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Cell-mediated immunity (CMI) to human wart virus and wart-associated tissue antigens.

Lymphocyte transformation (LT) and leucocyte migration inhibition in agarose were used to demonstrate cell-mediated immune response to purified human wart virus and wart tissue extract in various subjects with warts and those without past history of warts. Most individuals bearing warts for less than 1 year duration showed positive cell-mediated responses to both the virus and tissue extract whereas very few of those who had warts for longer duration responded to either antigenic preparation. The difference was statistically significant. Subjects who had warts in the past also showed positive responses but these tended to decrease in degree with time. Surprisingly a group of subjects who never had warts before also responded to stimulation with the virus, but not to the extract. The positive response to stimulation with wart tissue extract reflects the presence of wart associated antigens other than the virus. Cell-mediated immunity against the wart virus and wart-associated antigens is probably important in preventing the persistence or even establishment of disease but this protective immunity is short-lived. The lack of quantitative correlation between LT and leucocyte migration inhibition demonstrable in this study suggests that these two are separate events in in vitro lymphocyte stimulation with antigens.

Adult

Hunan wart-virus antibodies in patients with genital and skin warts.

A comparative follow-up study of the antibody response against human wart-virus was performed, using the immunodiffusion and complement fixation methods on patients with condylomas and skin warts. By the immunodiffusion method, 13% of the patients with skin warts and 3% of the patients with condylomas showed greater than or equal to fourfold increase of antibody titre during the follow-up of 2--35 months. The findings show some typical features of the weak antibody response of a chronic virus infection and suggest a serological overlapping between condyloma viruses and certain group of skin wart-viruses. The antibody prevalence in age-matched controls is shown to be significantly higher than that in the wart or condyloma patients' initial serum samples. This is indicative of the protective function of antibodies against warts and condylomas. Also the analysis of the history of warts in patients with condylomas suggests that protection against condylomas can be acquired from previous warts, evidently by immunological mechanisms. In a control group of medical students, human wart-virus antibodies were frequently (52%) found in subjects without any history of warts. This finding supports the view that human wart-virus can frequently induce latent or subclinical infections in human beings.

Adult

Warts and wart virus antibodies in patients with systemic lupus erythematosus.

Warts were found in 25 out of 56 patients with definite or probable systemic lupus erythematosus (SLE) but in only 19 out of 160 control patients. Warts were particularly prevalent in elderly patients with SLE. The corticosteroid and antimalarial drugs used to treat SLE did not influence the frequency of warts. Wart-virus antibodies were found significantly less often in patients with SLE than in controls: antibodies were detected in 23 out of 51 patients and in 40 out of 54 controls. Ihe findings suggest that some deficiency in the immune mechanisms of patients with SLE predisposes them to develop warts. There was an inverse correlation among the patients with SLE between the occurrence of warts and rheumatoid factor activity. This suggests that rheumatoid factor may interfere with resistance to warts.

Adolescent

Efflorescence of new warts: a sign of onset of involution in flat warts.

The sudden eruption of large numbers of tiny new warts in a patient with multiple flat warts often signals the onset of involution and subsequent regression of all flat warts. We have observed 5 such cases and, in this report, describe 2 cases in which the sudden efflorescence of many new warts was used as a sign to predict accurately the onset of involution and subsequent regression of all flat warts. Correlation of the histopathological and clinical findings provides an explanation for this phenomenon.

Adult

Superficial radiotherapy of warts: results of treating 531 warts.

The fear of injurious effects has almost completely halted the use of radiotherapy in the cure of warts. Over a period of 24 years, the authors have treated 531 warts with both orthovoltage and superficial radiation equipment without any adverse effects. The selection of superficial or orthovoltage units was not dependent on the size of the lesion and was thought to be completely random.

Adolescent

Immunology of human warts.

