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OBJECTIVES: To investigate receipt of antibiotics among patients with neuroborreliosis after initial antibiotic treatment, likely attributable to posttreatment symptoms. METHODS: We performed a nationwide, matched, population-based cohort study in Denmark (2009-2021). We included all Danish patients with neuroborreliosis, i.e. a positive Borrelia burgdorferi intrathecal antibody index test and a cerebrospinal fluid leukocyte count ≥10 × 106/l, and initially treated with doxycycline. To form a comparison cohort, we randomly extracted individuals from the general population matched 1:10 to patients with neuroborreliosis on date of birth and sex. The main outcome was receipt of doxycycline, and the secondary outcome was receipt of phenoxymethylpenicillin. We calculated short-term (<1 year) and long-term (≥1 year) hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: We included 463 patients with neuroborreliosis and 2,315 comparison cohort members. Compared with the comparison cohort members, patients with neuroborreliosis initially treated with doxycycline had increased receipt of additional doxycycline within 1 year (HR: 38.6, 95%CI: 17.5-85.0) and ≥1 years (HR: 3.5, 95%CI: 1.9-6.3). Compared with comparison cohort members, patients with neuroborreliosis had no increased receipt of phenoxymethylpenicillin (<1 year HR 1.0, 95%CI: 0.7-1.3; ≥1 years HR 1.2, 95%CI: 0.9-1.5). CONCLUSIONS: After initial antibiotic treatment, patients with neuroborreliosis have increased receipt of doxycycline particularly within one year after initial antibiotic therapy but also subsequently. The lack of increased receipt of phenoxymethylpenicillin suggests that the receipt of doxycycline was not merely due to differences in healthcare-seeking behaviour, increased risk of early Lyme borreliosis due to exposure, or differences in antibacterial usage in general.
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OBJECTIVES: To identify diagnostic opportunities, we investigated healthcare-seeking behaviour among patients with Lyme neuroborreliosis (LNB) within 28 weeks before diagnosis. METHODS: We conducted a population-based, nationwide matched nested case-control study (Denmark, 2009-2021). As cases, we included all Danish residents with LNB (positive Borrelia burgdorferi intrathecal antibody index test and cerebrospinal fluid pleocytosis). We randomly selected controls from the general population and matched 10:1 on date of birth and sex. Exposures were assignment of diagnostic codes for symptoms, contact to medical specialties, medical wandering, and undergoing diagnostic procedures. We calculated the weekly and 3-month proportions of individuals with exposures and calculated absolute risk differences with corresponding 95% CI. RESULTS: We included 1056 cases with LNB and 10 560 controls. Within 3 months before diagnosis, the most frequent assigned symptoms were pain (difference: 13.0%, 95% CI: 10.9-15.1). Cases with LNB exhibited increased contact with most specialties, particularly general practitioners (difference: 48.7%, 95% CI: 46.0-51.4), neurology (difference: 14.3%, 95% CI: 11.7-16.8), and internal medicine (difference: 11.1%, 95% CI: 8.7-13.5), and medical wandering (difference: 17.1%, 95% CI: 14.3-20.0). Common diagnostic procedures included imaging of the brain (difference: 10.2, 95% CI: 8.3-12.1), the spine (difference: 8.8%, 85% CI: 7.0-10.6), and the abdomen (difference: 7.2%, 95% CI: 5.4-9.1). The increase in healthcare-seeking behaviour was observed ≤12 weeks preceding diagnosis. DISCUSSION: Pain appears to be an ambiguous symptom of LNB, potentially contributing to delays in establishing the correct diagnosis. It would be difficult to identify patients with LNB more effectively as the increased healthcare-seeking behaviour preceding diagnosis is distributed across many medical specialties.
