Attenuation of Torque teno viral load over time in kidney transplantation recipients treated with calcineurin inhibitors is mitigated after conversion to belatacept.

Torque Teno Virus (TTV) is a non-pathogenic anellovirus, highly prevalent in healthy populations. Variations in its viral load have been associated with states of diminished immunity, as occurs after organ transplantation. It is hypothesized that TTV-load might be used as a diagnostic tool to guide prescription and dosing of immunosuppressive drugs. Not much is known about the effects of combined immunosuppressive drugs on TTV replication in renal transplantation. Belatacept was introduced to counter side-effects of calcineurin inhibitors (CNI). It was never widely adopted, mainly because its association with increased risk of rejection. To investigate the differential effects of a regimen based on calcineurin inhibitors versus belatacept on TTV-loads, we measured TTV-levels in 105 patients from two randomized controlled trials in kidney transplant recipients (KTRs). We observed that time after transplantation was inversely related to TTV-levels of patients that remained on a CNI-containing regime, whereas this decline over time was diminished after conversion to belatacept. In addition, a correlation with tacrolimus-trough levels and age were found. Our study is the first report on the impact of conversion from CNI to belatacept on TTV-levels in KTR. In conclusion, the time-related decline in TTV-levels is mitigated after conversion from CNI to belatacept.

HPV type-specific distribution among family members and linen in households of cutaneous wart patients.

BACKGROUND: Common and plantar warts are caused by human papillomaviruses (HPV). Mode of transmission of wart HPVs within families is largely unknown. OBJECTIVE: To demonstrate similarity of HPV type(s) among wart cases, family members and household linen. METHODS: In a cross-sectional study, swabs taken from 123 warts and foreheads of 62 index patients and 157 family members and from 58 kitchen towels and 59 bathroom mats were tested for DNA of 23 cutaneous wart-associated HPV types. Generalized estimating equations (GEE) were used to estimate the chance of detecting the same HPV type as was found in the index patients on the family contacts and on the kitchen towels and bathroom mats. RESULTS: HPV1, HPV2, HPV27 and HPV57 were the most prevalent types in the warts of the index patients. Altogether, 60 (42.3%) of the 142 family members without warts had HPV DNA on their foreheads. When HPV1 and HPV2 were found in the warts, these types were also frequently (>50%) found on the foreheads of index patients and their family members, as well as on the kitchen towels and the bathroom mats. HPV27 and HPV57 were less frequently found (<25%) on foreheads and linen. No associations were found for age, sex and site of HPV DNA presence. CONCLUSION: Dissemination of skin wart-causing HPV types, from wart cases to household contacts and linen, such as kitchen towels and bathroom mats, is more likely for HPV1 and HPV2 than for HPV27 and HPV57. The role of towels and bathroom mats in HPV transmission deserves further investigation.

Short-term outpatient follow-up of COVID-19 patients: A multidisciplinary approach.

BACKGROUND: Short-term follow-up of COVID-19 patients reveals pulmonary dysfunction, myocardial damage and severe psychological distress. Little is known of the burden of these sequelae, and there are no clear recommendations for follow-up of COVID-19 patients.In this multi-disciplinary evaluation, cardiopulmonary function and psychological impairment after hospitalization for COVID-19 are mapped. METHODS: We evaluated patients at our outpatient clinic 6 weeks after discharge. Cardiopulmonary function was measured by echocardiography, 24-hours ECG monitoring and pulmonary function testing. Psychological adjustment was measured using questionnaires and semi-structured clinical interviews. A comparison was made between patients admitted to the general ward and Intensive care unit (ICU), and between patients with a high versus low functional status. FINDINGS: Eighty-one patients were included of whom 34 (41%) had been admitted to the ICU. New York Heart Association class II-III was present in 62% of the patients. Left ventricular function was normal in 78% of patients. ICU patients had a lower diffusion capacity (mean difference 12,5% P = 0.01), lower forced expiratory volume in one second and forced vital capacity (mean difference 14.9%; P<0.001; 15.4%; P<0.001; respectively). Risk of depression, anxiety and PTSD were 17%, 5% and 10% respectively and similar for both ICU and non-ICU patients. INTERPRETATION: Overall, most patients suffered from functional limitations. Dyspnea on exertion was most frequently reported, possibly related to decreased DLCOc. This could be caused by pulmonary fibrosis, which should be investigated in long-term follow-up. In addition, mechanical ventilation, deconditioning, or pulmonary embolism may play an important role.

