útero/virologia , Adulto , Fatores Etários , Idoso , Transformação Celular Neoplásica , Costa Rica/epidemiologia , DNA Viral/análise , Estudos Epidemiológicos , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Lesões Pré-Cancerosas , Prevalência , Vagina/virologiaRESUMO
Human leukocyte antigen (HLA) variations may affect immune response to human papillomavirus infection and subsequent cervical neoplasia risk. We investigated the frequency and relationship between HLA-A-B and HLA-A-B-DR haplotypes among women with cervical cancer/high-grade lesions (n=365) and cytologically normal population controls (n=681) within three cervical neoplasia studies in the US and Costa Rica. Notable differences in haplotype frequencies were observed; the HLA-A*01-B*08 haplotype occurred in >5% of US Caucasians but in <1% of Costa Ricans. The most prevalent HLA-A*24-B*40-DR*04 haplotype in Costa Rica (5%) was found in <1% of US Caucasians. No HLA haplotype was significantly associated with cervical neoplasia, suggesting that individual allele associations reported to date (e.g. HLA-DR*13) are not likely explained by underlying haplotypes.
Assuntos
Antígenos HLA/genética , Haplótipos/genética , Displasia do Colo do Útero/genética , Neoplasias do Colo do Útero/genética , Costa Rica , Feminino , Predisposição Genética para Doença/genética , Antígenos HLA/imunologia , Haplótipos/imunologia , Humanos , Papillomaviridae/imunologia , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/imunologia , Fatores de Risco , Estados Unidos , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/imunologia , Displasia do Colo do Útero/virologiaRESUMO
BACKGROUND: Detailed epidemiologic studies of cervical type-specific human papillomavirus (HPV) infection in large populations are scarce. METHODS: We recruited a population-based cohort in Guanacaste, Costa Rica. Participants were interviewed, screened for cervical neoplasia, and tested for >40 HPV types by use of MY09/11 L1 consensus primer polymerase chain reaction. We estimated the risk factors for infection and the associations between type-specific HPV infections and cervical intraepithelial neoplasia (CIN) and cancer in 8514 sexually active women who had not undergone a hysterectomy. RESULTS: The overall HPV prevalence was 26.5%. The most common type was HPV-16 (3.6% of the population). HPV prevalence showed a U-shaped age-specific curve. Sexual behaviors were the main determinants of oncogenic and nononcogenic infections; age at first sexual intercourse was not independently associated with infection. Barrier contraceptive use was somewhat protective against infection. Oncogenic infections were strongly associated with risk of all grades of CIN and of cancer. Types 16, 18, and 58 were the most common in women diagnosed with CIN3 and cancer. Except for those that included HPV-16, multiple-type infections were associated with an increased risk (compared with that for single-type infections) of all grades of CIN and of cancer. CONCLUSIONS: We confirmed the bimodal age pattern of HPV infection in Guanacaste and the sexually transmitted nature of both oncogenic and nononcogenic HPV types.
Assuntos
Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Adulto , Fatores Etários , Idoso , Costa Rica/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Papillomaviridae/classificação , Infecções por Papillomavirus/complicações , Prevalência , Fatores de Risco , Neoplasias do Colo do Útero/virologiaRESUMO
BACKGROUND: Cross-sectional human papillomavirus (HPV) DNA prevalence peaks at young ages, reflecting sexual acquisition and typically rapid clearance. In some populations, HPV prevalence demonstrates a second peak in older women. Longitudinal data may help to explain this second peak. METHODS: We followed a population-based cohort of 7237 women in Guanacaste, Costa Rica, in which we had previously observed a second peak in the baseline HPV prevalence in older women. We tested for >40 HPV types by polymerase chain reaction. We analyzed age-specific patterns of acquisition and persistence 5-7 years after enrollment for individual HPV types. RESULTS: At enrollment and follow-up, cross-sectional data revealed U-shaped age-specific HPV prevalence curves for virtually every type, with higher prevalences in the younger and older women than in the middle-aged women. Prospectively, acquisition of types decreased significantly as women aged (PTrend<.05, for both), with the highest peak in young women and a secondary minor peak in older women. Type-specific persistence of HPV increased with age (PTrend<.0001). Overall, HPV acquisition predominated at younger ages, whereas persistent infections gradually became more prominent with age (PTrend<.0001). CONCLUSIONS: Newly apparent infections decreased, whereas persistence increased, with age; this latter tendency supports the utility of HPV screening in older women.
