Follow-Up Study of Effectiveness of 23-Valent Pneumococcal Polysaccharide Vaccine Against All-Type and Serotype-Specific Invasive Pneumococcal Disease, Denmark.

As a follow-up to a previous study, we investigated vaccine effectiveness (VE) of 23-valent pneumococcal polysaccharide vaccine (PPSV23) against invasive pneumococcal disease (IPD) among 1,254,498 persons >65 years of age as part of a vaccination program in Denmark during April 2020-January 2023. We assessed VE by using a Cox regression model and adjusted for age, sex, and underlying conditions. Using nationwide data, we estimated a VE of PPSV23 against all-type IPD of 32% and against PPSV23-serotype IPD of 41%. Because this follow-up study had more statistical power than the original study, we also estimated VE against IPD caused by PPSV23-serotypes excluding serotype 3; serotype 3; serotype 8; serotype 22F; PPSV23 non-PCV15 serotypes; PPSV23 non-PCV20 serotypes; and IPD over time. Our findings suggest PPSV23 vaccination can protect persons >65 years of age against IPD caused by all serotypes or serotype groupings, except serotype 3.

Systemic antibiotics for Pseudomonas aeruginosa infection in outpatients with non-hospitalised exacerbations of pre-existing lung diseases: a randomised clinical trial.

BACKGROUND: The effect of dual systemic antibiotic therapy against Pseudomonas aeruginosa in patients with pre-existing lung disease is unknown. To assess whether dual systemic antibiotics against P. aeruginosa in outpatients with COPD, non-cystic fibrosis (non-CF) bronchiectasis, or asthma can improve outcomes. METHODS: Multicenter, randomised, open-label trial conducted at seven respiratory outpatient clinics in Denmark. Outpatients with COPD, non-CF bronchiectasis, or asthma with a current P. aeruginosa-positive lower respiratory tract culture (clinical routine samples obtained based on symptoms of exacerbation not requiring hospitalisation), regardless of prior P. aeruginosa-status, no current need for hospitalisation, and at least two moderate or one hospitalisation-requiring exacerbation within the last year were eligible. Patients were assigned 1:1 to 14 days of dual systemic anti-pseudomonal antibiotics or no antibiotic treatment. Primary outcome was time to prednisolone or antibiotic-requiring exacerbation or death from day 20 to day 365. RESULTS: The trial was stopped prematurely based in lack of recruitment during the COVID-19 pandemic, this decision was endorsed by the Data and Safety Monitoring Board. Forty-nine outpatients were included in the study. There was a reduction in risk of the primary outcome in the antibiotic group compared to the control group (HR 0.51 (95%CI 0.27-0.96), p = 0.037). The incidence of admissions with exacerbation within one year was 1.1 (95%CI 0.6-1.7) in the dual antibiotic group vs. 2.9 (95%CI 1.3-4.5) in the control group, p = 0.037. CONCLUSIONS: Use of dual systemic antibiotics for 14 days against P. aeruginosa in outpatients with chronic lung diseases and no judged need for hospitalisation, improved clinical outcomes markedly. The main limitation was the premature closure of the trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03262142, registration date 2017-08-25.

High titers of neutralizing SARS-CoV-2 antibodies six months after symptom onset are associated with increased severity in COVID-19 hospitalized patients.