Source and Relevance of the BK Polyomavirus Genotype for Infection After Kidney Transplantation.

BACKGROUND: BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is a major threat for kidney transplant recipients (KTRs). The role of specific BKPyV genotypes/serotypes in development of BKPyVAN is poorly understood. Pretransplantation serotyping of kidney donors and recipients and posttransplantation genotyping of viremic recipients, could reveal the clinical relevance of specific BKPyV variants. METHODS: A retrospective cohort of 386 living kidney donor-recipient pairs was serotyped before transplantation against BKPyV genotype I-IV viral capsid protein 1 antigen, using a novel BKPyV serotyping assay. Replicating BKPyV isolates in viremic KTRs after transplantation were genotyped using real-time polymerase chain reaction and confirmed by means of sequencing. BKPyV serotype and genotype data were used to determine the source of infection and analyze the risk of viremia and BKPyVAN. RESULTS: Donor and recipient BKPyV genotype and serotype distribution was dominated by genotype I (>80%), especially Ib, over II, III and IV. Donor serotype was significantly correlated with the replicating genotype in viremic KTRs (P < .001). Individual donor and recipient serotype, serotype (mis)matching and the recipient replicating BKPyV genotype were not associated with development of viremia or BKPyVAN after transplantation. CONCLUSIONS: BKPyV donor and recipient serotyping and genotyping indicates the donor origin of replicating BKPyV in viremic KTRs but provides no evidence for BKPyV genotype-specific virulence.

Pretransplantation Donor-Recipient Pair Seroreactivity Against BK Polyomavirus Predicts Viremia and Nephropathy After Kidney Transplantation.

Kidney transplant donors are not currently implicated in predicting BK polyomavirus (BKPyV) infection in kidney transplant recipients. It has been postulated, however, that BKPyV infection originates from the kidney allograft. Because BKPyV seroreactivity correlates with BKPyV replication and thus might mirror the infectious load, we investigated whether BKPyV seroreactivity of the donor predicts viremia and BKPyV-associated nephropathy (BKPyVAN) in the recipient. In a retrospective cohort of 407 living kidney donor-recipient pairs, pretransplantation donor and recipient sera were tested for BKPyV IgG levels and correlated with the occurrence of recipient BKPyV viremia and BKPyVAN within 1 year after transplantation. Donor BKPyV IgG level was strongly associated with BKPyV viremia and BKPyVAN (p < 0.001), whereas recipient BKPyV seroreactivity showed a nonsignificant inverse trend. Pairing of high-BKPyV-seroreactive donors with low-seroreactive recipients resulted in a 10-fold increased risk of BKPyV viremia (hazard ratio 10.1, 95% CI 3.5-29.0, p < 0.001). In multivariate analysis, donor BKPyV seroreactivity was the strongest pretransplantation factor associated with viremia (p < 0.001) and BKPyVAN (p = 0.007). The proportional relationship between donor BKPyV seroreactivity and recipient infection suggests that donor BKPyV seroreactivity reflects the infectious load of the kidney allograft and calls for the use of pretransplantation BKPyV serological testing of (potential) donors and recipients.

Trichodysplasia spinulosa: a polyomavirus infection specifically targeting follicular keratinocytes in immunocompromised patients.