Assuntos
Colo do Útero/virologia , Papillomaviridae , Infecções por Papillomavirus/epidemiologia , Adulto , Fatores Etários , Idoso , Costa Rica/epidemiologia , Estudos Transversais , Feminino , Humanos , Prevalência , Estudos ProspectivosRESUMO
Determinants of human papillomavirus (HPV)-16 serological conversion and persistence were assessed in a population-based cohort of 10 049 women in Guanacaste, Costa Rica. Serologic responses to HPV-16 were measured in 7986 women by VLP-based enzyme-linked immunosorbent assay at both study enrollment (1993/94) and at 5-7 years of follow-up. Seropositive women were defined as >/=5 standard deviations above the mean optical density obtained for studied virgins at enrollment (n=573). Seroconnversion (n=409), persistence (n=675), and clearance (n=541) were defined based on enrollment and follow-up serology measurements. Age-specific distributions revealed that HPV-16 seroconversion was highest among 18- to 24-year-old women, steadily declining with age; HPV-16 seropersistence was lowest in women 65+ years. In age-adjusted multivariate logistic regression models, a 10-fold risk increase for HPV-16 seroconversion was associated with HPV-16 DNA detection at enrollment and follow-up; two-fold risk of seroconversion to HPV-16 was associated with increased numbers of lifetime and recent sexual partners and smoking status. Determinants of HPV-16 seropersistence included a 1.5-fold risk increase associated with having one sexual partner during follow-up, former oral contraceptive use, and a 3-fold risk increase associated with HPV-16 DNA detection at both enrollment and follow-up. Higher HPV-16 viral load at enrollment was associated with seroconversion, and higher antibody titres at enrollment were associated with seropersistence.
Assuntos
DNA Viral/análise , Modelos Teóricos , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Neoplasias do Colo do Útero/virologia , Adolescente , Adulto , Idoso , Anticorpos Antivirais/análise , Estudos de Coortes , Anticoncepcionais Orais , Costa Rica , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Testes Sorológicos , Comportamento SexualRESUMO
Due to the high prevalence of cancer-associated types of human papillomavirus (HPV) and the poorly reproducible histologic classification of low-grade lesions, identifying infected women at highest risk for cancer prior to neoplastic progression remains a challenge. We therefore explored the utility of p16INK4a immunostaining as a potential diagnostic and prognostic biomarker for cervical neoplasia using paraffin-embedded tissue blocks (punch biopsies and loop electrosurgical excision procedures) obtained from women referred to colposcopy during the enrollment phase of the Guanacaste Project (1993 to 1994). All blocks from 292 women selected by HPV status (HPV negative, nononcogenic HPV positive, or oncogenic HPV positive) and representing the diagnostic spectrum of the population [normal to precancer: cervical intraepithelial neoplasia (CIN) 3] were immunostained for p16INK4a using the p16INK4a research kit based on the monoclonal antibody clone E6H4 (MTM Laboratories, Heidelberg, Germany). For CIN3, the sensitivity of diffuse p16INK4a immunostaining was 100% and the specificity was 95%. For CIN2, the sensitivity and specificity for diffuse staining were 81.1% and 95.4%, respectively. Generalized to the 10,000-woman cohort, this translated to positive predictive value and negative predictive value of 13.9% and 100% for CIN3, respectively, and 20.4% and 99.7% for CIN2 or CIN3, respectively. Of women with an initial diagnosis of less than CIN2 for whom follow-up data for up to 5 to 7 years were available, 44% with diffuse staining developed persistent infection (CIN2 or CIN3). Whereas our data support the diagnostic potential for p16INK4a, further prospective studies with detailed follow-up determining the prognostic capacity of this marker are needed.
