Survival among people with HIV and their families in Denmark 1995-2021: a nationwide population-based cohort study.

Background: Survival among people with HIV (PWH) has vastly improved globally over the last few decades but remains lower than among the general population. We aimed to estimate time trends of survival among PWH and their families from 1995 to 2021. Methods: We conducted a registry-based, nationwide, population-based, matched cohort study. We included all Danish-born PWH from 1995 to 2021 who had been on antiretroviral therapy for 90 days, did not report intravenous drug use, and were not co-infected with hepatitis C (n = 4168). We matched population controls from the general population 10:1 to PWH by date of birth and sex (n = 41,680). For family cohorts, we identified siblings, mothers, and fathers of PWH and population controls. From Kaplan-Meier tables with age as time scale, we estimated survival from age 25. We compared PWH with population controls and families of PWH with families of population controls to calculate mortality rate ratios adjusted for sex, age, comorbidities, and education (aMRR). Findings: The median age of death among PWH increased from 27.5 years in 1995-1997 to 73.9 years (2010-2014), but thereafter survival increased only marginally. From 2015 to 2021, mortality was increased among PWH (aMRR 1.87 (95% CI: 1.65-2.11)) and siblings (aMRR: 1.25 (95% CI: 1.07-1.47)), mothers (aMRR: 1.30 (95% CI: 1.17-1.43)), and fathers (aMRR: 1.15 (95% CI: 1.03-1.29)) of PWH compared to their respective control cohorts. Mortality among siblings of PWH who reported heterosexual route of HIV transmission (aMRR: 1.51 (95% CI: 1.16-1.96)) was higher than for siblings of PWH who reported men who have sex with men as route of HIV transmission (aMRR 1.19 (95% CI: 0.98-1.46)). Interpretation: Survival among PWH improved substantially until 2010, after which it increased only marginally. This may partly be due to social and behavioural factors as PWH families also had higher mortality. Funding: Preben and Anna Simonsen's Foundation and Independent Research Fund Denmark.

Effects of high-dose versus standard-dose quadrivalent influenza vaccine among patients with diabetes: A post-hoc analysis of the DANFLU-1 trial.

AIM: High-dose quadrivalent influenza vaccine (QIV-HD) has been shown to be more effective than standard-dose (QIV-SD) in reducing influenza infection, but whether diabetes status affects relative vaccine effectiveness (rVE) is unknown. We aimed to assess rVE on change in glycated haemoglobin [HbA1c (∆HbA1c)], incident diabetes, total all-cause hospitalizations (first + recurrent), and a composite of all-cause mortality and hospitalization for pneumonia or influenza. METHODS: DANFLU-1 was a pragmatic, open-label trial randomizing adults (65-79 years) 1:1 to QIV-HD or QIV-SD during the 2021/22 influenza season. Cox proportional hazards regression was used to estimate rVE against incident diabetes and the composite endpoint, negative binomial regression to estimate rVE against all-cause hospitalizations, and ANCOVA when assessing rVE against ∆HbA1c. RESULTS: Of the 12 477 participants, 1162 (9.3%) had diabetes at baseline. QIV-HD, compared with QIV-SD, was associated with a reduction in the rate of all-cause hospitalizations irrespective of diabetes [overall: 647 vs. 742 events, incidence rate ratio (IRR): 0.87, 95% CI (0.76-0.99); diabetes: 93 vs. 118 events, IRR: 0.80, 95% CI (0.55-1.15); without diabetes: 554 vs. 624 events, IRR: 0.88, 95% CI (0.76-1.01), pinteraction = 0.62]. Among those with diabetes, QIV-HD was associated with a lower risk of the composite outcome [2 vs. 11 events, HR: 0.18, 95% CI (0.04-0.83)] but had no effect on ∆HbA1c; QIV-HD adjusted mean difference: ∆ + 0.2 mmol/mol, 95% CI (-0.9 to 1.2). QIV-HD did not affect the risk of incident diabetes [HR 1.18, 95% CI (0.94-1.47)]. CONCLUSIONS: In this post-hoc analysis, QIV-HD versus QIV-SD was associated with an increased rVE against the composite of all-cause death and hospitalization for pneumonia/influenza, and the all-cause hospitalization rate irrespective of diabetes status.

