Epidemiological and clinical insights into the enterovirus D68 upsurge in Europe 2021/22 and the emergence of novel B3-derived lineages, ENPEN multicentre study.

Enterovirus D68 (EV-D68) infections are associated with severe respiratory disease and acute flaccid myelitis (AFM). The European Non-Polio Enterovirus Network (ENPEN) aimed to investigate the epidemiological and genetic characteristics of EV-D68 and its clinical impact during the fall-winter season of 2021/22. From 19 European countries, 58 institutes reported 10,481 (6.8%) EV-positive samples of which 1,004 (9.6%) were identified as EV-D68 (852 respiratory samples). Clinical data was reported for 969 cases. 78.9% of infections were reported in children (0-5 years); 37.9% of cases were hospitalised. Acute respiratory distress was commonly noted (93.1%) followed by fever (49.4%). Neurological problems were observed in 6.4% of cases with six reported with AFM. Phylodynamic/Nextstrain and phylogenetic analyses based on 694 sequences showed the emergence of two novel B3-derived lineages, with no regional clustering. In conclusion, we describe a large-scale EV-D68 European upsurge with severe clinical impact and the emergence of B3-derived lineages.

Early detection of the emerging SARS-CoV-2 BA.2.86 lineage through integrated genomic surveillance of wastewater and COVID-19 cases in Sweden, weeks 31 to 38 2023.

The SARS-CoV-2 BA.2.86 Omicron subvariant was first detected in wastewater in Sweden in week 31 2023, using 21 highly specific markers from the 50 investigated. We report BA.2.86's introduction and subsequent spread to all 14 regions performing wastewater sampling, and on 70 confirmed COVID-19 cases, along with the emergence of sublineages JN.1 and JN.2. Further, we investigated two novel mutations defining the unique BA.2.86 branching in Sweden. Our integrated approach enabled variant tracking, offering evidence for well-informed public health interventions.

Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis.

BACKGROUND: Screening for human papillomavirus (HPV) infection is more effective in reducing the incidence of cervical cancer than screening using Pap smears. Moreover, HPV testing can be done on a vaginal sample self-taken by a woman, which offers an opportunity to improve screening coverage. However, the clinical accuracy of HPV testing on self-samples is not well-known. We assessed whether HPV testing on self-collected samples is equivalent to HPV testing on samples collected by clinicians. METHODS: We identified relevant studies through a search of PubMed, Embase, and CENTRAL. Studies were eligible for inclusion if they fulfilled all of the following selection criteria: a cervical cell sample was self-collected by a woman followed by a sample taken by a clinician; a high-risk HPV test was done on the self-sample (index test) and HPV-testing or cytological interpretation was done on the specimen collected by the clinician (comparator tests); and the presence or absence of cervical intraepithelial neoplasia grade 2 (CIN2) or worse was verified by colposcopy and biopsy in all enrolled women or in women with one or more positive tests. The absolute accuracy for finding CIN2 or worse, or CIN grade 3 (CIN3) or worse of the index and comparator tests as well as the relative accuracy of the index versus the comparator tests were pooled using bivariate normal models and random effect models. FINDINGS: We included data from 36 studies, which altogether enrolled 154 556 women. The absolute accuracy varied by clinical setting. In the context of screening, HPV testing on self-samples detected, on average, 76% (95% CI 69-82) of CIN2 or worse and 84% (72-92) of CIN3 or worse. The pooled absolute specificity to exclude CIN2 or worse was 86% (83-89) and 87% (84-90) to exclude CIN3 or worse. The variation of the relative accuracy of HPV testing on self-samples compared with tests on clinician-taken samples was low across settings, enabling pooling of the relative accuracy over all studies. The pooled sensitivity of HPV testing on self-samples was lower than HPV testing on a clinician-taken sample (ratio 0·88 [95% CI 0·85-0·91] for CIN2 or worse and 0·89 [0·83-0·96] for CIN3 or worse). Also specificity was lower in self-samples versus clinician-taken samples (ratio 0·96 [0·95-0·97] for CIN2 or worse and 0·96 [0·93-0·99] for CIN3 or worse). HPV testing with signal-based assays on self-samples was less sensitive and specific than testing on clinician-based samples. By contrast, some PCR-based HPV tests generally showed similar sensitivity on both self-samples and clinician-based samples. INTERPRETATION: In screening programmes using signal-based assays, sampling by a clinician should be recommended. However, HPV testing on a self-sample can be suggested as an additional strategy to reach women not participating in the regular screening programme. Some PCR-based HPV tests could be considered for routine screening after careful piloting assessing feasibility, logistics, population compliance, and costs. FUNDING: The 7th Framework Programme of the European Commission, the Belgian Foundation against Cancer, the International Agency for Research on Cancer, and the German Guideline Program in Oncology.