BACKGROUND: Viral shedding and neutralizing antibody (NAb) dynamics among patients hospitalized with severe coronavirus disease 2019 (COVID-19) and immune correlates of protection have been key questions throughout the pandemic. We investigated the duration of reverse transcriptase-polymerase chain reaction (RT-PCR) positivity, infectious viral shedding and NAb titers as well as the association between NAb titers and disease severity in hospitalized COVID-19 patients in Denmark 2020-2021. MATERIALS AND METHODS: Prospective single-center observational cohort study of 47 hospitalized COVID-19 patients. Oropharyngeal swabs were collected at eight time points during the initial 30 days of inclusion. Serum samples were collected after a median time of 7 (IQR 5 - 10), 37 (IQR 35 - 38), 97 (IQR 95 - 100), and 187 (IQR 185 - 190) days after symptom onset. NAb titers were determined by an in-house live virus microneutralization assay. Viral culturing was performed in Vero E6 cells. RESULTS: Patients with high disease severity had higher mean log2 NAb titers at day 37 (1.58, 95% CI [0.34 -2.81]), 97 (2.07, 95% CI [0.53-3.62]) and 187 (2.49, 95% CI [0.20- 4.78]) after symptom onset, compared to patients with low disease severity. Peak viral load (0.072, 95% CI [- 0.627 - 0.728]), expressed as log10 SARS-CoV-2 copies/ml, was not associated with disease severity. Virus cultivation attempts were unsuccessful in almost all (60/61) oropharyngeal samples collected shortly after hospital admission. CONCLUSIONS: We document an association between high disease severity and high mean NAb titers at days 37, 97 and 187 after symptom onset. However, peak viral load during admission was not associated with disease severity. TRIAL REGISTRATION: The study is registered at https://clinicaltrials.gov/ (NCT05274373).

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).

Exclusion of older adults and immunocompromised individuals in influenza, pneumococcal and COVID-19 vaccine trials before and after the COVID-19 pandemic.

BACKGROUND: Older adults and immunocompromised individulas are often excluded from vaccine trials. AIM: We hypothesised that during the coronavirus disease 2019 (COVID-19) pandemic, the proportion of trials excluding these patients decreased. METHODS: Using the US Food and Drug Administration and and European Medicines Agency search engines, we identified all vaccines approved against pneumococcal disease, influenza (quadrivalent vaccines), and COVID-19 from 2011 to 2021. Study protocols were screened for direct and indirect age exclusion criteria and exclusion of immunocompromised individuals. In addition, we reviewed the studies with no explicit exclusion criteria and investigated the actual inclusion of those individuals. RESULTS: We identified 2024 trial records; 1702 were excluded (e.g., use of other vaccine or risk group); and 322 studies were eligible for our review. Among the pneumococcal and influenza vaccine trials (n = 193), 81 (42%) had an explicit direct age exclusion, and 150 (78%) had an indirect age-related exclusion. In total, 163 trials (84%) trials were likely to exclude older adults. Among the COVID-19 vaccine trials (n = 129), 33 (26%) had direct age exclusion and 82 (64%) had indirect age exclusion; in total, 85 (66%) trials were likely to exclude older adults. Therefore was a 18% decrease in the proportion of trials with age-related exclusion between 2011 and 2021 (only influenza and pneumococcal vaccine trials) and 2020-2021 (only COVID-19 vaccine trials) (p = 0.014). In a sub-analysis assessing observational and randomised trials, the decrease was 25% and 9%, respectively. Immunocompromised individuals were included in 87 (45%) of the pneumococcal and influenza vaccine trials compared with 54 (42%) of the COVID-19 vaccine trials (p = 0.058). CONCLUSIONS: During the COVID-19 pandemic, we found a decrease in the exclusion of older adults from vaccine trials but no significant change in the inclusion of immunocompromised individulas.

Incidence, Risk Factors, and Consequences of Human Alphaherpesvirus Infections in Patients With Psoriasis Who Initiate Methotrexate or Biologic Agents.