Trichodysplasia spinulosa (TS) is a rare skin disease, caused by a specific polyomavirus, occurring in immunocompromised patients. The pathophysiological mechanisms of TS are not yet fully understood. By using polymerase chain reaction and skin biopsy immunostaining we report evidence, in a paediatric case, of follicular keratinocytes being the primary target of trichodysplasia spinulosa-associated polyomavirus.

High prevalence of cutaneous warts in elementary school children and the ubiquitous presence of wart-associated human papillomavirus on clinically normal skin.

BACKGROUND: One-third of Dutch primary school children have cutaneous warts; each year around 20% of them seek medical treatment. However, little is known about the epidemiology of the types of human papillomavirus (HPV) causing these warts. OBJECTIVES: To investigate the distribution of cutaneous wart-associated HPV types in three primary school classes by analysing skin swabs taken from warts, and the forehead, hand dorsum and sole of the foot of included children. METHODS: Using the hyperkeratotic skin lesion polymerase chain reaction/multiplex genotyping assay, each swab sample was used to genotype for 23 cutaneous wart-associated HPV types. RESULTS: Thirty-one (44%) of the 71 children had a total of 69 warts, with a maximum of six warts per child. In the wart swabs, HPV2, HPV27 and HPV57, members of Alphapapillomavirus species 4, were most frequently detected (27%, 32% and 14%, respectively), whereas HPV1 was only found in two plantar warts. The prevalence of HPV carriage, detected in swabs of clinically normal skin of the forehead, left hand and left sole was 80%, with the most prevalent types being HPV1 (59%), HPV2 (42%), HPV63 (25%) and HPV27 (21%). CONCLUSIONS: Cutaneous wart-associated HPV types were highly prevalent in primary school children, but did not correlate with the HPV types in warts. In contrast to the existing literature, HPV1 was frequently detected on clinically normal skin but was much less frequent in warts.

Prevalence of genital HPV infections and HPV serology in adolescent girls, prior to vaccination.

INTRODUCTION: Monitoring the prevalence of type-specific HPV-DNA infections before and shortly after introduction of routine HPV vaccination offers the opportunity to evaluate early effects of the vaccination program. With this aim a cohort study was set up of 14- to 16-year-old girls eligible for HPV vaccination in the Netherlands. Annually, HPV-DNA and antibody status in vaginal self-samples and in serum respectively, will be studied among vaccinated (58%) and unvaccinated girls (42%). Here we present baseline data on vaginal HPV-DNA status in relation to serum antibodies. METHODS: The 1800 enrolled girls filled out an internet-based questionnaire and provided a vaginal self-sample for genotype specific HPV-DNA detection using SPF(10) PCR amplification and reverse line probe hybridization. Furthermore, 64% of the girls provided a blood sample for HPV antibody analysis. IgG antibodies against virus-like particles were determined for 7 HPV genotypes. RESULTS: At baseline, type-specific HPV-DNA was detected in 4.4% (n = 79) of the 1800 girls: 2.7% (n = 49) concerned a high risk HPV type (hrHPV-DNA). The three most common types were HPV type 16, 18 and 51 (40%). Out of the hrHPV-DNA positive girls, 32% was seropositive vs. 12% in HPV-DNA negative girls (p<0.001). Risk factors independently associated with hrHPV-DNA infection among the sexually active girls were age >15 years vs. 14-15 years (OR = 2.6 (1.2-5.9)), age of sexual debut <14 vs. above 14 years (OR = 3.0 (1.1-8.2)), total number of lifetime partners above two vs. less than two partners (OR = 3.2 (1.3-8.0)) and age of partner >17 vs. under 17 years (OR = 4.2 (1.5-13.0)). CONCLUSION: A low hrHPV-DNA prevalence was found in the adolescent girls. The observed vs. expected age-related increase in HPV-DNA prevalence in this cohort in the coming years (with increased sexual activity) will provide understanding of the effect of HPV vaccination. Furthermore, this cohort study will offer the opportunity to improve knowledge of antibody responses following natural infection and vaccination.