Rapid advances have occurred in the characterization of human papilloma virus (HPV) types applying the new advanced techniques of restriction endonuclease analysis and molecular hybridization to human wart virus. Human papilloma virus can no longer be viewed as a single, homogeneous virus producing all varieties of clinical warts. At least three antigenically heterogeneous HPV types have been associated with common and plantar warts. Two additional HPV types have been found in patients with epidermodysplasia verruciformis. Condylomata acuminata and laryngeal papillomas contain viruses which are also distinct from the preceding viruses and may represent additional HPV types. This antigenic heterogeneity of HPV has important implications concerning the immunology of human warts which have not been taken into account in most previously published studies. Both antibody and cell-mediated responses may be seen in patients with active warts, but many patients with warts have no demonstrable immune reactions. The role of immunity in wart regression remains poorly understood. Nevertheless, the increased frequency of warts in patients receiving immunosuppressive drugs and with immune deficiency states and the immunologic alterations which occur in patients with regressing or cured warts compared to patients with active warts, particularly the increased frequency of cell-mediated responses and antibodies specific for viral antigens, support a possible role for immunity in the resolution of warts. The evidence to date, however, does not prove that immune mechanisms are directly responsible for the elimination of warts.

Adolescent

An assessment of methods of treating viral warts by comparative treatment trials based on a standard design.

A series of eleven comparative wart treatment trials undertaken between 1969 and 1975 and involving 1802 patients is described. A method of coding provided groups of patients matched for age, type, number and duration of warts, within which treatments could be randomized. The variation in response to treatment was shown to be influenced significantly by these factors and the level of cure to depend on the proportions of the various response groups within the population under consideration. These proportions were found to vary geographically and at different periods. In all the trials the results were assessed at 12 weeks. In the treatment of hand warts, the percentage cure of patients treated with liquid nitrogen fell significantly from 75 to 40% when the interval between freezings was increased from 3 to 4 weeks. The average number of freezings required for a cure was 3-1 amongst all patients cured by 6 or less freezings at intervals of 2 or 3 weeks. In a two-centre trial there was no significant difference between the percentage cure of patients with hand warts treated with liquid nitrogen (69%) and of those applying a paint containing salicylic and lactic acids (SAL) (67%). Patients receiving both treatments concurrently did better (78%) but the difference was not found to be statistically significant. In the treatment of simple plantar warts the percentage cure for the SAL paint (84%) was found to compare favourably with that for a podophyllin treatment (81%). Only one of the patients cured by the paint in that trial was found to have had a recurrence after 6 months. The paint was found to be satisfactory for use under general practice conditions. Additions to the formula did not alter its effectiveness. In the treatment of mosaic plantar warts the overall percentage cure for the SAL paint in a series of comparative trials (1969-75) was 45%. In these trials it was compared directly with one or more other preparations. No differences were found between its efficacy and that of 10% buffered gluteraldehyde (47%), 40% benzalkonium chloride dibromide (Callusolve 40) (30%) and 5% 5-fluorouracil in dimethyl sulphoxide (53%). Only 25% of thirty-six patients treated with 5% idoxuridine in dimethylsulphoxide were cured. Throughout the trials approximately 30% of patients with hand warts, 20% of those with simple plantar warts and 50% of those with mosaic plantar warts were found to be resistant to treatment. The adoption of treatment with SAL paint for hand warts and simple plantar warts by the general practitioners in the Edinburgh area has proved satisfactory. Only resistant cases are now referred to hospital and these can be treated within a few weeks instead of 4-5 months as was the case in 1969.

Benzalkonium Compounds

Decreased T cell levels in patients with warts.

Thymus-derived lymphocyte (T cell) levels were determined in 72 healthy patients who had viral warts, in 21 healthy patients who had been cured of warts from one to 15 years previously, and in 35 age-matched normal controls who had no history of warts. The mean percentage of lymphocytes that formed rosettes with sheep erythrocytes was less in patients with warts and patients previously cured of warts than in normal controls (P less than .001 and P less than .001, respectively). The number of total T cells/cu mm was decreased in untreated patients with warts (P less than .01) but was normal in patients cured of warts for more than one year. In addition, the morphology of the rosettes in the two patient groups differed from the controls; 32% had small numbers of sheep erythrocytes bound loosely to T cells compared with a rosette of numerous erythrocytes closely adherent to the T cell in 91% of the controls. The results suggest a defect of cellular immunity in many healthy patients with warts.

Adult

Molecular insights and therapeutic innovations in low-risk human papillomavirus-associated cutaneous wart.