BACKGROUND: Immunosuppressive agents may increase the risk of infections with human alphaherpesviruses. METHODS: We included all adult patients with moderate to severe psoriasis who initiated methotrexate (MTX) or biologic agents in a retrospective cohort study. An episode of alphaherpesviruses infection was defined as filling a prescription for systemic acyclovir, valacyclovir, or famciclovir. Using nationwide registries, we determined the incidence, risk factors, 180-day hospital contacts, and 30-day mortality following infection. RESULTS: We included 7294 patients; 4978 (68%) received MTX, and 2316 (32%) biologic agents. The incidence rates (95% confidence intervals) of alphaherpesviruses were 23 (20-27), 26 (19-35), 17 (11-27), and 6.7 (1.3-21) per 1000 person-years of follow-up in patients on MTX, tumor necrosis factor alpha (TNF-α) inhibitors, interleukin 12/23 (IL-12/23) inhibitors, and interleukin 17 (IL-17) inhibitors, respectively. Males had an unadjusted hazard ratio (HR) of 0.47 (P < .001) for alphaherpesvirus infection. Patients on IL-17 inhibitors had an adjusted HR of 0.24 (P = .048) compared to TNF-α inhibitors. Within 180 days after infection, 13%, 7.5%, and <0.5% of patients on MTX, TNF-α inhibitors, and IL-12/23 or IL-17 inhibitors, respectively, had hospital contacts, and the 30-day mortality for all groups was <0.5%. CONCLUSIONS: The incidence and risk of alphaherpesvirus infections were comparable between patients on MTX and TNF-α inhibitors, whereas use of IL-17 inhibitors was associated with a lower risk.

Comorbidity Increases the Risk of Invasive Meningococcal Disease in Adults.

BACKGROUND: Risk of invasive meningococcal disease (IMD) is increased in patients with complement deficiency and human immunodeficiency virus (HIV) infection. Risk associated with comorbidity is not well described. METHODS: This was a nationwide adult case-control study. Cases for the period 1977-2018 were identified by the national meningococcus reference laboratory. Matched controls were identified by registry linkage. Comorbidities diagnosed prior to IMD were based on the International Classification of Diseases, Eighth or Tenth Revision. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by logistic regression after adjustment for sex, age, and other comorbidities. RESULTS: We identified 1221 cases (45% male), with a median age of 45 years (interquartile range, 22-64 years). The dominant meningococcal serogroups were B (n = 738) and C (n = 337). Increased risk of IMD was associated with solid organ transplantation (SOT) (OR 40.47 [95% CI: 4.84-337.23]), hemolytic anemia (OR 7.56 [95% CI: 2.63-21.79]), renal disease (OR 2.95 [95% CI: 1.77-4.92]), liver disease (OR 2.54 [95% CI: 1.58-4.08]), cancer (OR 2.31 [95% CI: 1.85-2.89]), diabetes (OR 1.74 [95% CI: 1.27-2.39]), neurological disease (OR 1.72 [95% CI: 1.20-2.46]), and autoimmune disease (OR 1.70 [95% CI: 1.63-2.11]). Having 1, 2, and ≥3 comorbidities was associated with increased risk of IMD (ORs 1.6-3.5). Increased risk was not associated with specific serogroups. CONCLUSIONS: This study of adults with IMD over 4 decades showed increased risk of IMD associated with renal disease, immunological disorders, liver disease, cancer, and SOT ranging from a 2- to 40-fold increased risk. Vaccination may be warranted in these populations.

Effect of influenza vaccination in solid organ transplant recipients: A nationwide population-based cohort study.

Vaccination can prevent influenza in solid organ transplant (SOT) recipients. Using a modified season-specific approach over nine consecutive influenza seasons, we investigated influenza vaccination coverage and effectiveness in a population-based nationwide cohort study that included all SOT recipients aged ≥18 years who were living in Denmark from December 1, 2007 to April 1, 2016. The primary outcome was the season-specific risk of all-cause pneumonia admission. Secondary outcomes were season-specific influenza-related admission, intensive care unit (ICU) admission, and all-cause mortality. Crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. In total, 11 381 person-years of follow-up data were collected from 5745 SOT recipients, 48% of whom were vaccinated. Influenza vaccination was associated with a reduced risk of all-cause pneumonia admission (aHR, 0.83; 95% CI, 0.69-0.99; p = .035) and all-cause mortality (aHR, 0.60; 95% CI, 0.47-0.76; p = .001), but not influenza-related admission (aHR, 0.75; 95% CI, 0.46-1.22; p = .24) or ICU admission (aHR, 0.84; 95% CI, 0.67-1.06; p = .14) during the same season. Despite these benefits, uptake of influenza vaccination among SOT recipients was low. Therefore, annual influenza vaccination needs to be prioritized.