Factors associated with the seroprevalence of 26 cutaneous and two genital human papillomavirus types in organ transplant patients.

Viral skin infections are commonly present in organ transplant recipients (OTR). In this study, we aimed to identify factors associated with human papillomavirus (HPV) infections in OTR. Patients with solid-organ transplants were recruited from the outpatient nephrology and dermatology clinics in five European countries. Only patients with no current or past skin cancer were included in this analysis. Serum samples were analysed for antibodies to the L1 proteins of 26 cutaneous and two genital HPV types from five phylogenetic genera (α, ß, γ, µ and ν). The most consistent association was found between recreational sun exposure and the seroprevalence of all tested genera, except α. The antibody presence of any ß type was higher among people who had been transplanted at least 23 years prior to participation than in those who had been transplanted for less than 7 years. The prevalence of two γ-HPV types (60 and 65) and three ß-HPV types (15, 38 and 49) was associated with time since transplantation. The presence of a high number of warts was associated with the presence of any µ-PV or ν-PV types, and having greater than 50 keratotic skin lesions was almost significantly associated with the presence of antibodies to two or more γ-PV. Discrepancies in the results of the present study, as well as in previous reports, may depend on different methodologies and on geographical variations. Our results also indicate that further research with more standardized methods is needed to clarify the role of cutaneous HPV in OTR.

A case-control study of betapapillomavirus infection and cutaneous squamous cell carcinoma in organ transplant recipients.

We examined the association between betapapillomavirus (betaPV) infection and cutaneous squamous cell carcinoma (SCC) in organ transplant recipients. A total of 210 organ transplant recipients with previous SCC and 394 controls without skin cancer were included. The presence of 25 betaPV types in plucked eyebrow hairs was determined using a human papillomavirus (HPV) DNA genotyping assay, and antibodies for the 15 most prevalent betaPV types were detected using multiplex serology. We used multivariate logistic regression models to estimate associations between various measures of betaPV infection and SCC. BetaPV DNA was highly prevalent (>94%) with multiple types frequently detected in both groups. We found a significant association between SCC and the concordant detection of both antibodies and DNA for at least one betaPV type (adjusted OR 1.6; 95% CI 1.1;2.5). A borderline-significant association with SCC was found for HPV36 (adjusted OR 2.4; CI 1.0;5.4), with similar associations for HPV5, HPV9 and HPV24. These data provide further evidence of an association between betaPV infection and SCC in organ transplant recipients. Confirmation of a betaPV profile predictive of risk for SCC may pave the way for clinically relevant pretransplant HPV screening and the development of preventive and therapeutic HPV vaccination.

Marked differences in Betapapillomavirus DNA and antibody prevalence between patients with psoriasis and those with atopic dermatitis.

BACKGROUND: Recent studies revealed that Betapapillomavirus (betaPV) infections are highly prevalent. Skin diseases such as psoriasis, characterized by keratinocyte hyperproliferation, and atopic dermatitis (AD), dominated by cutaneous inflammation, might have an impact on viral life cycle and immune response induction. OBJECTIVES: To investigate whether betaPV infection is different in psoriasis and AD. METHODS: Twenty-seven patients with psoriasis and 17 with AD were included for betaPV genotyping using eyebrow hairs, and for seroresponse determination. RESULTS: BetaPV DNA was found significantly more often in patients with psoriasis than in those with AD (100% vs. 81%, P=0·022) and the mean number of betaPV types was higher (4·8 vs. 2·1 types, P=0·002). In contrast, the seroprevalence in patients with AD was significantly higher compared with that in patients with psoriasis (88% vs. 56%, P=0·023). Type-specific concordance of serological response to the betaPV type detected in eyebrow hairs was 27% in patients with psoriasis and 47% in those with AD (P=0·019). CONCLUSIONS: We speculate that the condition of the skin and the immunological state of the patients have an important impact on the life cycle of betaPV.

