Biomedical subjects

Joakim Dillner

Publications and source records attributed to Joakim Dillner.

At least 19 recordsLinked to original sources

PubMed2006

Cutaneous human papillomaviruses persist on healthy skin.

Cutaneous human papillomaviruses (HPVs) are frequently found in healthy skin and have also been implicated in non-melanoma skin cancer. For genital HPV types, a persistent infection with one of the high-risk types is a prerequisite for the development of cervical cancer. However, there is only limited data on whether infections with cutaneous HPV types persist over time. Serial forehead swab samples collected from 63 volunteers (42 healthy individuals and 31 renal transplant recipients (RTRs)), sampled 6.3 years (range: 5.0-7.0 years) apart, were analyzed for HPV using general primer PCR, cloning, and sequencing. Among the healthy individuals, the prevalences of HPV were 69% (29/42) at enrolment and 71% (30/42) at follow-up. Among the individuals positive at baseline, 48% (14/29) had a persistent infection. Among the RTRs, 71% (15/21) were positive for HPV at enrolment and 90% (19/21) at follow-up. A persistent infection was detected in 33% (5/15). In total, HPV was detected in 44 of the samples collected at baseline and the same virus was found at follow-up in 43% (19/44). Persistence was not significantly associated with age, sex, immunosuppressive treatment, history of warts, or genus of HPV. We conclude that cutaneous HPV infections commonly persist over several years on healthy skin.

Base Sequence↗

PubMed2006

Activation of maternal Epstein-Barr virus infection and risk of acute leukemia in the offspring.

After identifying an association between maternal Epstein-Barr virus (EBV) reactivation and acute lymphoblastic leukemia (ALL), the authors analyzed a nested case-control study within Finnish and Icelandic maternity cohorts with 7 million years of follow-up to confirm EBV's role in ALL. Offspring of 550,000 mothers were followed up to age 15 years during 1975-1997 by national cancer registries to identify leukemia cases. Mothers of cases and three quarters of matched mothers of controls were identified by national population registers. First-trimester sera from mothers of 304 ALL cases and 39 non-ALL cases and from 943 mothers of controls were analyzed for antibodies to viral capsid antigen, early antigen, and EBV transactivator protein ZEBRA. Relative risk, estimated as odds ratio (95% confidence interval), was adjusted for birth order and sibship size. Combining early antigen and/or ZEBRA immunoglobulin G antibodies with the presence of viral capsid antigen immunoglobulin M antibodies did not increase the estimate for ALL risk for viral capsid antigen immunoglobulin M alone (odds ratio = 1.9, 95% confidence interval: 1.2, 3.0). Both ZEBRA immunoglobulin G antibodies and viral capsid antigen immunoglobulin M antibodies were associated with an increased risk of non-ALL in the offspring (odds ratio = 4.5, 95% confidence interval: 1.3, 16; odds ratio = 5.6, 95% confidence interval: 1.1, 29, respectively), suggesting EBV reactivation in the mothers of non-ALL cases. EBV reactivation may be associated with a proportion of childhood leukemia.

Adolescent↗

PubMed2006

Subtype HPV38b[FA125] demonstrates heterogeneity of human papillomavirus type 38.

The human papillomaviruses (HPVs) exist as more than 100 distinct types. While variants of HPV are common, only few HPV subtypes have been reported. HPV type 38 has been proposed to be associated with nonmelanoma skin cancer (NMSC), with reported prevalences of up to 55%. A subtype of HPV38 was cloned, completely sequenced and found to have a 96% sequence similarity to prototype HPV38 in the L1 open reading frame. The presence of prototype HPV38 and HPV38b[FA125] was examined in paired biopsies of tape-stripped skin lesions and healthy skin from 269 immunocompetent patients by real-time PCR. Prototype HPV38 and HPV38b[FA125] were present in seven (3%) and five (2%) lesions, respectively, in viral loads ranging from one copy per 150 cells to one copy per 70,000 cells. In summary, we found that HPV38 is heterogeneous and is one of so far only few HPVs that contain subtypes. The heterogeneity needs to be considered in studies of the biology of this virus.

Aged↗

PubMed2006

Chapter 28: Studies to assess the long-term efficacy and effectiveness of HPV vaccination in developed and developing countries.