Incidence and severity of SARS-CoV-2 infections in liver and kidney transplant recipients in the post-vaccination era: Real-life data from Denmark.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been associated with a high risk of adverse outcomes in solid organ transplant (SOT) recipients in the pre-vaccination era. In this retrospective cohort study, we examined the incidence and severity of COVID-19 in kidney and liver transplant recipients in Denmark in the post-vaccination era, from December 27, 2020, to December 27, 2021. We included 1428 SOT recipients with 143 cases of first-positive SARS-CoV-2 PCR test. The cumulative incidence of first-positive SARS-CoV-2 PCR test 1 year after initiation of vaccination was 10.4% (95% CI: 8.8-12.0), and the incidence was higher in kidney than in liver transplant recipients (11.6% [95% CI: 9.4-13.8] vs. 7.4% [95% CI: 5.1-9.8], p = .009). After the first-positive SARS-CoV-2 PCR test, the hospitalization rate was 31.5% (95% CI: 23.9-39.1), and 30-day all-cause mortality was 3.7% (95% CI: 0.5-6.8). Hospitalization was lower in vaccinated than in unvaccinated SOT recipients (26.4% [95% CI: 18.1-34.6] vs. 48.5% [95% CI: 31.4-65.5], p = .011), as was mortality (1.8% [95% CI: 0.0-4.3] vs. 9.1% [95% CI: 0.0-18.9], p = .047). In conclusion, SOT recipients remain at high risk of adverse outcomes after SARS-CoV-2 infections, with a lower risk observed in vaccinated than in unvaccinated SOT recipients.

Differences and Temporal Changes in Risk of Invasive Pneumococcal Disease in Adults with Hematological Malignancies: Results from a Nationwide 16-Year Cohort Study.

BACKGROUND: Patients with hematological malignancies (HM) are known to carry an increased risk of invasive pneumococcal disease (IPD). However, temporal variations in IPD risks following a cancer diagnosis remain poorly characterized. To inform vaccine guidelines and patient management, we assessed the IPD incidence among patients with HM and other malignancies. METHODS: The study population included all individuals aged ≥15 years during 2000-2016 in Denmark. Variations in incidences of IPD over time and between different types of hematological malignancies and diagnoses were assessed by Poisson regression. RESULTS: During 85 002 224 person-years of observation, 13 332 episodes of a first IPD were observed, of which 765 (5.7%) occurred among individuals with HM. Among HM patients, the IPD incidence rate decreased continuously during the study period (rate ratio per year, 0.91; 95% confidence interval, .90-.92). The risk of IPD in patients with HM was up to 39 times higher when compared to the background population and was highest for multiple myeloma, acute lymphoblastic leukemia, and chronic lymphocytic leukemia. Unlike other malignancies, the increased IPD risk did not wane with the time since HM diagnosis. We found a vaccination uptake of only ≤2% in patients with HM and ≤1% for those with other types of malignancies. CONCLUSIONS: Adults with HM in general and patients with lymphoid malignancies in particular have an increased risk for IPD, compared with patients with other types of cancer and with individuals free of cancer. The pneumococcal vaccination uptake is extremely low in this at risk-population. Efforts to prevent IPD in HM patients are continuously warranted.

Venous Thromboembolism and Major Bleeding in Patients With Coronavirus Disease 2019 (COVID-19): A Nationwide, Population-Based Cohort Study.