An analysis of clustering of betapapillomavirus antibodies.

Betapapillomaviruses (betaPVs) may contribute to the aetiology of cutaneous squamous cell carcinoma. However, no high-risk types have yet been identified, possibly because the high frequency of co-infection prevents a straightforward analysis of the independent effects of individual viruses. This study aimed to determine whether specific virus types were more likely to co-occur than others, thereby reducing the number of parameters needed in statistical models. Antibody data were analysed from controls who participated in case-control studies in The Netherlands, Italy and Australia and from participants in the German Nutrition Survey. Cluster analysis and two ordination techniques were used to identify patterns. Evidence of clustering was found only according to the number of viruses to which antibodies were detected. The lack of clustering of specific viral types identified suggests that if there are betaPV types that are independently related to skin carcinogenesis, they are unlikely to be identified using standard epidemiological methods.

Trends of skin diseases in organ-transplant recipients transplanted between 1966 and 2006: a cohort study with follow-up between 1994 and 2006.

BACKGROUND: Skin diseases are frequently observed in organ-transplant recipients (OTRs). OBJECTIVES: To count the registered skin diseases in all 2136 OTRs who had been transplanted in a single centre between 1966 and 2006 and to calculate their relative contribution in relation to the number of years after transplantation. METHODS: All registered skin diseases which were entered into a computerized system between 1994 and 2006 at the Leiden University Medical Centre were counted and their relative contributions were calculated. RESULTS: Between 1994 and 2006, 2408 skin diseases were registered in 801 of 1768 OTRs who were at risk during this specific time period. The most commonly recorded diagnoses were skin infections (24.0%) followed by benign skin tumours (23.3%) and malignant skin lesions (18.2%). The relative contributions of infectious and inflammatory disorders decreased with time after transplantation, whereas the contribution of squamous cell carcinomas strongly increased with time. CONCLUSIONS: This study gives a systematic overview of the high burden of skin diseases in OTRs. The relative distributions of skin diseases importantly changed with time after transplantation, with squamous cell carcinoma contributing most to the increasing burden of skin diseases with increasing time after transplantation.

[Skin cancer and other skin disorders in patients following solid organ transplantation]. / Huidkanker en andere huidaandoeningen bij patiënten na transplantatie van een solide orgaan.

Solid organ transplant patients have an increased risk of cutaneous squamous cell carcinomas compared to the immunocompetent population, and often develop multiple and sometimes aggressive tumours. There are few published studies or reviews, which provide guidance to the clinician in the management of these patients. In the prevention of skin cancer in organ transplant patients, patient education about the harmful effects of ultraviolet radiation, sun protection, and the early recognition of (pre)malignant skin lesions should be emphasised. Furthermore, close follow-up by a dermatologist and treatment of (pre)malignant lesions in an early stage are necessary. Chemoprevention of skin cancer can be achieved through systemic retinoids. Reduction of the dose of immunosuppressive agents can be considered. Excision is the first treatment of choice for squamous cell and basal cell carcinomas. In selected rumours curettage and electrodessication can be performed.

[Human papillomavirus in the aetiology of skin cancer]. / Humaan papillomavirus in de etiologie van huidkanker.

At present, human papillomavirus (HPV) infection is chiefly known for its causal relationship with cervical cancer. Apart from genital types, the papillomavirus family consists of numerous human cutaneous types. The majority belongs to the so-called epidermodysplasia-verruciformis(EV)-HPV types that are potentially involved in skin cancer development. Non-melanoma skin cancers, especially cutaneous squamous cell carcinoma contain HPV DNA (30-60%). In immune-suppressed organ transplant recipients this percentage increases up to 90. Recent epidemiological studies show a statistically significant association between EV-HPV infection and squamous cell carcinoma. In addition recent experimental studies show specific EV-HPV types have a potential to transform cells that is comparable to high-risk genital HPV types. These data indicate that cutaneous HPV infections and squamous cell carcinoma development are associated.