Assuntos
Biomarcadores Tumorais/análise , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/patologia , Adolescente , Adulto , Estudos de Casos e Controles , Colo do Útero/patologia , Colo do Útero/virologia , Estudos de Coortes , Colposcopia/métodos , Costa Rica/epidemiologia , DNA Viral/análise , Feminino , Humanos , Imuno-Histoquímica , Incidência , Indicadores e Reagentes , Pessoa de Meia-Idade , Infecções por Papillomavirus/epidemiologia , Medição de Risco , Sensibilidade e Especificidade , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologia , Esfregaço Vaginal , Displasia do Colo do Útero/epidemiologia , Displasia do Colo do Útero/virologiaRESUMO
OBJECTIVE: The Guanacaste study ("Guanacaste Project," or GP), was designed to investigate the role of human papillomavirus (HPV) infection and its cofactors in the development of cervical neoplasia and to evaluate new cervical cancer screening technologies. The follow-up phase of the GP was designed to study why a small proportion of women infected with HPV develop cervical intraepithelial neoplasia grade 2 (CIN 2), CIN 3, or cancer (these three together are globally referred to as > or = CIN 2, that is, CIN 2 or worse). The purpose of this article is to describe this prospective study in detail and to present the preliminary findings regarding the incidence of cervical neoplasia. METHODS: A cohort of 10 049 randomly selected women from 18 to 97 years old from Guanacaste, a province in northwestern Costa Rica, was intensively screened in 1993-1994 and then followed up for seven years after being enrolled. A questionnaire for demographic and risk factors was administered, and a pelvic examination was performed on sexually active women at each follow-up visit in order to obtain samples for screening tests and for research purposes. The final diagnosis given at the end of the enrollment phase categorized women into several groups according to the perceived risk of their developing either high-grade precursors of cancer or cancer. These groups were followed up at different intervals according to the risk of developing > or = CIN 2. The most active follow-up (every 6-12 months) was concentrated on the women most likely to develop >or = CIN 2, based on cytology (n = 492). The remainder of the cohort was followed either annually (n = 2 574) or after five to seven years of passive follow-up (n = 3 926). All women with possibly severe lesions detected by any technique were referred to colposcopy for further evaluation and treatment, and they were also censored from the study. Lesions >or = CIN 2 served as both the censoring outcome and our surrogate for cancer risk. RESULTS: Participation during follow-up was high (near 90%). Suspected > or = CIN 2 by any screening technique censored 4.6% of women. Most of the women censored because of suspected > or = CIN 2 came from the large group perceived at entry as being at low risk of developing > or = CIN 2, but the greatest rates of progression to > or = CIN 2 were observed among women perceived at entry to be at highest risk of > or = CIN 2, based on their cytology, virology, or sexual behavior. CONCLUSIONS: The GP is the largest population-based longitudinal cohort for the study of HPV and cervical neoplasia in the world, and its results will hopefully let us soon plan future worldwide prevention strategies. Research projects such as this one require the long-term commitment of a large multidisciplinary team and ample financial resources. The intensive effort and expertise applied in all aspects of this study were key factors in its success as a model of cooperative, interdisciplinary cancer research in Latin America. Quality control played an important role at all times during the study and made it possible to adapt new diagnostic and screening technology to Guanacaste. The systematic follow-up of a population-based group of close to 10 000 women in Guanacaste should permit careful, time-dependent evaluation of factors postulated to be linked to the development of cervical cancer as well as the evaluation of clinical markers of disease progression. The study results that have already been published have validated sensitive screening techniques and have also promoted the use of more affordable screening techniques in resource-poor, developing countries. The GP has also contributed to building knowledge for the search for vaccines against HPV as part of the effort to develop an effective tool to reduce the incidence and mortality of cervical cancer worldwide.
Assuntos
Programas de Rastreamento , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Displasia do Colo do Útero/etiologia , Displasia do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Colposcopia/estatística & dados numéricos , Costa Rica/epidemiologia , Progressão da Doença , Feminino , Humanos , Incidência , Entrevistas como Assunto , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Infecções por Papillomavirus/epidemiologia , Estudos Prospectivos , Distribuição Aleatória , Fatores de Risco , Inquéritos e Questionários , Neoplasias do Colo do Útero/epidemiologia , Displasia do Colo do Útero/epidemiologiaRESUMO