BACKGROUND: Venous thromboembolism (VTE) is a potentially fatal complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and thromboprophylaxis should be balanced against risk of bleeding. This study examined risks of VTE and major bleeding in hospitalized and community-managed SARS-CoV-2 patients compared with control populations. METHODS: Using nationwide population-based registries, 30-day risks of VTE and major bleeding in SARS-CoV-2 positive patients were compared with those of SARS-CoV-2 test-negative patients and with an external cohort of influenza patients. Medical records of all COVID-19 patients at 6 departments of infectious diseases in Denmark were reviewed in detail. RESULTS: The overall 30-day risk of VTE was 0.4% (40/9460) among SARS-CoV-2 patients (16% hospitalized), 0.3% (649/226 510) among SARS-CoV-2 negative subjects (12% hospitalized), and 1.0% (158/16 281) among influenza patients (59% hospitalized). VTE risks were higher and comparable in hospitalized SARS-CoV-2 positive (1.5%), SARS-CoV-2 negative (1.8%), and influenza patients (1.5%). Diagnosis of major bleeding was registered in 0.5% (47/9460) of all SARS-CoV-2 positive individuals and in 2.3% of those hospitalized. Medical record review of 582 hospitalized SARS-CoV-2 patients observed VTE in 4% (19/450) and major bleeding in 0.4% (2/450) of ward patients, of whom 31% received thromboprophylaxis. Among intensive care patients (100% received thromboprophylaxis), risks were 7% (9/132) for VTE and 11% (15/132) for major bleeding. CONCLUSIONS: Among people with SARS-CoV-2 infection in a population-based setting, VTE risks were low to moderate and were not substantially increased compared with SARS-CoV-2 test-negative and influenza patients. Risk of severe bleeding was low for ward patients, but mirrored VTE risk in the intensive care setting.

Improved Survival Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Treated With Remdesivir and Dexamethasone. A Nationwide Population-Based Cohort Study.

BACKGROUND: There are limited data on outcomes of moderate to severe coronavirus disease 2019 (COVID-19) among patients treated with remdesivir and dexamethasone in a real-world setting. We sought to compare the effectiveness of standard of care (SOC) alone versus SOC plus remdesivir and dexamethasone. METHODS: Two population-based nationwide cohorts of individuals hospitalized with COVID-19 during February through December 2020 were studied. Death within 30 days and need of mechanical ventilation (MV) were compared by inverse probability of treatment weighted (ITPW) logistic regression analysis and shown as odds ratio (OR) with 95% confidence interval (CI). RESULTS: The 30-days mortality rate of 1694 individuals treated with remdesivir and dexamethasone in addition to SOC was 12.6% compared to 19.7% for 1053 individuals receiving SOC alone. This corresponded to a weighted OR of 30-day mortality of 0.47 (95% CI: .38-.57) for patients treated with remdesivir and dexamethasone compared to patients receiving SOC alone. Similarly, progression to MV was reduced (OR 0.36; 95% CI: .29-.46). CONCLUSIONS: Treatment of moderate to severe COVID-19 during June through December that included remdesivir and dexamethasone was associated with reduced 30-day mortality and need of MV compared to treatment in February through May.

First wave of COVID-19 hospital admissions in Denmark: a Nationwide population-based cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated disease coronavirus disease 2019 (COVID-19), is a worldwide emergency. Demographic, comorbidity and laboratory determinants of death and of ICU admission were explored in all Danish hospitalised patients. METHODS: National health registries were used to identify all hospitalized patients with a COVID-19 diagnosis. We obtained demographics, Charlson Comorbidity Index (CCI), and laboratory results on admission and explored prognostic factors for death using multivariate Cox proportional hazard regression and competing risk survival analysis. RESULTS: Among 2431 hospitalised patients with COVID-19 between February 27 and July 8 (median age 69 years [IQR 53-80], 54.1% males), 359 (14.8%) needed admission to an intensive care unit (ICU) and 455 (18.7%) died within 30 days of follow-up. The seven-day cumulative incidence of ICU admission was lower for females (7.9%) than for males (16.7%), (p < 0.001). Age, high CCI, elevated C-reactive protein (CRP), ferritin, D-dimer, lactate dehydrogenase (LDH), urea, creatinine, lymphopenia, neutrophilia and thrombocytopenia within ±24-h of admission were independently associated with death within the first week in the multivariate analysis. Conditional upon surviving the first week, male sex, age, high CCI, elevated CRP, LDH, creatinine, urea and neutrophil count were independently associated with death within 30 days. Males presented with more pronounced laboratory abnormalities on admission. CONCLUSIONS: Advanced age, male sex, comorbidity, higher levels of systemic inflammation and cell-turnover were independent factors for mortality. Age was the strongest predictor for death, moderate to high level of comorbidity were associated with a nearly two-fold increase in mortality. Mortality was significantly higher in males after surviving the first week.