Human papillomavirus (HPV) is a DNA virus that belongs to the Papillomaviridae family. Among the various types, high-risk strains are associated to malignancy, whereas low-risk types cause benign skin warts due to persistent infection. Unlike high-risk HPVs, low-risk HPV genomes remain in an episomal state while expressing E6/E7 proteins. These proteins exhibit a reduced ability to degrade pRb and p53, which finally leads to controlled epithelial hyperplasia instead of developing malignancy. Infection with low-risk HPV activates distinct host signaling pathways, ultimately promoting the proliferation of keratinocytes and formation of warts. Simultaneously, it triggers host innate and adaptive immune responses that often clear the lesion. This review focuses on low-risk types that cause skin warts by analyzing the molecular pathways, particularly the integrin-FAK-PI3K/AKT, Hippo-YAP/TAZ pathway along with MAPK-ERK pathways that promotes cutaneous benign wart formation. This article further studies clinical management strategies for HPV associated warts, including primary destructive treatment (cryotherapy, keratolytics, excision), immunotherapies (imiquimod, interferon injections or intralesional antigen), and novel adjunctive therapies with clinical evidence including photodynamic therapy, intralesional chemotherapeutics, and emerging HPV vaccination strategies. Among these, for benign skin warts, intralesional immunotherapy, particularly Candida antigen, and intralesional HPV vaccination have shown encouraging responses clinically. But extensive controlled clinical studies are necessary to establish their efficacy and clinical value as a standard medicine. This review therefore, generates a comprehensive overview of papilloma virus mediated skin warts and their management for both clinicians and researchers.

Humans

Immunity in wart resolution.

The involvement of the humoral and cell-mediated immune systems in the regression of wart infection has been investigated extensively in recent years. This review examines the supporting evidence for the roles of humoral and cellular immunity in wart regression and its possible implications. From the available data it does not appear that a conclusion can be drawn that only humoral or cell-mediated immunity is involved, or that both are essential, in the regression of wart infection. Studies by several investigators, however, suggest that, since agents known to stimulate the cell-mediated immune system have been reported to be followed by the successful resolution of warts, the cell-mediated immune system appears to play a critical role in wart resolution. It may be that the direction which should be taken in eradication of warts resistant to conventional modalities of treatment is one which relies upon the stimulation of the patient's immune system in a very specific manner. Probably the most efficient way to accomplish this, based on available data, would be by autogenous vaccination. Following the patient's humoral and cell-mediated immune response prior to, during, and following treatment with autogenous vaccination may help to elucidate the precise mechanism by which the successful resolution of warts occurs.

Antibody Formation

Regression of warts. An immunological study.

Altogether 173 patients with warts were under observation for at least 3 and in most cases 6 months. In 80% of the patients wart-virus antibodies were present and could be measured by immunodiffusion (I.D.) and in 20% also by complement-fixation (C.F.) techniques. The mean duration of the warts in patients with C.F. antibodies was 0-6 years and in the others 1-9 years. The occurence of C.F. antibodies (IgG) was associated with rapid healing; 75% of these patients were cured during the first 2 months of the observation period. In contrast, of the patients with antibodies measurable only by the I.D. technique (IgM and/or low titres of IgG), only 16% were cured during the first 2 months and they had a fairly constant cure-rate (approximately 9% per month) during the 6 months' observation period. The results indicate that the cure of warts is partly connected with immunological phenomena, especially with the presence of C.F. antibodies. In other cases wart regression may be mainly a non-immune process, perhaps due to a limited lifespan of wart cells.

Adolescent

Effect of injections of small doses of human fibroblast interferon into genital warts. A pilot study.

Eleven male patients with genital warts were given injections of fibroblast interferon (300 u) and placebo into the bases of two similar warts. The changes in size of the treated warts compared with that of the controls suggested that interferon did inhibit the growth of the warts. The dose given was probably insufficient for a dramatic effect. In one patient, however, a wart on the penile shaft was injected with interferon and did disappear within two weeks whereas an untreated meatal wart increased in size.

Adolescent

[Immunotherapy of warts. Is it an experimental model for cancer immunotherapy?].

The warts produced by virus Papova, provedly cancerous, have immunological characteristics that allow to establish some analogies with cancer. Its immunotherapy is studied with levamisole and by means of a delayed immunity reaction "in situ" with regulated intensity. The level of delayed immunity in the patient with warts is established by quantitative DNCB test, finding that the same is impaired in 60% of men and 87% of women. The levamisol therapy cures 54% of warts. The patients that not cure but improve their delayed immunity level after the treatment with levamisol, are submitted to external application of DNCB, using a concentration calculated on the quantitative test results. With regard to their delayed immunity we introduce a new group of patients: the hiperergic type or reactive to 2,5 microgram of DNCB that cures their warts by the sole action of the test. Once obtained the curve of the distribution of delayed immunity values in the warts population before and after the levamisole therapy, we observe that the first is identical to that of cancer patients. In view of the tight relation among diseases with impaired delayed immunity, such as warts, herpes, aphtas, piodermitis and cancer (residual or postsurgical), we propose the same management, control and immunotherapy for all of them.