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BACKGROUND: Radicular pain is the most predominant symptom among adults with Lyme neuroborreliosis (LNB) but the duration preceding and following diagnosis remains unknown. We aimed to investigate whether patients with LNB have increased obtainment of analgesics before and after diagnosis and for how long. METHODS: We performed a nationwide, population-based, matched cohort study (2009-2021). all Danish residents with LNB (positive Borrelia burgdorferi intrathecal antibody index test and cerebrospinal fluid pleocytosis) were included. To form a comparison cohort, individuals from the general population were randomly extracted and matched 10:1 to patients with LNB on age and sex. Outcomes were obtainment of simple analgesics, antiepileptics, tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, tramadol, and other opioids. We calculated monthly and six-monthly proportions of individuals with obtainment of analgesics and absolute risk differences. RESULTS: 1,056 patients with LNB and 10,560 comparison cohort members were included. An increased proportion of patients with LNB obtained analgesics from 3 months before study inclusion, especially simple analgesics, tramadol, and other opioids. Within the 0-1-month period after study inclusion, patients with LNB most frequently obtained simple analgesics (15 %), antiepileptics (11 %), and tramadol (10 %). Thereafter, obtainment of analgesics declined within a few months. A slightly larger proportion of patients with LNB obtained antiepileptics up to 2.5 years after diagnosis. CONCLUSIONS: Up to 3 months preceding diagnosis, LNB was preceded by increased obtainment of analgesics, which suggests diagnostic delay. Importantly, most patients with LNB did not obtain analgesics after the immediate disease course, although obtainment remained more frequent up to 2.5 years after.
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Background: Vaccine breakthrough SARS-CoV-2 infections are common and of clinical and public health concern. However, little is known about the immunological characteristics of patients hospitalized due to these infections. We aimed to investigate and compare immune cell subpopulations and induced immune responses in vaccinated and non-vaccinated patients hospitalized with severe COVID-19. Methods: A nested case-control study on adults (≥ 18 years) who received at least two doses of a mRNA-COVID-19 vaccine and were hospitalized with SARS-CoV-2 breakthrough infections and severe COVID-19 between January 7, 2021, and February 1, 2022, were eligible for inclusion. Age- and sex-matched non-vaccinated controls were identified. Immunophenotyping was performed using a custom-designed 10-color flow cytometry prefabricated freeze-dried antibody panel (DuraClone, Beckman Coulter (BC), Brea, Calif). TruCulture (Myriad RBM, Austin, USA) was used to assess induced immune response in whole blood, revealing different critical signaling pathways as a proxy for immune function. All samples were obtained within 48 hours of admission. Results: In total, 20 hospitalized patients with severe COVID-19 and a breakthrough SARS-CoV-2 infection were included, ten vaccinated and ten non-vaccinated patients. Vaccinated patients had lower concentrations of CD19 B cells (p = 0.035), naïve CD4 T cells (p = 0.015), a higher proportion of γδ1 T cells (p = 0.019), and higher unstimulated immune cell release of IL-10 (p = 0.015). Conclusion: We observed immunological differences between vaccinated and non-vaccinated patients hospitalized due to severe COVID-19 that indicate that vaccinated patients had lower B cell concentrations, lower concentrations of CD4 naïve T cells, a skewed gamma-delta V1/V2 ratio, and an exaggerated IL-10 response at admission. These results could indicate a suboptimal immune response involved in SARS-CoV-2 breakthrough infections that cause severe COVID-19 in vaccinated adults. However, the sample size was small, and further research is needed to confirm these results.
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Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/prevención & control , Masculino , Femenino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Anciano , Estudios de Casos y Controles , Vacunas contra la COVID-19/inmunología , Adulto , Hospitalización , Vacunación , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Inmunofenotipificación , Infección IrruptivaRESUMEN
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.