Differences in the Impact of Pneumococcal Serotype Replacement in Individuals With and Without Underlying Medical Conditions.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have had a well-documented impact on the incidence of invasive pneumococcal disease (IPD). However, declines in IPD due to vaccine-targeted serotypes have been partially offset by increases in IPD due to nonvaccine serotypes (NVTs). The goal of this study was to quantify serotype-specific changes in the incidence of IPD that occurred in different age groups, with or without certain comorbidities, following the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) and 13-valent pneumococcal conjugate vaccine (PCV13) in the childhood vaccination program in Denmark. METHODS: We used nationwide surveillance data for IPD and a hierarchical Bayesian regression framework to estimate changes in the incidence of IPD associated with the introduction of PCV7 (2007) and PCV13 (2010) while controlling for serotype-specific epidemic cycles and unrelated secular trends. RESULTS: Following the introduction of PCV7 and PCV13 in children, the net impact of serotype replacement varied considerably by age group and comorbidities. Differences in the magnitude of serotype replacement were due to variations in the incidence of NVTs in the different risk groups before the introduction of PCVs. The relative increases in the incidence of IPD caused by specific NVTs did not differ appreciably between risk groups in the postvaccination period. Serotype replacement offset a greater proportion of the benefit of PCVs in strata in which the NVTs comprised a larger proportion of cases prior to the introduction of the vaccines. CONCLUSIONS: These findings could help to predict the impact of next-generation PCVs in specific risk groups.

Impact of 13-valent pneumococcal conjugate vaccination in invasive pneumococcal disease incidence and mortality.

BACKGROUND: The impact of the 13-valent pneumococcal conjugate vaccine (PCV13) at the population level is unclear. We explored PCV13's effect in reducing invasive pneumococcal disease (IPD)-related morbidity and mortality, and whether serotype-specific changes were attributable to vaccination or expected as a part of natural, cyclical variations. METHODS: This was a Danish nationwide population-based cohort study based on the linkage of laboratory surveillance data and the Danish Civil Registration System. Changes in IPD incidence and mortality during baseline (2000-2007), 7-valent pneumococcal conjugate vaccine (PCV7) (2008-2010), and PCV13 (2011-2013) periods were estimated. Predicted incidences of serotypes were estimated controlling for cyclical trends from historical patterns observed during the past 20 years. RESULTS: We observed a 21% reduction (95% confidence interval [CI], 17%-25%) in IPD incidence in the total population after PCV13's introduction, and a 71% reduction (95% CI, 62%-79%) in children aged <2 years, considered as the vaccine effectiveness. We estimated a 28% reduction (95% CI, 18%-37%) in IPD-related 30-day mortality, from 3.4 deaths (95% CI, 3.2-3.6) per 100 000 population in the pre-PCV period to 2.4 (95% CI, 2.2-2.7) in the PCV13 period. The decline in mortality was observed across all age groups but was mainly related to mortality reductions in the nonvaccinated population. For serotypes 1 and 3, there were no significant changes in incidence beyond what would be expected from natural cyclical patterns. Serotype 19A significantly increased following PCV7's introduction, but the incidence declined toward baseline in 2012. CONCLUSIONS: PCV13 has brought greater benefits than we had expected in our setting. We observed a further decline on IPD incidence shortly after the shift from PCV7 to PCV13 in the national immunization program. This decline was accompanied by a substantial population-level decline in pneumococcal-related mortality of nearly 30% among nonvaccinated persons.

Mannose-binding lectin gene, MBL2, polymorphisms are not associated with susceptibility to invasive pneumococcal disease in children.