OBJETIVOS: El estudio de cohorte de Guanacaste, o Proyecto Epidemiológico Guanacaste, fue diseñado para investigar el papel que desempeñan la infección por el virus del papiloma humano (VPH) y sus cofactores en el desarrollo de neoplasias cervicouterinas y para evaluar nuevas tecnologías de tamizaje del cáncer del cuello de útero. La fase de seguimiento de este proyecto se diseñó para analizar por qué una pequeña parte de las mujeres infectadas por el VPH desarrollan neoplasias intraepiteliales cervicouterinas (NIC) grados 2 y 3, o cáncer (que en lo adelante se llamarán en conjunto > NIC 2, es decir, NIC 2 o peor). El propósito de este artículo es describir en detalle ese estudio prospectivo y presentar los resultados preliminares relacionados con la incidencia de neoplasias cervicouterinas. MÉTODOS: Se realizó el tamizaje intensivo de una cohorte de 10 049 mujeres de 18 a 97 años de edad seleccionadas aleatoriamente en Guanacaste, provincia del noroeste de Costa Rica, en 1993-1994 con un seguimiento ulterior de siete años. A las participantes se les aplicó un cuestionario para conocer sus características demográficas y sus factores de riesgo, y a las sexualmente activas se les realizó además un examen pélvico en cada una de las visitas de seguimiento, a fin de obtener muestras para las pruebas de tamizaje y la investigación. El diagnóstico obtenido al final de la fase de captación permitió clasificar a las mujeres en varios grupos de acuerdo con el riesgo que presentaban de desarrollar cáncer o alguno de sus precursores de alto grado. Estos grupos tuvieron seguimientos a intervalos diferentes, según su riesgo de desarrollar > NIC 2. El seguimiento más activo (cada 6-12 meses) se concentró en las mujeres con mayores probabilidades de desarrollar > NIC 2, según los resultados citológicos (n = 492). Las mujeres restantes recibieron visitas de seguimiento anualmente (n = 2 574) o después de cinco a siete años de seguimiento pasivo (n = 3 926). A todas las mujeres en quienes se detectaron lesiones que pudieran ser graves, por cualquiera de las técnicas empleadas, se les remitió a una evaluación ulterior mediante colposcopia y a tratamiento médico, y se retiraron del estudio. Las lesiones > NIC 2 se utilizaron como criterio para la salida del estudio y como indicadores indirectos del riesgo de cáncer. RESULTADOS: La participación durante la fase de seguimiento fue alta (cercana al 90%). Cualquier indicio de > NIC 2, según cualquiera de las técnicas...
Objective. The Guanacaste study ("Guanacaste Project," or GP), was designed to investigate the role of human papillomavirus (HPV) infection and its cofactors in the development of cervical neoplasia and to evaluate new cervical cancer screening technologies. The follow-up phase of the GP was designed to study why a small proportion of women infected with HPV develop cervical intraepithelial neoplasia grade 2 (CIN 2), CIN 3, or cancer (these three together are globally referred to as ≥ CIN 2, that is, CIN 2 or worse). The purpose of this article is to describe this prospective study in detail and to present the preliminary findings regarding the incidence of cervical neoplasia. Methods. A cohort of 10 049 randomly selected women from 18 to 97 years old from Guanacaste, a province in northwestern Costa Rica, was intensively screened in 19931994 and then followed up for seven years after being enrolled. A questionnaire for demographic and risk factors was administered, and a pelvic examination was performed on sexually active women at each follow-up visit in order to obtain samples for screening tests and for research purposes. The final diagnosis given at the end of the enrollment phase categorized women into several groups according to the perceived risk of their developing either high-grade precursors of cancer or cancer. These groups were followed up at different intervals according to the risk of developing ≥ CIN 2. The most active follow-up (every 612 months) was concentrated on the women most likely to develop ≥ CIN 2, based on cytology (n = 492). The remainder of the cohort was followed either annually (n = 2 574) or after five to seven years of passive follow-up (n = 3 926). All women with possibly severe lesions detected by any technique were referred to colposcopy for further evaluation and treatment, and they were also censored from the study. Lesions ≥ CIN 2 served as both the censoring outcome and our surrogate for cancer risk. Results. Participation during follow-up was high (near 90%). Suspected ≥ CIN 2 by any screening technique censored 4.6% of women. Most of the women censored because of suspected ≥ CIN 2 came from the large group perceived at entry as being at low risk of developing ≥ CIN 2, but the greatest rates of progression to ≥ CIN 2 were observed among women perceived at entry to be at highest risk of ≥ CIN 2, based on their cytology, virology, or sexual behavior. Conclusions. The GP is the largest population-based longitudinal cohort for the study of HPV and cervical neoplasia in the world, and its results will hopefully let us soon plan future worldwide prevention strategies. Research projects such as this one require the long-term commitment of a large multidisciplinary team and ample financial resources. The intensive effort and expertise applied in all aspects of this study were key factors in its success as a model of cooperative, interdisciplinary cancer research in Latin America. Quality control played an important role at all times during the study and made it possible to adapt new diagnostic and screening technology to Guanacaste. The systematic follow-up of a population-based group of close to 10 000 women in Guanacaste should permit careful, time-dependent evaluation of factors postulated to be linked to the development of cervical cancer as well as the evaluation of clinical markers of disease progression. The study results that have already been published have validated sensitive screening techniques and have also promoted the use of more affordable screening techniques in resource-poor, developing countries. The GP has also contributed against HPV as part of the effort to develop an effective tool to reduce the incidence and mortality of cervical cancer worldwide