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Infecciones Neumocócicas , Vacunas Neumococicas , Serogrupo , Streptococcus pneumoniae , Humanos , Vacunas Neumococicas/inmunología , Vacunas Neumococicas/administración & dosificación , Infecciones Neumocócicas/prevención & control , Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/microbiología , Infecciones Neumocócicas/inmunología , Dinamarca/epidemiología , Femenino , Anciano , Masculino , Streptococcus pneumoniae/inmunología , Streptococcus pneumoniae/clasificación , Estudios de Seguimiento , Anciano de 80 o más Años , Eficacia de las Vacunas , VacunaciónRESUMEN
BACKGROUND: Lyme borreliosis is a tick-borne disease caused by the bacterium Borrelia burgdorferi (Bb) sensu lato complex. Previous studies have suggested an association between Lyme borreliosis and heart failure, which have been suggested to be a possible manifestation of Lyme carditis. We aimed to investigate the risk of heart failure among individuals tested for serum Bb antibodies, and serum Bb seropositive individuals. METHODS: We performed a matched nationwide cohort study (Denmark, 1993-2020) and included 52,200 Bb seropositive individuals, and two age- and sex-matched comparison cohorts: 1) 104,400 Bb seronegative comparison cohort members, and 2) 261,000 population controls. We investigated the risk associated with 1) being tested for serum Bb antibodies, and 2) being Bb seropositive. Outcomes were: 1) a composite of heart failure, cardiomyopathy, and/or myocarditis diagnosis, and 2) redemption of cardiovascular medicine used for treatment of heart failure. We calculated short-term odds ratios (aOR) (within 1 month) and long-term hazard rates (aHR) (after 1 month) adjusted for age, sex, diabetes, pre-existing heart failure, and kidney disease. RESULTS: Compared with the population controls, individuals tested for Bb antibodies, regardless of the test result, had increased short-term risk of heart failure, cardiomyopathy, and myocarditis (aOR 8.3, 95 %CI: 6.7-10.2), and both increased short- and long-term risk of redemption of cardiovascular medicine (aOR 4.3, 95 %CI: 3.8-4.8, aHR 1.13, 95 % CI: 1.11-1.15). The Bb seropositive individuals had no increased short- or long-term risk of any outcome compared with Bb seronegative comparison cohort members. CONCLUSIONS: In conclusion, Bb antibody tests seemed to be performed in the diagnostic work-up of heart failure, but Bb seropositivity was not associated with heart failure.
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Anticuerpos Antibacterianos , Insuficiencia Cardíaca , Enfermedad de Lyme , Humanos , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/microbiología , Masculino , Femenino , Persona de Mediana Edad , Enfermedad de Lyme/epidemiología , Enfermedad de Lyme/microbiología , Anciano , Estudios de Cohortes , Anticuerpos Antibacterianos/sangre , Adulto , Grupo Borrelia Burgdorferi/inmunología , Sistema de Registros , Factores de Riesgo , Adulto Joven , Borrelia burgdorferi/inmunología , Adolescente , Anciano de 80 o más AñosRESUMEN
OBJECTIVES: To investigate the short- and long-term risks of atrioventricular block and other cardiac conduction disorders associated with being tested for Borrelia burgdorferi (Bb) antibodies or Bb seropositivity as measures of confounding by indication and Bb infection, respectively. METHODS: We performed a nationwide population-based matched cohort study (Denmark, 1993-2021). We included 52 200 Bb-seropositive individuals (stratified as only Bb-IgM-seropositive [n = 26 103], only Bb-IgG-seropositive [n = 18 698], and Bb-IgM-and-IgG-seropositive [n = 7399]) and two age- and sex-matched comparison cohorts: 104 400 Bb-seronegative individuals and 261 000 population controls. We investigated the risk associated with being tested for serum Bb antibodies and being Bb seropositive. Outcomes were atrioventricular block and other conduction disorders. We calculated short-term odds ratios (aOR) (within 1 month), and long-term hazard ratios (aHR) (after 1 month) adjusted for age, sex, diabetes, chronic heart failure, and kidney disease with 95% CI. RESULTS: Compared with population controls, individuals tested for Bb antibodies had increased short- and long-term risks of atrioventricular block (aOR 47.9, 95% CI: 30.0-76.7, aHR 1.3, 95% CI:1.2-1.3), and other conduction disorders (aOR 18.2, 95% CI: 10.1-32.8, aHR 1.2, 95% CI: 1.1-1.4). Compared with Bb-seronegative individuals, only Bb-IgM-and-IgG-seropositive individuals had increased short-term risk of atrioventricular block (aOR: 2.1, 95% CI: 1.5-3.1). DISCUSSION: The results suggest that Bb antibody testing is included in the diagnostic work-up of conduction disorders. Finally, that Bb seropositivity is not associated with other conduction disorders than atrioventricular block or with increased long-term risk of conduction disorders.