BACKGROUND: Most children are transiently colonized with Streptococcus pneumoniae, but very few develop invasive pneumococcal disease (IPD). Host genetic variation of innate immunity may predispose to IPD. We investigated the effect of genetic variation in the mannose-binding lectin gene, MBL2, on susceptibility and disease severity of IPD in previously healthy children aged <5 years. METHODS: IPD cases were identified through national registries. DNA was obtained from the Danish Neonatal Screening Biobank. Pneumococcal serotypes were determined by Quellung reaction. The associations between MBL2 diplotypes and IPD susceptibility, serotypes, and outcome were investigated using logistic regression analysis. RESULTS: We included 372 cases with meningitis, 907 with bacteremia, and 1263 age- and sex-matched controls; 2372 individuals were successfully genotyped and assigned MBL2 diplotypes. The median age in our combined case series was 13 months. Children with defective diplotypes were not at higher risk for meningitis than children with other diplotypes (odds ratio [OR], 0.85; 95% confidence interval [CI], .56-1.28). Similar results were found for bacteremia (OR, 0.89; 95% CI, .68-1.15) as well as for all cases (OR, 0.87; 95% CI, .70-1.09). There was no association with susceptibility to recurrent IPD (n = 12) for children with defective diplotypes compared with cases with a single episode (OR, 0.53; 95% CI, .07-4.13) and with all controls (OR, 0.46; 95% CI, .06-3.56). There was no association between diplotypes and mortality or between diplotypes and pneumococcal serotypes. CONCLUSIONS: Defective MBL2 polymorphisms did not predict increased IPD susceptibility in children born in Northern Europe.

Incidence and risk factors for invasive pneumococcal disease in HIV-infected and non-HIV-infected individuals before and after the introduction of combination antiretroviral therapy: persistent high risk among HIV-infected injecting drug users.

BACKGROUND: Invasive pneumococcal disease (IPD) is an important cause of morbidity among individuals infected with human immunodeficiency virus (HIV). We described incidence and risk factors for IPD in HIV-infected and uninfected individuals. METHODS: Nationwide population-based cohort study of HIV-infected adults treated at all Danish HIV treatment centers during 1995-2012. Nineteen population-matched controls per HIV-infected individual were retrieved. The risk of IPD was assessed using Poisson regression. RESULTS: The incidence of IPD was 304.7 cases per 100 000 person-years of follow-up (PYFU) in HIV-infected and 12.8 per 100 000 PYFU in HIV-uninfected individuals. After adjusting for confounders, HIV infection (relative risk [RR], 24.4 [95% confidence interval [CI], 23.7-25.1]), male sex (RR, 1.20 [95% CI, 1.16-1.24]), increasing age (per year) (RR, 1.03 [95% CI, 1.03-1.04]), and calendar period (pre-cART RR, 2.80 [95% CI, 2.70-2.91] compared with late cART) were significantly associated with an increased risk of IPD. Among HIV-infected individuals, male sex (RR, 1.57 [95% CI, 1.49-1.66]), smoking (RR, 1.34 [95% CI, 1.26-1.42]), and injecting drug use (RR, 2.51 [95% CI, 2.26-2.67]) were associated with an increased risk of IPD. Detectable viral loads (RR, 1.88 [95% CI, 1.79-1.98]) and a relative fall in CD4 T-cell counts were also associated with an increased risk (≥500 to 350-500 CD4 T cells/µL: RR, 1.29 [95% CI, 1.21-1.37] and <100 cells/µL: RR, 7.4 [95% CI, 6.87-8.02]). The risk of IPD declined over time, although this was not the case for IDUs where the risk remained unchanged. CONCLUSIONS: The incidence of IPD in HIV-infected individuals remained significantly higher than the incidence observed in non-HIV-infected subjects, despite the widespread use of cART. IDUs have a persistently high risk of IPD. Injecting drug use, smoking, and the receipt of cART are suitable targets for preventive measures in the future.