Rationale and design of NUDGE-FLU-CHRONIC and NUDGE-FLU-2: Two nationwide randomized trials of electronic nudges to increase influenza vaccination among patients with chronic diseases and older adults during the 2023/2024 influenza season.

BACKGROUND: Yearly influenza vaccination is strongly recommended for older adults and patients with chronic diseases including cardiovascular disease (CVD); however, vaccination rates remain suboptimal, particularly among younger patients. Electronic letters incorporating behavioral nudges are highly scalable public health interventions which can potentially increase vaccination, but further research is needed to determine the most effective strategies and to assess effectiveness across different populations. The purpose of NUDGE-FLU-CHRONIC and NUDGE-FLU-2 are to evaluate the effectiveness of electronic nudges delivered via the Danish governmental electronic letter system in increasing influenza vaccination among patients with chronic diseases and older adults, respectively. METHODS: Both trials are designed as pragmatic randomized implementation trials enrolling all Danish citizens in their respective target groups and conducted during the 2023/2024 influenza season. NUDGE-FLU-CHRONIC enrolls patients aged 18-64 years with chronic diseases. NUDGE-FLU-2 builds upon the NUDGE-FLU trial conducted in 2022/2023 and aims to expand the evidence by testing both previously successful and new nudges among adults ≥65 years during a subsequent influenza season. Persons with exemptions from the electronic letter system are excluded from both trials. In both trials, participants are randomized in a 2.45:1:1:1:1:1:1 ratio to either receive no electronic letter (usual care) or to receive one of 6 different behaviorally informed electronic letters. NUDGE-FLU-CHRONIC has randomized 299,881 participants with intervention letters delivered on September 24, 2023, while NUDGE-FLU-2 has randomized 881,373 participants and delivered intervention letters on September 13, 2023. Follow-up is currently ongoing. In both trials, the primary endpoint is receipt of influenza vaccination on or before January 1, 2024, and the secondary endpoint is time to vaccination. Clinical outcomes including respiratory and cardiovascular hospitalizations, all-cause hospitalization, and mortality are included as prespecified exploratory endpoints. Prespecified individual-level pooled analyses will be conducted across NUDGE-FLU, NUDGE-FLU-CHRONIC, and NUDGE-FLU-2. DISCUSSION: NUDGE-FLU-CHRONIC is the first nationwide randomized trial of electronic nudges to increase influenza vaccination conducted among 18-64-year-old high-risk patients with chronic diseases. NUDGE-FLU-2 will provide further evidence on the effectiveness of electronic nudges among older adults ≥65 years. Collectively, the NUDGE-FLU trials will provide an extensive evidence base for future public health communications. TRIAL REGISTRATION: NUDGE-FLU-CHRONIC: Clinicaltrials.gov: NCT06030739, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030739. NUDGE-FLU-2: Clinicaltrials.gov: NCT06030726, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030726.

Vaccines against respiratory syncytial virus.

Respiratory syncytial virus (RSV is) a common respiratory virus responsible for considerable morbidity and mortality among infants, elderly with comorbidity, and immunocompromised adults. Two vaccines, Abrysvo and Arexvy, have been approved for prevention of severe RSV infection in adults ≥ 60 years of age. In addition, Abrysvo is approved for use during pregnancy to protect infants from RSV-associated lower respiratory tract infection. Currently, there is no national recommendation for the use of the vaccines, but vaccination of elderly at highest risk of severe RSV infection should be considered in a shared clinical decision making.

Evidence for a 10-year TBE vaccine booster interval: an evaluation of current data.

INTRODUCTION: Tick-borne encephalitis (TBE) is rapidly spreading to new areas in many parts of Europe. While vaccination remains the most effective method of protection against the disease, vaccine uptake is low in many endemic countries. AREAS COVERED: We conducted a literature search of the MEDLINE database to identify articles published from 2018 to 2023 that evaluated the immunogenicity and effectiveness of TBE vaccines, particularly Encepur, when booster doses were administered up to 10 years apart. We searched PubMed with the MeSH terms 'Encephalitis, Tick-Borne/prevention and control' and 'Vaccination' for articles published in the English language. EXPERT OPINION: Long-term immunogenicity data for Encepur and real-world data on vaccine effectiveness and breakthrough infections following the two European TBE vaccines, Encepur and FSME-Immun, have shown that extending the booster interval from 3-5 years to 10 years does not negatively impact protection against TBE, regardless of age. Such extension not only streamlines the vaccination schedules but may also increase vaccine uptake and compliance among those living in endemic regions.