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Anticuerpos Antibacterianos , Borrelia burgdorferi , Enfermedad de Lyme , Marcapaso Artificial , Humanos , Masculino , Femenino , Anticuerpos Antibacterianos/sangre , Borrelia burgdorferi/inmunología , Anciano , Persona de Mediana Edad , Enfermedad de Lyme/epidemiología , Enfermedad de Lyme/inmunología , Estudios de Cohortes , Bloqueo Atrioventricular/inmunología , Bloqueo Atrioventricular/epidemiología , Adulto , Factores de Riesgo , Anciano de 80 o más Años , Trastorno del Sistema de Conducción Cardíaco/inmunología , Trastorno del Sistema de Conducción Cardíaco/epidemiología , Inmunoglobulina G/sangreRESUMEN
OBJECTIVES: In a nationwide, matched cohort study, we aimed to investigate risks of haematologic cancers among individuals tested for Borrelia burgdorferi (Bb) antibodies, and among serum Bb seropositive individuals. METHODS: We identified all Bb seropositive individuals in Denmark (1993-2020) (n = 52 200) and constructed two age- and sex-matched comparison cohorts: (a) Bb seronegative controls (n = 104 400) and (b) background population controls (n = 261 000). We calculated short-term OR (aOR) (<1 month of study inclusion), and long-term hazard ratios (aHR) (>1 month after study inclusion) adjusted for age and sex. We stratified seropositive individuals on only Bb-IgM seropositive (n = 26 103), only Bb-IgG seropositive (n = 18 698), and Bb-IgM-and-IgG seropositive (n = 7399). RESULTS: Compared with the background population, individuals tested for Bb antibodies had increased short-term (aOR: 12.6, 95% CI: 10.1-15.6) and long-term (aHR: 1.3, 95% CI: 1.2-1.4) risk of haematologic cancers. The Bb seropositive individuals had no increased risk of haematologic cancers compared with those who tested negative for Bb, except that Bb-IgM-and-IgG seropositive individuals had increased long-term risk of chronic lymphatic leukaemia (aHR: 2.0, 95% CI: 1.2-3.4). DISCUSSION: Our results suggest that Bb antibody testing is included in the work-up of unspecific symptoms preceding diagnosis of haematologic cancers. Bb-IgM-and-IgG seropositivity was associated with a two-fold increased long-term risk of chronic lymphatic leukaemia, which warrants further investigation.
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Grupo Borrelia Burgdorferi , Borrelia burgdorferi , Neoplasias Hematológicas , Leucemia Linfocítica Crónica de Células B , Enfermedad de Lyme , Humanos , Enfermedad de Lyme/diagnóstico , Enfermedad de Lyme/epidemiología , Enfermedad de Lyme/microbiología , Estudios de Cohortes , Anticuerpos Antibacterianos , Neoplasias Hematológicas/epidemiología , Inmunoglobulina G , Inmunoglobulina MRESUMEN
Disease mechanisms underlying neurological and neuropsychiatric symptoms after coronavirus disease 2019 (COVID-19), termed neuro-COVID, are poorly understood. Investigations of the cerebrospinal fluid (CSF) for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies, as well as autoantibodies against neuronal surface antigens, could improve our understanding in that regard. We prospectively collected CSF and blood from patients investigated by lumbar puncture for neurological or neuropsychiatric symptoms during or after COVID-19. Primary outcomes were the presence of (i) SARS-CoV-2 RNA in CSF via polymerase chain reaction (PCR), (ii) SARS-CoV-2 immunoglobulin G (IgG) anti-S receptor-binding-domain antibodies via the Euroimmun and Wantai assays and (iii) IgG autoantibodies against neuronal surface antigens using commercial cell- and tissue-based assays (Euroimmun). Secondary outcomes were (i) routine CSF investigations and (ii) correlation between SARS-CoV-2 antibody levels in CSF with serum levels, blood-brain barrier permeability and peripheral inflammation. We obtained CSF from 38 COVID-19 patients (mean age 56.5 ± 19.2 years, 53% women) who developed neurological and neuropsychiatric symptoms. CSF pleocytosis (>5 cells) was observed in 9/38 patients (23.7%), elevated CSF protein (>0.50â g/L) in 13/38 (34.2%) and elevated CSF/serum albumin ratio in 12/35 (34.3%). PCR for SARS-CoV-2 RNA in CSF was negative in all. SARS-CoV-2 CSF antibodies were detected in 15/34 (44.1%; Euroimmun assay) and 7/31 (22.6%; Wantai assay) individuals, but there were no signs of intrathecal SARS-CoV-2 IgG production. SARS-CoV-2 CSF antibodies were positively correlated with serum levels (R = 0.93, P < 0.001), blood-brain barrier permeability (R = 0.47, P = 0.006), peripheral inflammation (R = 0.51, P = 0.002) and admission to the intensive care unit [odds ratio (OR) 17.65; 95% confidence interval (CI) 1.18-264.96; P = 0.04; n = 15]. Cell-based assays detected weakly positive NMDAR, LGI1 and CASPR2 antibodies in serum of 4/34 (11.8%) patients but not in CSF. The tissue-based assay showed anti-neuronal fluorescence in CSF from one individual, staining for Purkinje cells. In summary, whereas we did not detect active SARS-CoV-2 infection in the CSF, SARS-CoV-2 antibodies were prevalent. The absence of intrathecal antibody production points towards blood-brain barrier impairment as the origin of CSF SARS-CoV-2 antibodies. In contrast, CSF autoantibodies against neuronal surface antigens were rare. There was no evidence for a clinical correlate of these antibodies. We conclude that, rather than specific autoimmune neuronal injury, non-specific effects of critical illness including an impaired blood-brain barrier are more likely to contribute to neuro-COVID.