Clinical Trials as Topic

Failure of flat warts to recur in electrosurgically altered skin.

Two men with recurring flat warts in the beard area have been observed for five and ten years, respectively. Both have depigmented patches at sites where flat warts had been removed by electrosurgical destruction. Crops of new warts appear periodically. These develop always on the normally pigmented skin and have never been found in the leukodermic areas. Flat warts have been observed repeatedly at the margin of depigmented and normal skin; these invariably enlarge toward the normal skin and never encroach on leukodermic skin. The failure of flat warts to develop in electrosurgically treated skin, if substantiated, would indicate that local tissue factors influence resistance to development of flat warts. Perhaps this phenomenon is similar to that reported in Darier's disease, where partial-thickness excision of involved skin has resulted in resistance to recurrent disease.

Electrosurgery

Antigenic relationships between polypeptides derived from plantar and hand wart viruses.

Guinea pigs immunized with polypeptides derived from plantar and hand wart viruses developed both humoral and cell mediated immunity. The specificity of the antiserum was determined by indirect immunofluorescence (IF) tests and cellular immunity by intradermal tests. While whole plantar and hand wart virus particles (PV and HV) appeared to be immunologically analogous, they had different polypeptide patterns as shown by analysis on acrylamide slab gels. In particular, the P2 polypeptide (major virus protein) with different mol. wt. for PV (56750) and HV (54500) induced the production of high antibody titres in the animals and the immune sera specifically labelled wart substrates as shown in thie IF test, demonstrating that no cross humoral reaction occurs between these two polypeptides. Furthermore, a delayed hypersensitivity reaction was observed in P2 polypeptide-inoculated guinea pigs when whole particles were introduced in skin tests, but a total cross reactivity between PV and HV was noticed at the cellular level. However, the study of the virus isolated from the lesions of a patient (Ri) bearing extensive common hand warts has shown that the virus particles possessed all the biochemical and immunological characteristics of PV, in particular with regard to the P2 polypeptide. Such a case may represent plantar-like warts located on the hands.

Animals

An immunoelectron microscopic localization of wart associated antigens present in human papilloma virus (HPV) infected cells.

Wart associated antigens were observed by the indirect immunoperoxidase technique in light and electron microscopy. Positive reaction products could be found in the nuclei of wart cells, in which virus particles were labeled with a specific immune rabbit serum and with human sera from patients with warts. Tissue antigens, differing from the viral labeled inclusions, were detected within the cytoplasm of some infected cells, by means of IgM and IgG antibodies from patients with warts. In these particular cells the positive reaction occurred in irregular patterns giving microgranular precipitates, which suggests that the antigen was not uniform. No staining was observed on the cell surface. This study has shown direct immunomorphological evidence in vivo of a specific immune reaction in man directed against whole virus and wart specific cellular antigens.

Animals

Genital warts: incidence of associated genital infections.

Two hundred and seventy-eight men and 200 women who presented to a Special Treatment Clinic with genital warts were screened for accompanying genital infections. One hundred and twenty-nine of 212 presentations (61%) in women compared to 98 of 303 presentations (32%) in men were accompanied by another genital infection P less than 0.001). Recurrent presentation with warts was commoner in men (P less than 0.001). In both sexes recurrences were less likely to be accompanied by another genital infection. (P less than 0.002). Yeasts (25%), C. vaginale (21%), N.gonorrhoea (12%) and T. vaginalis (12%) were the commonest pathogens in women. Non-specific genital infection (17%) and gonorrhoea (10%) were the commonest accompanying infections in men. The identification and treatment of these infections, especially in women, is important for the rapid eradication of warts, for, by increasing genital moisture they can create and maintain a favourable environment for wart proliferation. In addition to screening all patients with warts for other sexually transmitted diseases, women should be screened for yeasts and C. vaginale.

Candidiasis, Vulvovaginal