Effectiveness of high-dose versus standard-dose quadrivalent influenza vaccine against recurrent hospitalizations and mortality in relation to influenza circulation: A post-hoc analysis of the DANFLU-1 randomized clinical trial.

OBJECTIVES: To evaluate the relative effectiveness of high-dose quadrivalent influenza vaccine (QIV-HD) versus standard-dose quadrivalent influenza vaccine (QIV-SD) against recurrent hospitalizations and its potential variation in relation to influenza circulation. METHODS: We did a post-hoc analysis of a pragmatic, open-label, randomized trial of QIV-HD versus QIV-SD performed during the 2021-2022 influenza season among adults aged 65-79 years. Participants were enrolled in October 2021-November, 2021 and followed for outcomes from 14 days postvaccination until 31 May, 2022. We investigated the following outcomes: Hospitalizations for pneumonia or influenza, respiratory hospitalizations, cardio-respiratory hospitalizations, cardiovascular hospitalizations, all-cause hospitalizations, and all-cause death. Outcomes were analysed as recurrent events. Cumulative numbers of events were assessed weekly. Cumulative relative effectiveness estimates were calculated and descriptively compared with influenza circulation. The trial is registered at Clinicaltrials.gov: NCT05048589. RESULTS: Among 12,477 randomly assigned participants, receiving QIV-HD was associated with lower incidence rates of hospitalizations for pneumonia or influenza (10 vs. 33 events, incidence rate ratio [IRR] 0.30 [95% CI, 0.14-0.64]; p 0.002) and all-cause hospitalizations (647 vs. 742 events, IRR 0.87 [95% CI, 0.76-0.99]; p 0.032) compared with QIV-SD. Trends favouring QIV-HD were consistently observed over time including in the period before active influenza transmission; i.e. while the first week with a ≥10% influenza test positivity rate was calendar week 10, 2022, the first statistically significant reduction in hospitalizations for pneumonia or influenza was already observed by calendar week 3, 2022 (5 vs. 15 events, IRR 0.33 [95% CI, 0.11-0.94]; p 0.037). DISCUSSION: In a post-hoc analysis, QIV-HD was associated with lower incidence rates of hospitalizations for pneumonia or influenza and all-cause hospitalizations compared with QIV-SD, with trends evident independent of influenza circulation levels. Our exploratory results correspond to a number needed to treat of 65 (95% CI 35-840) persons vaccinated with QIV-HD compared with QIV-SD to prevent one additional all-cause hospitalization per season. Further research is needed to confirm these hypothesis-generating findings.

Herpes Virus Infections in Kidney Transplant Patients (HINT) - a prospective observational cohort study.

BACKGROUND: Kidney transplant recipients receive maintenance immunosuppressive therapy to avoid allograft rejection resulting in increased risk of infections and infection-related morbidity and mortality. Approximately 98% of adults are infected with varicella zoster virus, which upon reactivation causes herpes zoster. The incidence of herpes zoster is higher in kidney transplant recipients than in immunocompetent individuals, and kidney transplant recipients are at increased risk of severe herpes zoster-associated disease. Vaccination with adjuvanted recombinant glycoprotein E subunit herpes zoster vaccine (RZV) prevents herpes zoster in older adults with excellent efficacy (90%), and vaccination of kidney transplant candidates is recommended in Danish and international guidelines. However, the robustness and duration of immune responses after RZV vaccination, as well as the optimal timing of vaccination in relation to transplantation remain unanswered questions. Thus, the aim of this study is to characterize the immune response to RZV vaccination in kidney transplant candidates and recipients at different timepoints before and after transplantation. METHODS: The Herpes Virus Infections in Kidney Transplant Patients (HINT) study is a prospective observational cohort study. The study will include kidney transplant candidates on the waiting list for transplantation (n = 375) and kidney transplant recipients transplanted since January 1, 2019 (n = 500) from all Danish kidney transplant centers who are offered a RZV vaccine as routine care. Participants are followed with repeated blood sampling until 12 months after inclusion. In the case of transplantation or herpes zoster disease, additional blood samples will be collected until 12 months after transplantation. The immune response will be characterized by immunophenotyping and functional characterization of varicella zoster virus-specific T cells, by detection of anti-glycoprotein E antibodies, and by measuring cytokine profiles. DISCUSSION: The study will provide new knowledge on the immune response to RZV vaccination in kidney transplant candidates and recipients and the robustness and duration of the response, potentially enhancing preventive strategies against herpes zoster in a population at increased risk. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05604911).