COVID-19 Vaccine Effectiveness in Autumn and Winter 2022 to 2023 Among Older Europeans.

Importance: In the context of emerging SARS-CoV-2 variants or lineages and new vaccines, it is key to accurately monitor COVID-19 vaccine effectiveness (CVE) to inform vaccination campaigns. Objective: To estimate the effectiveness of COVID-19 vaccines administered in autumn and winter 2022 to 2023 against symptomatic SARS-CoV-2 infection (with all circulating viruses and XBB lineage in particular) among people aged 60 years or older in Europe, and to compare different CVE approaches across the exposed and reference groups used. Design, Setting, and Participants: This case-control study obtained data from VEBIS (Vaccine Effectiveness, Burden and Impact Studies), a multicenter study that collects COVID-19 and influenza data from 11 European sites: Croatia; France; Germany; Hungary; Ireland; Portugal; the Netherlands; Romania; Spain, national; Spain, Navarre region; and Sweden. Participants were primary care patients aged 60 years or older with acute respiratory infection symptoms who were recruited at the 11 sites after the start of the COVID-19 vaccination campaign from September 2022 to August 2023. Cases and controls were defined as patients with positive and negative, respectively, reverse transcription-polymerase chain reaction (RT-PCR) test results. Exposures: The exposure was COVID-19 vaccination. The exposure group consisted of patients who received a COVID-19 vaccine during the autumn and winter 2022 to 2023 vaccination campaign and 14 days or more before symptom onset. Reference group included patients who were not vaccinated during or in the 6 months before the 2022 to 2023 campaign (seasonal CVE), those who were never vaccinated (absolute CVE), and those who were vaccinated with at least the primary series 6 months or more before the campaign (relative CVE). For relative CVE of second boosters, patients receiving their second booster during the campaign were compared with those receiving 1 booster 6 months or more before the campaign. Main Outcomes and Measures: The outcome was RT-PCR-confirmed, medically attended, symptomatic SARS-CoV-2 infection. Four CVE estimates were generated: seasonal, absolute, relative, and relative of second boosters. CVE was estimated using logistic regression, adjusting for study site, symptom onset date, age, chronic condition, and sex. Results: A total of 9308 primary care patients were included, with 1687 cases (1035 females; median [IQR] age, 71 [65-79] years) and 7621 controls (4619 females [61%]; median [IQR] age, 71 [65-78] years). Within 14 to 89 days after vaccination, seasonal CVE was 29% (95% CI, 14%-42%), absolute CVE was 39% (95% CI, 6%-60%), relative CVE was 31% (95% CI, 15% to 44%), and relative CVE of second boosters was 34% (95% CI, 18%-47%) against all SARS-CoV-2 variants. In the same interval, seasonal CVE was 44% (95% CI, -10% to 75%), absolute CVE was 52% (95% CI, -23% to 82%), relative CVE was 47% (95% CI, -8% to 77%), and relative CVE of second boosters was 46% (95% CI, -13% to 77%) during a period of high XBB circulation. Estimates decreased with time since vaccination, with no protection from 180 days after vaccination. Conclusions and Relevance: In this case-control study among older Europeans, all CVE approaches suggested that COVID-19 vaccines administered in autumn and winter 2022 to 2023 offered at least 3 months of protection against symptomatic, medically attended, laboratory-confirmed SARS-CoV-2 infection. The effectiveness of new COVID-19 vaccines against emerging SARS-CoV-2 variants should be continually monitored using CVE seasonal approaches.

Decline of the new Swedish variant of Chlamydia trachomatis after introduction of appropriate testing.

OBJECTIVE: The longitudinal epidemiological development of the new variant of Chlamydia trachomatis was studied after appropriate testing procedures had been introduced when the strain was detected in 2006. METHODS: The number of cases of the new variant of C trachomatis was followed from 2007 through 2011 from the laboratory records. Testing for C trachomatis is centralised to one laboratory with around 80-85 000 persons being tested annually in a population of 1.1 million. RESULTS: During the 5-year period, 410 973 patients were tested of which 25 723 cases were positive. The proportion of the new variant of all positive cases declined from 30% in 2007 to 6% in 2011. While the number of the new variant of C trachomatis declined, the ordinary wild-type strains remained largely unchanged. CONCLUSIONS: A selective decline of the new variant of C trachomatis has occurred after appropriate laboratory testing was introduced. A new balance point between 5% and 10% for the new variant seems to be gradually approached.