Human papillomavirus infection and skin cancer risk in organ transplant recipients.

Warts and squamous cell carcinomas are important cutaneous complications in organ transplant recipients. The role of infection with human papillomaviruses (HPV) in the development of cutaneous squamous cell carcinoma is still unclear. An extremely diverse group of HPV types, mainly consisting of epidermodysplasia-verruciformis (EV)-associated HPV types, can be detected in benign, premalignant, and malignant skin lesions of organ transplant recipients. Frequently, there are multiple HPV types present in single skin biopsies. Typically, the prevalence of viral warts rises steadily after transplantation and a strong association exists between the number of HPV-induced warts and the development of skin cancer. The interval between the transplantation to the development of warts is clearly shorter than the interval from transplantation to the diagnosis of the first skin cancer. A comparison of transplant recipients with and without skin cancer, however, showed an equally high prevalence of EV-HPV DNA in keratotic skin lesions in both groups of patients and the detection rate and spectrum of HPV infection in hyperkeratotic papillomas, actinic keratoses, and squamous cell carcinomas was also similar. HPV DNA can frequently be detected in patients with hyperproliferative disorders like psoriasis and antibodies against HPV in patients with regenerating skin (e.g., after extensive second degree burns). Latent infection with EV-HPV seems to be widespread. The hair follicle region might be the reservoir of EV-HPV. The E6 protein from a range of cutaneous HPV types effectively inhibits apoptosis in response to UV-light induced damage. It is therefore conceivable that individuals who are infected by EV-HPV are at an increased risk of developing actinic keratoses and squamous cell carcinomas, possibly by chronically preventing UV-light induced apoptosis.

[Recurrent laryngeal nerve paralysis after thyroid gland operations. Etiology and consequences]. / Recurrenslähmungen nach Schilddrüsenoperationen. Ursachen und Konsequenzen.

In the period of 1 January 1990 to 31 December 1996 the thyroidectomy cases we performed were immediately followed by vocal cord evaluation using a flexible bronchoscope while the patient was still on the operating table. If an obvious cord paralysis was discovered, an exploration of the recurrent laryngeal nerve, to the level of the larynx, was performed. If the nerve was found to be intact, no further measures were taken. A severed nerve underwent suture repair. If an otolaryngologist diagnosed a vocal cord paralysis 1-5 days after surgery, a reoperation was recommended except in the cases where postoperative bronchoscopy had shown an easily mobile cord or the recurrent nerve was completely dissected during the operation. Within this 7-year period, we performed 3492 thyroidectomy operations. The diagnosis of subsequent unilateral postoperative vocal cord paralysis occurred in 48 cases. In 33 of these cases the status of the nerve in the surgical field was known: 4 patients had an intact nerve proved by complete dissection during thyroidectomy, in two patients the lesions of the nerve were detected intraoperatively (1 transsection, 1 partial resection), and 27 cases were followed by reoperation. Of the 33 patients mentioned above, in 19 instances the recurrent laryngeal nerve was found to be intact; 3 displayed signs of local trauma, and 11 were found to be severed with total discontinuity. Those patients with an intact nerve, or local nerve trauma only, went on to develop normal function within 6 months in 20 (91%) of 22 cases. Of the 11 with a severed nerve, 8 showed "autoparalysis" with good voice within 4-8 months, after suture repair in 10 cases. The patient with partial resection had no repair of the nerve. If immediate postoperative evaluation showed mobility of the vocal cords but a paralysis was detected later by an otolaryngologist and repeat intervention was not done, vocal cord function was spontaneously restored in 9 of 11 patients. Four patients refused reoperation. From 1990 to 1991, the recurrent laryngeal nerve was not always dissected during our thyroidectomy operations. However, this was done routinely from 1991 to 1996. Routine intraoperative dissection of the vocal cord nerve reduced the rate of postoperative cord paralysis from 2.0% to 1.2%. It also reduced the frequency of intraoperative nerve injury with total discontinuity from 0.58% to 0.23%.