Correction: Universal varicella vaccination in Denmark: Modeling public health impact, age-shift, and cost-effectiveness.

[This corrects the article DOI: 10.1371/journal.pgph.0001743.].

Late relapse of cutaneous larva migrans.

Cutaneous larva migrans is a common disease in the tropics and among travelers. The itchy, serpentigious rash often appears within days to weeks after transmission. There are only few reported cases of late relapses. Here, we present a case of a relapse of cutaneous larva migrans more than one year after exposure.

HPV vaccination for immunosuppressed women.

Immunocompromised women are at increased risk of having HPV detected and developing HPV-related diseases such as genital warts, anogenital dysplasia, and cancer. This review aims to summarize the current literature regarding the immunogenicity of the HPV vaccine in immunocompromised women and to discuss whether HPV vaccination may be able to reduce the risk of cervical dysplasia and cancer. HPV vaccination induces an immune response in these women; however, it is unknown whether vaccination is effective in reducing the risk of cervical dysplasia and cancer. Further research is needed.

Pulmonary cystic echinococcosis acquired during a short-term tourist travel.

Background: Cystic echinococcosis is non-endemic in Denmark and primarily diagnosed in migrants from endemic areas. Here, we report a case of pulmonary cystic echinococcosis in a Danish woman with no history of longer-term stays abroad, only holiday travelling to tourist destinations. This is the first case reported in international literature from Denmark where the causative parasite was identified to species and genotype level. Case: A 27-year-old pregnant Danish woman was admitted for examination because of haemoptysis for three months.Chest X-ray and computed tomography revealed a cystic structure in the left lung and a left-sided thoracotomy was performed to remove the cyst. Postoperative histopathological examination revealed a hyaline membrane and protoscoleces. Subsequently, infection with Echinococcus granulosus was confirmed by molecular methods. The causative agent was further characterised as E. granulosus sensu stricto G1, which is not known to have an established life cycle in Denmark. It was concluded that the infection was most likely acquired during a tourist travel to an endemic country. The patient was treated with albendazole for four weeks. Conclusion: This case of pulmonary cystic echinococcosis in a person who had lived in Denmark and had history of only short-term tourist travelling abroad highlights that the disease may be acquired during tourist travelling. Thus, a diagnosis of cystic echinococcosis should be considered not only in migrants from endemic countries but also in travellers upon incidental findings of a lung or liver cysts. The case also exemplifies the importance of reaching a diagnosis at species and genotype level.

COVID-19 impact on EuroTravNet infectious diseases sentinel surveillance in Europe.

BACKGROUND: The COVID-19 pandemic resulted in a sharp decline of post-travel patient encounters at the European sentinel surveillance network (EuroTravNet) of travellers' health. We report on the impact of COVID-19 on travel-related infectious diseases as recorded by EuroTravNet clinics. METHODS: Travelers who presented between January 1, 2019 and September 30, 2021 were included. Comparisons were made between the pre-pandemic period (14 months from January 1, 2019 to February 29, 2020); and the pandemic period (19 months from March 1, 2020 to September 30, 2021). RESULTS: Of the 15,124 visits to the network during the 33-month observation period, 10,941 (72%) were during the pre-pandemic period, and 4183 (28%) during the pandemic period. Average monthly visits declined from 782/month (pre-COVID-19 era) to 220/month (COVID-19 pandemic era). Among non-migrants, the top-10 countries of exposure changed after onset of the COVID-19 pandemic; destinations such as Italy and Austria, where COVID-19 exposure peaked in the first months, replaced typical travel destinations in Asia (Thailand, Indonesia, India). There was a small decline in migrant patients reported, with little change in the top countries of exposure (Bolivia, Mali). The three top diagnoses with the largest overall decreases in relative frequency were acute gastroenteritis (-5.3%), rabies post-exposure prophylaxis (-2.8%), and dengue (-2.6%). Apart from COVID-19 (which rose from 0.1% to 12.7%), the three top diagnoses with the largest overall relative frequency increase were schistosomiasis (+4.9%), strongyloidiasis (+2.7%), and latent tuberculosis (+2.4%). CONCLUSIONS: A marked COVID-19 pandemic-induced decline in global travel activities is reflected in reduced travel-related infectious diseases sentinel surveillance reporting.