We review studies of the implementation of human papillomavirus (HPV) vaccination programmes in developed and developing countries. The review spans the period from establishment of long-term vaccine efficacy follow-up studies, operational research on issues of vaccine preparedness, and relevant predictive modelling studies during the pre-licensure phase to plans of phase IV effectiveness trials, forms of epidemiological surveillance, and further operational research in the post-licensure phase. Much of the research is already ongoing. Depending on the results of the planned immuno bridging studies among HIV-negative and HIV-positive women, further phase III and/or phase IV trials may be warranted.

Developed Countries↗

PubMed2006

Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses.

BACKGROUND: More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods. MATERIAL AND METHODS: A summary is given from recently published meta-analyses on three possible clinical applications of human papillomavirus (HPV)-DNA testing: triage of women with equivocal or low-grade cytological abnormalities; prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not but not least, primary screening for cervical cancer and pre-cancer. RESULTS: Consistent evidence is available indicating that HPV-triage with the Hybrid Capture-2 assay (HC2) is more accurate (significantly higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results. When triaging women with low-grade squamous intraepithelial lesions (LSIL), a reflex HC2 test does not show a significantly higher sensitivity, but a significantly lower specificity compared to a repeat Pap smear. After treatment of cervical lesions, HPV testing easily detects (with higher sensitivity and not lower specificity) residual or recurrent CIN than follow-up cytology. Primary screening with HC2 generally detects 23% (95% confidence interval, CI: 13-23%) more CIN-2, CIN-3, or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASCUS) or LSIL, but is 6% (95% CI: 4-8%) less specific. By combined HPV and cytology screening, a further 4% (95% CI: 3-5%) more CIN-3 lesions can be identified but at the expense of a 7% (95% CI: 5-9%) loss in specificity, in comparison with isolated HC2 screening. CONCLUSIONS: Sufficient evidence exists to recommend HPV testing in triage of women with atypical cytology and in surveillance after treatment of CIN lesions. In the United States, recently reviewed knowledge has resulted in the approval of combined cytology and HC2 primary screening in women older than 30 years. However, in Europe, cytology-based screening still remains the standard screening method. The European screening policy will be reviewed based on the longitudinal results of randomised population trials which are currently underway.

DNA, Viral↗

PubMed2006

Chapter 23: International Standard reagents for harmonization of HPV serology and DNA assays--an update.

International reference materials such as International Standard reagents facilitate quality assurance of essential biopharmaceutical products and related in vitro diagnostic tests. Standardization of antibody and DNA measurements and harmonization of laboratory procedures are key to the success of cancer prevention strategies through screening methods as well as for development and implementation of vaccination against the human papillomavirus (HPV). The WHO supported the preparation and initial analysis of a panel of candidate serological and DNA reference reagents aimed at facilitating inter-laboratory comparisons and detection of HPV worldwide. Two international collaborative studies assessed the performance of various HPV antibody and HPV-DNA detection assays and examined the feasibility of generating HPV antibody and DNA standard reagents. These studies showed that improvement in performance and comparability of assays is urgently needed and that the use of the same International Standard reference reagent could significantly improve performance and comparability. It is hoped that the establishment of International Units and International Standards for HPV antibody and DNA analysis will be pursued with high priority.

Humans↗

PubMed2006

Results of the first WHO international collaborative study on the standardization of the detection of antibodies to human papillomaviruses.

Detection of genotype-specific human papillomavirus (HPV) capsid antibody in serum suggests past HPV infection. Also, these antibodies appear to correlate with vaccine-induced protection against infection, at least in animal models. However, each laboratory defines a reactive result differently and there is no agreed definition of what level of response indicates sero-reactivity. Standardization of assays for HPV capsid antibody will therefore assist with HPV vaccine development and epidemiology. This study was undertaken to investigate the specificity and sensitivity of assays in current use for measuring antibody to the major viral capsid protein L1 of HPV. Ten laboratories from 8 countries each analyzed 12 coded serum samples, which were derived from an uninfected woman, from naturally infected women and from individuals immunized with different vaccine candidates currently under clinical development. Study samples were assayed by methods in routine use in the participating laboratories. Nine assays were based on virus-like particles (VLPs) of 1 or more HPV genotypes. One laboratory used bacterially expressed major capsid protein L1 of HPV genotypes as antigen. There was considerable interlaboratory variation in estimated antibody levels. However, ranking of the potency of HPV 16 reactivity across the 12 test sera was consistent for all 10 laboratories. Expression of HPV 16 antibody levels relative to that of a single serum sample from an HPV16-infected woman considerably improved the interlaboratory assay comparability. Establishment of an International Standard for antibodies to HPV 16 would therefore facilitate the comparison of HPV antibody measurements between laboratories and assays.