Randomized healthservices study of human papillomavirus-based management of low-grade cytological abnormalities.

Human papillomavirus (HPV)-based management of women with borderline atypical squamous cells of undetermined significance (ASCUS) or mildly abnormal cervical intraepithelial neoplasia (CINI) cervical cytology has been extensively studied in the research setting. We wished to assess safety and health care resource use of a real-life health care policy using HPV triaging. All 15 outpatient clinics involved in the organized population-based screening program in Stockholm, Sweden screening program were randomized to either continue with prior policy (colposcopy of all women with ASCUS/CINI) or to implement a policy with HPV triaging and colposcopy only of HPV-positive women. The trial enrolled the 3,319 women who were diagnosed with ASCUS (n = 1,335) or CINI (n = 1,984) in Stockholm during 17th March 2003 to 16th January 2006. Detection of high-grade cervical lesions (CINII+) and health care cost consumption was studied by registry linkages. The proportion of histopathology-verified CINII+ was similar for the two policies (395 of 1,752 women (22.5%; 95% Confidence interval [CI]: 20.6-24.6%) had CINII+ diagnosed with HPV triaging policy, 318 of 1,567 women (20.3%; 95%CI: 18.3-22.4%) had CINII+ with colposcopy policy). Sixty-four percent of women with ASCUS and 77% of women with CINI were HPV positive. HPV-positivity was age-dependent, with 81% of women below 35 years of age and 44% of women above 45 years of age testing HPV-positive. HPV triaging was cost-effective only above 35 years of age. In conclusion, a real-life randomized healthservices study of HPV triaging of women with ASCUS/CINI demonstrated similar detection of CINII+ as colposcopy of all women.

Genotyping of human papillomavirus in triaging of low-grade cervical cytology.

OBJECTIVE: The objective of the study was to evaluate whether typing of human papillomavirus (HPV) among women with low-grade cervical cytology can improve the ability to identify women with cervical cancer or cervical intraepithelial neoplasia grade III (CIN III or worse). STUDY DESIGN: A total of 1595 women with low-grade cervical cytology participating in a randomized implementation trial of HPV triaging using Hybrid Capture II were also HPV genotyped and CIN III or worse predictive values evaluated. RESULTS: HPV 16 was detected in 57% of cases with CIN III or worse but only among 24% of all tested women. Testing for the 3 HPV types with highest risk (HPV16/31/33) detected 77% of CIN III or worse, with 36% of women testing positive. Positivity for the other high-risk HPV types had a decreased risk for CIN III or worse. CONCLUSION: Different high-risk HPV types confer different risks for the presence of CIN III or worse, implying that HPV genotyping could be useful for the optimization of triaging strategies.

Norovirus strains belonging to the GII.4 genotype dominate as a cause of nosocomial outbreaks of viral gastroenteritis in Sweden 1997--2005. Arrival of new variants is associated with large nation-wide epidemics.

BACKGROUND: In recent years an increase of the incidence of nosocomial outbreaks caused by noroviruses has been observed throughout Sweden, with high peaks noted in the winter seasons 2002/2003 and 2004/2005, respectively. OBJECTIVES: To phylogenetically characterize norovirus strains causing nosocomial outbreaks from 1997 to 2005 and estimate the impact of norovirus-like disease on the Swedish health care system during the peak season 2002/2003 when a new variant of norovirus occurred. STUDY DESIGN: Stool samples from 115 randomly selected nosocomial outbreaks occurring during 1997--2005 throughout Sweden were studied by RT-PCR and sequencing. In addition, to investigate the impact on the health-care system, a questionnaire was distributed to infection control units (n=90) serving all Swedish hospitals, nursing homes and other health-care institutions during the largest epidemic of nosocomial outbreaks. RESULTS: Sequencing of 279 nucleotides of the norovirus RNA polymerase gene in stools containing norovirus RNA showed that strains belonging to the GII.4 genotype dominated. Each of the two large epidemics was due to a new variant within this cluster. The questionnaire revealed that 30,000-35,000 episodes of nosocomial norovirus-like infections occurred in 80 of 82 major Swedish hospitals affected in 2002/2003. CONCLUSION: New norovirus variants within the cluster GGII.4 may have a major impact on the health-care system.

Around-the-clock, rapid diagnosis of influenza by means of membrane chromatography antigen testing confirmed by polymerase chain reaction.

One rapid membrane chromatography test and 2 immunofluorescence tests were compared with polymerase chain reaction as tools for the diagnosis of influenza in 277 patients treated in an emergency department. The sensitivity on days 1-3 of symptoms was 71% for the rapid membrane chromatography test, 70% for the first immunofluorescence test, and 79% for the second immunofluorescence test. Rapid tests are useful for round-the-clock identification of influenza, with follow-up polymerase chain reaction used for confirmation.