Assuntos
Humanos , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Displasia do Colo do Útero/etiologia , Displasia do Colo do Útero/prevenção & controle , Programas de Rastreamento , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/prevenção & controle , Algoritmos , Displasia do Colo do Útero/epidemiologia , Colposcopia , Costa Rica/epidemiologia , Progressão da Doença , Incidência , Entrevistas como Assunto , Programas de Rastreamento , Infecções por Papillomavirus/epidemiologia , Estudos Prospectivos , Inquéritos e Questionários , Distribuição Aleatória , Fatores de Risco , Neoplasias do Colo do Útero/epidemiologiaAssuntos
Displasia do Colo do Útero , Programas de Rastreamento , Papillomaviridae , Algoritmos , Colposcopia , Costa Rica , Entrevistas como Assunto , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Progressão da Doença , Incidência , Estudos Prospectivos , Inquéritos e Questionários , Distribuição Aleatória , Fatores de RiscoRESUMO
Small volumes of cervical secretions have limited measurements of immunity at the cervix, which may be important to studies of human papillomavirus (HPV). We report the use of recycling immunoaffinity chromatography to efficiently study immune profiles in cervical secretions. Frozen pairs of plasma and cervical secretions (collected on ophthalmic sponges) were selected randomly from women with normal cervical cytology (n = 50) participating in a natural history study of HPV in Guanacaste, Costa Rica. Single 25- micro l aliquots of plasma and (diluted) cervical secretions were assayed for interleukin (IL) -1 beta, -2, -4, -6, -8, -10, -12, -13, -15, IFN-alpha, -beta, -gamma, tumor necrosis factor-alpha, -beta, RANTES (regulated on activation normal T-cell express and secreted), MCP-1 (monocyte chemoattractant protein), -2, -3, macrophage inflammatory protein-1 alpha, -1 beta (regulated on activation normal T-cell express and secreted), macrophage colony-stimulating factor, IgG, IgA, and cyclooxygenase 2. All of the specimens were tested as blind replicates, and refrozen plasma was retested 4 months later. To evaluate the reproducibility of the repeat measurements and to examine the correlation between plasma and cervical secretions, we calculated kappa values with 95% confidence intervals among categorized analyte values and Spearman correlation coefficients (rho) among detectable, continuous analyte values. Measurements of all of the analytes in either plasma or cervical secretions were highly reproducible, with all of the kappa > or = 0.78 (70% above 0.90), and all of the rho > or = 0.88 (96% above 0.90). Only IL-1 beta (kappa = 0.60 and rho = 0.82) and IL-6 (kappa = 0.50 and rho = 0.78) levels were strongly correlated between plasma and cervical secretions. IFN-gamma, tumor necrosis factor-beta, RANTES, MCP-1, MCP -2, macrophage inflammatory protein-1 alpha, and macrophage colony-stimulating factor levels were especially poorly correlated between plasma and cervical secretions (kappa < or = 0.25 and rho < or = 0.25). We conclude that recycling immunoaffinity chromatography is a reproducible method of measuring immune profiles from biological specimens, and immune profiles are not well correlated between plasma and cervical secretions, perhaps necessitating cervical collections to study cervix-specific immunity in HPV natural history studies.
Assuntos
Biomarcadores/sangue , Cromatografia/métodos , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Adulto , Distribuição por Idade , Idoso , Muco do Colo Uterino/virologia , Quimiocina CCL2/análise , Quimiocina CCL5/análise , Quimiocina CCL8 , Estudos de Coortes , Intervalos de Confiança , Costa Rica/epidemiologia , Feminino , Humanos , Técnicas Imunológicas , Incidência , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Proteínas Quimioatraentes de Monócitos/análise , Probabilidade , Fatores de Risco , Manejo de Espécimes , Fator de Necrose Tumoral alfa/análiseRESUMO
Human papillomavirus (HPV) seroprevalence and determinants of seropositivity were assessed in a 10049-woman population-based cohort in Guanacaste, Costa Rica. Serologic responses based on VLP-based ELISA were obtained from the plasma collected at study enrollment in 1993/1994 for HPV-16 (n=9949), HPV-18 (n=9928), HPV-31 (n=9932), and HPV-45 (n=3019). Seropositivity was defined as five standard deviations above the mean optical density obtained for studied virgins (n=573). HPV-16, -18, -31, and -45 seroprevalence was 15, 15, 16, and 11%, respectively. Of women DNA-positive for HPV-16, -18, -31, or -45, seropositivity was 45, 34, 51, and 28%, respectively. Peak HPV seroprevalence occurred a decade after DNA prevalence; lifetime number of sexual partners was the key determinant of seropositivity independent of DNA status and age. DNA- and sero-positive women showed the highest risk for concurrent CIN3/cancer, followed by DNA-positive, sero-negative women.