Antibodies, Viral↗

PubMed2006

A report on the current status of European research on the use of human papillomavirus testing for primary cervical cancer screening.

Cervical cancer remains a significant public health concern, both at a global and a European level. A number of new technologies such as diagnostic tests for human papillomavirus (HPV) have a potential to assist with the reduction of this disease. However, both the efficacy and the cost-effectiveness of these new technologies must be established in properly designed trials before they can be implemented within national public health programs. Our study reviews the randomized controlled trials that are currently being conducted in Europe to establish the performance of HPV testing as a primary cervical cancer screening test.

DNA, Viral↗

PubMed2006

Epidemiology of Kaposi's Sarcoma herpesvirus (HHV8) in Västerbotten County, Sweden.

A population-based serosurvey of Human Herpesvirus type 8 (HHV8) in Västerbotten County, an area of Northern Sweden with high incidence of Kaposi's Sarcoma, was conducted. Serum samples from an age- and sex-stratified random sample of 520 subjects (260 men and 260 women) participating in a population-based biobanking project were tested for antibodies against HHV8, using a sensitive indirect immunofluorescence assay to latent and lytic HHV8 antigens. Buffy coat DNA was also analyzed for viral DNA using real time PCR assay. HHV8 DNA was not detectable in any one of the buffy coat samples. Eighty-four subjects (16.2%) were HHV8 seropositive, 14.4% for the lytic HHV8 antigen, and 1.7% for the latent HHV8 antigen. HHV8 seroprevalences were not associated significantly with sex or age. HHV8 seropositivity was more common among smokers (OR: 1.95, 95% CI: 1.02-3.75), but was less common among consumers of wine and spirits (OR: 0.44, 95% CI: 0.25-0.77 and OR: 0.50, 95% CI: 0.26-0.95, respectively). In summary, HHV8 has an intermediate high and stable seroprevalence rate in Northern Sweden, but environmental determinants that can explain the viral distribution were not found.

Adult↗

PubMed2006

Serological diagnosis of human polyomavirus infection.

Measurement of antibody titres to the human polyomaviruses BK and JC has for many years had to rely on Hemagglutination inhibition. In recent years, viral serology based on virus-like particles (VLPs) in enzyme immunoassays (EIAs) has become widely used for a variety of viruses. We sought to establish a modern method for serological diagnosis of BK and JC viruses, by using purified VLPs containing the VP1 major capsid proteins. Antibody titres in assays based on VLPs of BKV (strain SB) showed no correlation to the titres in similar JCV assays. BKV (SB) seropositivity increases rapidly with increasing age of the children and reaches a 98 % seroprevalence at 7-9 years of age, whereas JCV seroprevalences increase more slowly with increasing age reaching 51 % positivity among children 9-11 years of age. The antibody levels are almost identical in serial samples taken up to 5 years apart, suggesting that both BKV and JCV VLP seropositivitities are usually stable over time and can be used to measure cumulative exposure to these viruses. Serology using SV40 VLPs showed strong cross-reactivity with human polyomaviruses, in particular with BKV strain AS, and establishing a specific VLP-based serology assay for SV40 required blocking with several hyperimmune sera to the human polyomaviruses. SV40-specific seropositivity also increased with increasing age of children, reaching 14% seroprevalence among children 7-9 years of age, but had limited stability over time in serial samples.

Antibodies, Viral↗

PubMed2006

Should donors be allowed to give broad consent to future biobank research?

Large international biobank studies can make substantial contributions to scientific research by validation of the biological importance of previous research and by identification of previously unknown causes of disease. However, regulations for patient consent that are too strict and discrepancies in national policies on informed consent might hinder progress. Therefore, establishment of common ground for ethical review of biobank research is essential. In this essay, broad consent is defined on a scale between strictly specified (eg, for a specific study) and blanket consent (ie, with no restrictions regarding the purpose of the research). Future research includes that which might not be planned or even conceptualised when consent is obtained. In conclusion, broad consent and consent for future research are valid ethically and should be recommended for biobank research provided that: personal information related to research is handled safely; donors of biological samples are granted the right to withdraw consent; and new research studies or changes to the legal or ethical authority of a biobank are approved by an ethics-review board.