Travel demographics, patterns, and plans among adult Nordic travelers.

Background: Despite the high frequency of international travel from Nordic countries annually, data describing demographics, patterns, and plans of travel among Nordic inhabitants are scarce. Methods: In 2018, an online questionnaire covering travel patterns, plans, and knowledge about travel-related diseases was sent to Nordic inhabitants 18-74 years of age. At-risk travelers were defined as those who had traveled outside Europe and North America during the previous 2 years. Results: Of the 5407 respondents included, 4371 (80.8%) had traveled abroad within the past 2 years. Among the respondents, 37.0% (n = 1999) were at-risk travelers. The most frequent travel destinations were Europe (n = 3907, 89.4%) and Asia (n = 1019, 23.3%). Russia/Eurasia was a more common destination for Finnish travelers than the other travelers (10.6% vs 2.3-4.1%). Most at-risk travelers had traveled for leisure/tourism (n = 1329, 66.5%). Visiting friends and relatives was more frequent among Norwegian and Swedish travelers (n = 105, 22.0% and n = 98, 19.4%, respectively) than Finnish travelers (n = 74, 12.7%). The elderly traveled often and made up 21.4% of at-risk travelers. Conclusions: Travel demographics, destinations, and future travel plans were similar across the Nordic countries. More than one third had traveled outside Europe/North America. One third were either elderly or visiting friends or relatives.

Cost of non-communicable diseases in people living with HIV in the Central Denmark Region.

OBJECTIVE: To estimate the economic burden of non-communicable diseases (NCDs) in people living with HIV (PLWH) in Denmark. METHODS: We conducted a cohort study using population-based Danish medical registries including all adult residents of the Central Denmark Region registered with a first-time HIV-diagnosis during the period 2006-2017. For each PLWH, we matched 10 persons without HIV from the background population by birth year, sex and municipality of residence. Information on healthcare utilization and costs for the PLWH and non-HIV cohorts was retrieved from register data. For each cohort, we estimated the annual costs for major disease categories (HIV care, other somatic care, and psychiatric care) in the period from 3 years before to 9 years after diagnosis/matching date. RESULTS: We identified 407 PLWH and 4070 persons from the background population. The total healthcare costs during the study period were approximately three times higher for PLWH compared to the non-HIV cohort (€76 198 vs. €23 692). Average annual cost of hospital care, primary care and selected prescription medicine was estimated to be €6987 per year in the years after the diagnosis compared to €2083 per year in the non-HIV cohort. In PLWH, the cost of NCDs and psychiatric care was approximately two times higher than the cost of HIV care. CONCLUSION: PLWH have higher healthcare costs stemming from three areas: excess cost due to the HIV infection, the treatment of NCDs, and psychiatric care.

A Pragmatic Randomized Feasibility Trial of Influenza Vaccines.