Assuntos
Anticorpos Antivirais/sangue , Papillomaviridae/imunologia , Infecções por Papillomavirus/epidemiologia , Displasia do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Virais/imunologia , Estudos de Coortes , Costa Rica/epidemiologia , DNA Viral/análise , Feminino , Humanos , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Estudos Soroepidemiológicos , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/virologiaRESUMO
Hybrid Capture 2 Test using probe B (HC2-B) is a clinical test for the detection of 13 human papillomavirus (HPV) types associated with cervical cancer (oncogenic types), but the potential clinical significance of HC2-B cross-reactivity with untargeted (nononcogenic) HPV types has not been fully evaluated. Thus, HC2-B test results on 954 clinical cervical specimens from a population-based natural history study of HPV in Costa Rica were compared with the data from testing of the same specimens twice by HPV type-specific MY09/MY11 L1 consensus primer PCR. Specimens positive by PCR for single HPV types not targeted by HC2-B were used for determining type-specific cross-reactivity. Effects of cross-reactivity on clinical performance were estimated by calculating sensitivity and specificity with and without cross-reactivity for the detection of high-grade cervical lesions. HC2-B tested positive for single infections by untargeted (cross-reactive) types 11, 53, 61, 66, 67, 70, 71, and 81. Cross-reactivity was strongly associated with PCR signal strength (P(Trend) = 0.0001) and cervical abnormalities (P = 0.0002, Pearson chi(2)). We estimated that HC2-B cross-reactivity resulted in minor changes in screening performance. Clinical sensitivity increased from 84.3% to 87.9%, clinical specificity decreased from 89.6% to 88.1%, and referral rates increased from 11.7% to 13.2% for detection of >or=cervical intraepithelial neoplasia grade 2. The clinical effect of cross-reactivity varied by cytologic interpretation. Among women with normal cytologic interpretations, cross-reactivity significantly improved the accuracy of identifying cytologically nonevident histology of >or=cervical intraepithelial neoplasia grade 2 because of increased sensitivity with maintained specificity. However, among women with equivocal or mildly abnormal cytologic interpretations, cross-reactivity decreased the accuracy of HPV testing because of substantial decreases in specificity. In summary, cross-reactivity with nononcogenic HPV types had little effect on the overall clinical performance of HC2-B as a general screening test, but reduction of cross-reactivity might improve the performance of HPV testing for triage of equivocal or mildly abnormal cytologic interpretations.
Assuntos
Reações Cruzadas/fisiologia , Hibridização de Ácido Nucleico , Papillomaviridae/isolamento & purificação , Adulto , Fatores Etários , Estudos de Coortes , Costa Rica/epidemiologia , DNA Viral/isolamento & purificação , Medicina Baseada em Evidências , Feminino , Humanos , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Sensibilidade e Especificidade , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/epidemiologia , Infecções Tumorais por Vírus/virologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologia , Saúde da MulherRESUMO
To comprehensively explore the relationship between human leukocyte antigen (HLA) class I alleles and cervical neoplasia, a subset of participants from 3 large US and Costa Rican cervix studies were typed for HLA class I alleles. Study subjects were women with cervical cancer or high-grade squamous epithelial lesions (HSILs; n=365) or low-grade squamous epithelial lesions (LSILs; n=275) or who were cytologically normal (control subjects; n=681). Allele-disease associations were assessed by logistic regression analysis. Consistent associations across all studies were observed for HLA-CW*0202 with a combined odds ratio of 0.53 (95% confidence interval [CI], 0.29-0.89) for cancer or HSILs and 0.58 (95% CI, 0.37-1.04) for LSILs, compared with control subjects and adjusted for study. This finding supports the hypothesis that a single allele may be sufficient to confer protection against cervical neoplasia. Given the relationship between HLA-C and its receptors on natural killer (NK) cells, a role is proposed for NK function in human papillomavirus infection and cervical neoplasia.