Confidentiality↗

PubMed2005

Chlamydia trachomatis infection and persistence of human papillomavirus.

Human papillomavirus (HPV) persistence is the major cause of cervical cancer, but most HPV infections will not persist and risk factors for HPV persistence are not well known. Chlamydia (C.) trachomatis infection seems to also be associated with cervical cancer. We investigated whether C. trachomatis infection is a risk factor for HPV persistence. In a cohort of 12,527 women participating in a population-based HPV screening trial in Sweden, 6,418 women completed testing for HPV DNA by general primer PCR and typing by reverse dot blot hybridization. On average 19 months later, 303 women that had been HPV-positive and had normal cytology at enrollment completed a new HPV test. Environmental exposures were assessed by an 87-item questionnaire. Previous sexually transmitted infections were also investigated by serology. At follow-up, 44% of the women were positive for the same type of HPV DNA as at enrollment. Persistence correlated with length of follow-up (p < 0.01) and condom use seemed to protect against HPV persistence (p < 0.05). The most significant risk factor for persistent presence of HPV DNA was self-reported history of previous C. trachomatis infection (relative risk in multivariate model = 2.09; 95% confidence interval = 1.05-4.18). We conclude that persistence of oncogenic HPV infections is more likely among women with a previous C. trachomatis infection.

Adult↗

PubMed2005

No serological evidence of association between prostate cancer and infection with herpes simplex virus type 2 or human herpesvirus type 8: a nested case-control study.

Sexual history has consistently been found to be a risk factor for the development of prostate cancer. An association between prostate cancer and herpes simplex virus type 2 (HSV-2) or Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (HHV-8) infections has also been reported. Linkage of data on a cohort of 20,243 healthy Finnish men identified 165 cases of prostate cancer that were diagnosed up to 24 years after donation of a serum sample. Two control subjects were matched by age, sex, and municipality of residence to each case patient. Serum levels of immunoglobulin G against HSV-2 and HHV-8 were determined. Neither HSV-2 infection (odds ratio [OR], 0.93 [95% confidence interval {CI}, 0.44-1.96]) nor HHV-8 infection (OR, 0.74 [95% CI, 0.19-2.88]) was associated with prostate cancer.

Adolescent↗

PubMed2005

Maternal human polyomavirus infection and risk of neuroblastoma in the child.

To investigate if polyomavirus infection during pregnancy is linked to development of neuroblastoma in the child, serum samples of 115 index mothers from the pregnancy where the child eventually developed neuroblastoma were identified and matched with serum samples from 8 control mothers per index mother. The samples were tested for specific IgG and IgM antibodies to BK and JC virus using enzyme immunoassays based on purified yeast-expressed virus-like particles (VLPs). The serum samples as well as 10 neuroblastoma cell lines were also analyzed using Real Time (TaqMan) PCR for detection and quantification of BK virus DNA. The BK virus IgG seroprevalence was similar among index mothers (80%) and control mothers (83%) [OR 0.8; 95% confidence interval (95% CI): 0.5-1.3]. BK virus IgM was also not associated with neuroblastoma risk (OR was OR = 0.6; 95% with CI, 0.2-1.9). Also JC virus had no association, neither for IgG (OR = 0.9; 95% CI, 0.6-1.4) nor for IgM (OR = 0.9; 95% CI, 0.4-1.9). All serum samples and all neuroblastoma cell lines were negative for BKV DNA. In summary, a comprehensive cohort using both serology and polyomavirus DNA detection found no evidence for association between BKV or JCV polyomaviruses and neuroblastoma.

Adolescent↗

PubMed2005

Heparan sulfate proteoglycans interact exclusively with conformationally intact HPV L1 assemblies: basis for a virus-like particle ELISA.

In this article, we demonstrate that interaction of human papillomavirus-like particles (HPV-VLPs) with the putative glucosaminoglycan binding receptor is strictly dependent on conformational integrity. Such conformations are present on VLPs and capsomeres but not on monomers of the major capsid protein, L1, confirming reports that capsomeres can induce virus-neutralizing antibodies. Furthermore, we show the suitability of this specific interaction for development of VLP-based enzyme-linked immunosorbent assays (ELISAs), using heparin for indirect coupling of VLPs to microtiter plates, which may add an intrinsic quality control. This avoids presentation of linear, often highly cross-reactive epitopes of L1. In addition, heparin specifically interacts with a wide variety of HPV types, making it a prime candidate for a universal capture molecule.