Peptide vaccination with an anchor-replaced CTL epitope protects against human papillomavirus type 16-induced tumors expressing the wild-type epitope.

Anchor residues in cytotoxic T-lymphocyte (CTL) epitope-bearing peptides are buried deep in the major histocompatibility complex (MHC) class I antigen-presenting groove and are essential for binding to MHC class I molecules. We investigated whether anchor residue replacement affects the ability of a CTL epitope to be bound and transported by MHC class I molecules and transporter associated with antigen (TAP), respectively, and affects its functionality in vivo. Therefore, both anchor residues, at positions 5 and 9, of the H-2Db-restricted CTL epitope HPV16 E7 49-57 RAHYNIVTF were systematically exchanged for one of the 19 other naturally occurring amino acid (AA). Only replacement at anchor position 9 with residues V, I, L, or M, which are documented Db motif-anchor residues at that position, allowed binding to the MHC class I H-2Db molecule as well as transport by TAP with the same efficiency as the wild-type epitope. In B6 mice (H-2b), these anchor-modified peptide epitopes efficiently induced CTL that specifically recognized the wild-type epitope. Conversely, wild-type epitope-induced CTL recognized the V9-, I9-, L9-, and M9-replaced epitopes, respectively. In terms of tumor protection against a challenge with HPV16-transformed cells, the V9-replaced epitope was as efficient as the wild-type epitope E7 49-57. Taken together, our data demonstrate that specific CTL epitope anchor replacements are allowed with respect to MHC class I binding and TAP transport, as well as with respect to antigenicity and immunogenicity in vivo. The results presented are relevant to CTL epitope-based peptide vaccine development.

Fatal Scedosporium prolificans infection in a leukemic patient.

The case is described of a 42-year-old patient with acute myeloid leukemia who received two courses of chemotherapy complicated by prolonged bone marrow depression. He was admitted to hospital with fever, hepatosplenomegaly and bilateral nodular pulmonary infiltrates. After admission diffuse cutaneous skin nodules, and hypodense lesions in the hemispheres and cerebellum developed. Cultures of cerebrospinal fluid, bronchoalveolar lavage fluid, skin biopsy specimens and blood revealed Scedosporium prolificans, indicative of disseminated mycosis. Treatment with amphotericin B and fluconazole was unsuccessful and the patient died within five days after admission. Features that may enhance early recognition of Scedosporium prolificans infection by both clinicians and microbiologists, as well as options in the treatment of infection with this fungal agent are discussed.

Cytotoxic T lymphocytes raised against a subdominant epitope offered as a synthetic peptide eradicate human papillomavirus type 16-induced tumors.

Previously, we have shown that immunization with human papillomavirus (HPV) type 16-derived cytotoxic T lymphocyte (CTL) epitope E7 49-57 (RAHYNIVTF) renders C57BL/6 mice insensitive to tumors formed by HPV16-transformed cells. In this study, we provide evidence that E7 49-57 is expressed as a subdominant CTL epitope on HPV16-transformed C57BL/6 cells. Using acid peptide elution, it is shown that HPV16-transformed cells express another CTL epitope, besides E7 49-57, which appears to be dominant. We demonstrate that a CTL line raised against the subdominant CTL epitope, offered as synthetic peptide E7 49-57, eradicates established HPV16-induced tumors in mice. Our data show that synthetic peptide-induced CTL can be applied successfully in vivo against (virus-induced) tumor, and emphasize that subdominant CTL epitopes are useful targets for immunotherapy. Furthermore, it is illustrated for the first time that HPV16-specific CTL interfere directly with HPV16-induced tumors.