A randomized trial of basing treatment on human papillomavirus and/or cytology results in low-grade cervical lesion triage.

OBJECTIVE: This study was undertaken to compare management algorithms that base treatment with loop electrosurgical excision procedure on human papillomavirus and/or repeat Papanicolaou test smear results. STUDY DESIGN: A randomized trial that referred 674 women with either atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions cytology results, detected in organized screening to treatment either (1) if they were positive in a repeat Papanicolaou test smear and/or a human papillomavirus test or (2) if they were positive in the repeat Papanicolaou test smear test only. Women who tested positive were treated, regardless of colposcopic findings. RESULTS: There were 208 of 337 (62%) women who were treated in the human papillomavirus /Papanicolaou test smear group (187/337 because of HPV positivity) and 138 of 337 (41%) in the Papanicolaou test smear only group. Histopathologically diagnosed cervical intraepithelial neoplasia grade 2 or worse was found among 112 of 337 (33.2%) women in the human papillomavirus/Papanicolaou test smear group compared with 85 of 337 (25.2%) women in the Papanicolaou test smear only group (P < .05). Twenty-one women with cervical intraepithelial neoplasia 2+ had normal colposcopy. CONCLUSION: For adequate cervical intraepithelial neoplasia 2+ sensitivity, the decision to use loop electrosurgical excision procedure needs to be based on human papillomavirus testing results and should not exclude women with normal colposcopy.

Strengthening prevention programs to eliminate cervical cancer in the Nordic countries.

Disease trend studies based on birth cohort analysis and serological studies indicate that recent generations have a higher prevalence of oncogenic Human Papilloma Virus (HPV) types, and are likely to be at higher risk of cancer than previous generations. This implies that prevention strategies to protect young populations from HPV-associated cancers need to be strengthened, and hence organized implementation of vaccination and better screening programs are being considered. In this context, randomized large-scale policy evaluations will be instrumental in accelerating disease control and improve effective prevention programs. This report shares experiences from Nordic countries with examples of prevention strategies through vaccination and cervical screening. The same principles as set up for organized programs and new HPV technologies may apply for screening and vaccination as key tools to eliminate cervical cancer in the Nordic countries and globally.

European Code against Cancer, 4th Edition: Cancer screening.

In order to update the previous version of the European Code against Cancer and formulate evidence-based recommendations, a systematic search of the literature was performed according to the methodology agreed by the Code Working Groups. Based on the review, the 4th edition of the European Code against Cancer recommends: "Take part in organized cancer screening programmes for: Bowel cancer (men and women); Breast cancer (women); Cervical cancer (women)." Organized screening programs are preferable because they provide better conditions to ensure that the Guidelines for Quality Assurance in Screening are followed in order to achieve the greatest benefit with the least harm. Screening is recommended only for those cancers where a demonstrated life-saving effect substantially outweighs the potential harm of examining very large numbers of people who may otherwise never have, or suffer from, these cancers, and when an adequate quality of the screening is achieved. EU citizens are recommended to participate in cancer screening each time an invitation from the national or regional screening program is received and after having read the information materials provided and carefully considered the potential benefits and harms of screening. Screening programs in the European Union vary with respect to the age groups invited and to the interval between invitations, depending on each country's cancer burden, local resources, and the type of screening test used For colorectal cancer, most programs in the EU invite men and women starting at the age of 50-60 years, and from then on every 2 years if the screening test is the guaiac-based fecal occult blood test or fecal immunochemical test, or every 10 years or more if the screening test is flexible sigmoidoscopy or total colonoscopy. Most programs continue sending invitations to screening up to the age of 70-75 years. For breast cancer, most programs in the EU invite women starting at the age of 50 years, and not before the age of 40 years, and from then on every 2 years until the age of 70-75 years. For cervical cancer, if cytology (Pap) testing is used for screening, most programs in the EU invite women starting at the age of 25-30 years and from then on every 3 or 5 years. If human papillomavirus testing is used for screening, most women are invited starting at the age of 35 years (usually not before age 30 years) and from then on every 5 years or more. Irrespective of the test used, women continue participating in screening until the age of 60 or 65 years, and continue beyond this age unless the most recent test results are normal.

Population-based study of screening test performance indices of three human papillomavirus DNA tests.