Antibodies, Viral↗

PubMed2005

Colposcopic and histopathologic evaluation of women participating in population-based screening for human papillomavirus deoxyribonucleic acid persistence.

OBJECTIVE: Evaluation of colposcopic and histopathological findings in women screened for cervical human papillomavirus deoxyribonucleic acid persistence. STUDY DESIGN: A total of 12 527 women, aged 32 to 38 years old, attending the population-based cervical cancer screening program in Sweden were randomized 1:1 to mock testing or human papillomavirus deoxyribonucleic acid testing by general primer 5+/6+ polymerase chain reaction and subsequent typing. Human papillomavirus deoxyribonucleic acid-positive women with a normal Papanicolaou smear (n=341) and an equal number from the control group were human papillomavirus tested on average 19 months later. One hundred nineteen women with type-specific human papillomavirus persistence and 111 controls were referred to colposcopy, and 84.8% attended. RESULTS: Histopathology from colposcopically directed biopsies confirmed cervical intraepithelial neoplasia grade 2 or 3 in 28 of 100 of the women with human papillomavirus deoxyribonucleic acid persistence and in 2 of 95 among controls. CONCLUSION: Among women with normal Papanicolaou smear attending population-based screening, the positive predictive value of human papillomavirus deoxyribonucleic acid persistence for detection of biopsy-confirmed cervical intraepithelial neoplasia 2 or 3 was 29%.

Adult↗

PubMed2005

Heparin-based ELISA reduces background reactivity in virus-like particle-based papillomavirus serology.

The interaction between human papillomavirus (HPV) particles and cell surface heparan sulfate requires intact conformation of the HPV particles. Type-specific HPV serology is currently based on virus-like particles (VLPs) with intact conformation. Presence of incorrectly folded VLPs in VLP preparations is recognized as an important cause of cross-reactivity in HPV serology. Heparin-coated microtitre plates were evaluated for capturing conformationally correct VLPs and improving the type specificity of HPV serology. Hybrid VLPs between HPV16 and HPV11, which had been found to have significant reactivity with children's sera and a batch of HPV18 VLPs that had failed the quality control because of significant reactivity with sera from virginal women, were tested in parallel with heparin ELISA, ordinary ELISA and type-specific mAb capture ELISA. Control sera from children that had detectable reactivity with HPV16/11 hybrid VLPs in ordinary ELISA did not react in heparin-based ELISA, but some hybrid VLPs also had background reactivity in capture ELISAs. Control sera from virginal women that had some reactivity with a poor quality HPV18 VLP preparation in ordinary ELISA had no reactivity in heparin or capture ELISA, suggesting that certain VLP preparations expose cross-reactive epitopes that are not exposed on VLPs with heparin-binding ability. As the sensitivity was similar or only marginally affected by the use of heparin plates, use of heparin-coated plates may improve the type specificity of VLP-based ELISAs and reduce interassay variability attributable to variable quality of different VLP batches.

Adolescent↗

PubMed2005

Prevalence and stability of human serum antibodies to simian virus 40 VP1 virus-like particles.

Possible human infection with simian virus 40 (SV40) has been of great concern ever since SV40 was discovered in polio vaccines. Human populations are SV40-seropositive, but because of serological cross-reactivity between SV40 and the human polyomaviruses BK virus (BKV) and JC virus (JCV), it is debatable whether these antibodies are specific. An SV40-specific serological assay was established, based on purified virus-like particles (VLPs), where the SV40 VLPs were blocked with hyperimmune sera to BKV and JCV. Competition with SV40 hyperimmune sera was used as a confirmatory test. Among 288 Swedish children of between 1 and 13 years of age, 7.6 % had SV40-specific antibodies. SV40 seroprevalence reached a peak of 14 % at 7-9 years of age. Among 100 control patients with benign tumours, 9 % were SV40-seropositive. However, SV40 DNA was not detectable in corresponding buffy-coat samples. In serial samples taken up to 5 years apart from 141 Finnish women participating in the population-based serological screening for congenital infections, only two of 141 women were SV40-seropositive in both samples. Six women seroconverted and eight women had a loss of antibodies over time. None of the SV40-seropositive samples contained detectable SV40 DNA. In conclusion, there is a low prevalence of SV40-specific antibodies in the Nordic population. The SV40 antibodies appear to have a low stability over time and their origin is not clear.

Adolescent↗