BACKGROUND: The relative vaccine effectiveness (rVE) of high-dose quadrivalent influenza vaccines (QIV-HD) versus standard-dose quadrivalent influenza vaccines (QIV-SD) against hospitalizations and mortality in the general older population has not been evaluated in an individually randomized trial. Because of the large sample size required, such a trial will need to incorporate innovative, pragmatic elements. METHODS: We conducted a pragmatic, open-label, active-controlled, randomized feasibility trial in Danish citizens aged 65 to 79 years during the 2021­2022 influenza season. Participants were randomly assigned 1:1 to receive QIV-HD or QIV-SD. Randomization was integrated into routine vaccination practice, and the trial relied solely on nationwide administrative health registries for data collection. Outcomes consisted of a feasibility assessment and descriptive rVE estimates. RESULTS: We invited 34,000 persons to participate. A total of 12,477 randomly assigned participants were included in the final analyses. Mean (±SD) age was 71.7±3.9 years, and 5877 (47.1%) were women. Registry-based data collection was feasible, with complete follow-up data for 99.9% of participants. Baseline characteristics were comparable to those of the overall Danish population aged 65 to 79 years. The incidence of hospitalization for influenza or pneumonia was 10 (0.2%) of 6245 in the QIV-HD group and 28 (0.4%) of 6232 in the QIV-SD group (rVE, 64.4%; 95% confidence interval, 24.4 to 84.6). All-cause death occurred in 21 (0.3%) and 41 (0.7%) participants in the QIV-HD and QIV-SD groups, respectively (rVE, 48.9%; 95% confidence interval, 11.5 to 71.3). CONCLUSIONS: Conducting a pragmatic randomized trial of QIV-HD versus QIV-SD using existing infrastructure and registry-based data collection was feasible. The findings of lower incidence of hospitalization for influenza or pneumonia and all-cause mortality in the QIV-HD group compared with the QIV-SD group require replication in a future, fully powered trial. (Funded by Sanofi; ClinicalTrials.gov number, NCT05048589.)

Outcome of SARS-CoV-2 infection among patients with common variable immunodeficiency and a matched control group: A Danish nationwide cohort study.

The risk of severe adult respiratory coronavirus-2 (SARS-CoV-2) infection and the course of the infection among individuals with common variable immunodeficiency (CVID) relative to the general population have been a matter of debate. We conducted a Danish nationwide study comparing the timing of SARS-CoV-2 vaccination, the risk of first confirmed SARS-CoV-2 infection, re-infection, and the outcome of infection among individuals with CVID relative to an age- and gender matched control group. Cox regression was used to calculate incidence rate ratios. The CVID patients received SARS-CoV-2 vaccinations earlier than those included in the population control group. Even so, the risks of both first infection and re-infection were increased among the individuals with CVID. The CVID group also had increased risk for hospital contacts due to SARS-CoV-2 infection relative to the general population. However, reassuringly, the risk of mechanical ventilation and death did not differ between the groups, but the numbers were low in both groups, making the estimates uncertain. Though this is the largest study to investigate the risk of SARS-CoV-2 infections and outcomes hereof among individuals with CVID relative to the general population, we cannot rule out minor differences in severity, which might only be detectable with an even larger sample size.

A progressing inflammatory pulmonary infiltrate in a patient with hyper IgE syndrome.

A young man known with autosomal dominant hyper IgE syndrome and changes on his chest radiograph was presumed to be infected with Aspergillus and treated with antifungal medicine for 11 months without effect. Positron emission tomography/computed tomography imaging was suggestive of Aspergilloma but bronchoalveolar lavage cultures, cytology as well as biochemistry were negative for Aspergillus. Finally, a transthoracic computed tomography-guided biopsy did not support the diagnosis of fungal infection as only chronic inflammatory changes were found. The patient was treated with Prednisolone after which the changes on his chest X-ray regressed.

Assessing the proportion of the Danish population at risk of clinically significant drug-drug interactions with new oral antivirals for early treatment of COVID-19.

OBJECTIVES: The oral antiviral drugs nirmatrelvir/ritonavir (NMV/r) and molnupiravir have been approved for early outpatient treatment of COVID-19 to prevent severe disease. Ritonavir, contained in NMV/r, is known to have significant drug-drug interactions (DDI) with several drugs frequently used by the elderly. This communication puts the problem with DDI with oral antiviral COVID-19 treatment into perspective by assessing the percentage of the elderly population at risk of severe COVID-19, using drugs with significant DDI with oral antivirals. METHODS: We estimated the size of the Danish population at risk of significant DDI with antiviral COVID-19 treatment using the number of claimed prescriptions for drugs predicted to interact with NMV/r in Denmark in 2020. RESULTS: Danish prescription data demonstrate the extensive use of drugs likely to interact with NMV/r. Anticoagulants contraindicated during NMV/r treatment were used by 20% of people ≥65 years and 30% of people ≥80 years. Statins that must be paused during NMV/r treatment were used by 15-18%. More than one in five used either analgesics, calcium channel blockers, or digoxin. CONCLUSION: There is major potential for significant DDI with NMV/r in the elderly population at risk of severe COVID-19 disease. This calls for clear guidance for prescribers to ensure patient safety and treatment success.