In order to evaluate three common human papillomavirus (HPV) DNA tests for key performance indices in population-based cervical screening, we sampled 12,527 women aged 32-38 years who attended invitational, population-based screening and followed them for 4 years with comprehensive registry linkages. Three different HPV DNA tests (GP5+/6+ general primer PCR (using either AmpliTaq or AmpliTaq Gold DNA polymerase), Amplicor PCR and Hybrid Capture II were evaluated using baseline samples from women who on follow-up developed cervical intraepithelial neoplasia grade 2 or worse (CINII+) (n = 197) as well as a representative subsample of the women in the cohort (n = 794). The population-based HPV prevalence, sensitivity for future cervical intraepithelial neoplasia grade 2 or worse (CINII+), and absolute risk of CINII+ was 7.1%, 87.1%, and 23.2% for AmpliTaq GP5+/6+ PCR, 11.9%, 88.9%, and 11.0% for AmpliTaq Gold GP5+/6+ PCR, 15.7%, 93.4%, and 9.8% for Amplicor, 10.0%, 92.9%, and 15.3% for Amplicor with raised cut-off, and 7.8%, 79.7%, and 16.9% for Hybrid Capture II. In conclusion, AmpliTaq GP5+/6+ PCR and Amplicor with raised cut-off value have adequate performance indices for primary screening.

A comparison of the human papillomavirus test and Papanicolaou smear as a second screening method for women with minor cytological abnormalities.

BACKGROUND: Of the estimated one million Papanicolaou (pap) smears performed annually in Sweden, about 4% show any degree of abnormality. Approximately, 1% of these cases contain moderate or severe atypia (high-grade squamous intraepithelial lesions) and the rest contain low-grade atypia. Recommendations for the management of minor abnormalities vary in various parts of Sweden. Generally, a second Pap smear is obtained 4-6 months after the first one showing low-grade atypia. The aim of this study is to compare the sensitivity of human papilloma virus (HPV)-DNA testing for the detection of cervical intraepithelial neoplasia (CIN) 2-3 with that of a second Pap smear in women, who had low-grade atypia in their first Pap smear. METHODS: Women with low-grade atypia in the Stockholm area, detected at a population-based cytology screening, were enrolled. A repeat Pap smear, HPV test, and colposcopically directed biopsies were obtained. For the detection of HPV, Hybrid Capture II (HC II) was used. RESULTS: The HPV-DNA test was positive in 66% of the 177 participating women. The sensitivity of the second Pap smear and HPV-DNA test to detect CIN 2-3 was 61 (95% CI = 45-74) and 82% (95% CI = 67-91), respectively. The positive and negative predictive values of HPV testing were 27 (95% CI = 18-35) and 89% (95% CI = 80-97), respectively. CONCLUSIONS: In Sweden, a second Pap smear is often obtained for the follow-up of women with low-grade atypia. The results of our study show that compared to the second Pap smear, HPV testing with HC II is a more sensitive method for detecting high-grade lesions.

Comparison between the Hybrid Capture II test and a PCR-based human papillomavirus detection method for diagnosis and posttreatment follow-up of cervical intraepithelial neoplasia.

Human papillomavirus (HPV) infection is the major cause of cervical cancer and its precursor, cervical intraepithelial neoplasia (CIN), and HPV testing has therefore been proposed for improved triaging and follow-up of women treated for CIN. We compared two common HPV DNA detection tests (Hybrid Capture II [HCII] and PCR-enzyme immunosorbent assay (EIA) using the primers GP5+/GP6+ followed by HPV typing with reverse dot blot hybridization) for sensitivity and specificity for detection of CIN and of CIN recurrence after treatment. Two hundred and thirty-nine women referred to the Department of Obstetrics and Gynaecology in Västerås, Sweden, were enrolled because of atypical Pap smears; 177 of these were later treated for dysplasia by conization or loop diathermy. Samples for HPV DNA testing were taken before and 4 to 6 months after treatment. There was substantial agreement between the HCII and PCR-EIA (kappa, 0.70 before treatment and 0.72 after treatment). The sensitivity for histopathologically confirmed CIN III was 100.0% for PCR-EIA and 95.6% for HCII. For patients with CIN II or worse (CIN II+), the sensitivities were 92.9% (PCR-EIA) and 91.8% (HCII). The specificities for CIN II+ in the pretreatment setting were 30.4% for PCR-EIA and 24.1% for HCII. After treatment, the sensitivities for CIN III in cytology were 100.0% by both methods, and for CIN II+, sensitivities were 80.0% by both methods. The specificities for CIN II+ in the posttreatment setting were 83.5% for PCR and 85.4% for HCII. In conclusion, the sensitivities of both PCR-EIA and HCII are high and almost equal, suggesting that both methods are suitable as tools for detection and posttreatment follow-up of CIN II-III.