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Currently, SARS-CoV-2 have been detected in farmed mink in 13 different countries. Due to the high susceptibility and transmissibility among mink, great concerns of mink serving as a reservoir to generate novel variants with unknown virulence and antigenic properties arose. These concerns have consequently resulted in entire mink productions being culled and banned. This study investigates the post-vaccination antibody response in the Canadian farmed mink vaccinated with a commercial Index spike protein-based vaccine, approved for use in cats, and compares the antibody response to that observed post infection in Danish farmed mink. Blood samples were obtained from 50 mink at the Canadian Centre for Fur Animal Research (CCFAR), Dalhousie University (Truro, Canada). The sera were initially analyzed for antibodies by enzyme-linked immunosorbent assay (ELISA), and selected sera was subsequently tested in a virus neutralization tests. The levels of neutralizing antibodies were evaluated for an ancestral D614G strain and a recent circulating SARS-CoV-2 variant of concern (Omicron BA.4). The results revealed that the vaccine induced a strong antibody response in mink by reaching antibody titer levels of up to 1:12800 in the ELISA. Moreover, high levels of neutralizing antibodies were obtained, and despite the great level of genetic differences between the ancestral and Omicron BA.4 strains, the vaccinated mink showed high levels of cross-reacting neutralizing antibodies. Interestingly, the antibody levels towards SARS-CoV-2 in the Canadian vaccinated mink were significantly higher than observed in recently SARS-CoV-2 infected Danish mink and equal to anamnestic responses following re-infection. In conclusion, the vaccine used in the Canadian farmed mink was able to induce a strong and broad-reacting antibody response in mink, which could limit the spread of SARS-CoV-2 in farmed mink and thereby reduce the risk of mink serving as a SARS-CoV-2 reservoir for human infections.
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COVID-19 , Vacunas , Humanos , Animales , Gatos , Formación de Anticuerpos , Canadá , Visón , SARS-CoV-2 , Vacunación/veterinaria , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Glicoproteína de la Espiga del CoronavirusRESUMEN
BACKGROUND: People living with HIV (PLWH) have higher incidence of pneumococcal disease compared to people without HIV. Immunization with pneumococcal vaccines is recommended, but serological non-response to pneumococcal vaccination is common for largely unknown reasons. METHODS: PLWH on antiretroviral treatment and no prior pneumococcal vaccination received the 13-valent pneumococcal conjugate vaccine (PCV13) followed 60 days later by the 23-valent polysaccharide vaccine (PPV23). Serological response was evaluated 30 days post-PPV23 by antibodies against 12 serotypes covered by both PCV13 and PPV23. Seroprotection was defined as a ≥2-fold rise to a level above 1.3 µg/ml in geometric mean concentration (GMC) across all serotypes. Associations with non-responsiveness were evaluated by logistic regression. RESULTS: Fifty-two virologically suppressed PLWH (median age of 50 years (IQR 44-55) and median CD4 count of 634 cells/mm3 (IQR 507-792)) were included. Forty-six percent (95 % CI 32-61, n = 24) achieved seroprotection. Serotypes 14, 18C and 19F had the highest, and serotypes 3, 4 and 6B the lowest GMCs. Pre-vaccination GMC levels less than 100 ng/ml were associated with increased odds of non-responsiveness compared to levels above 100 ng/ml (adjusted OR 8.7, 95 % CI 1.2-63.6, p = 0.0438). CONCLUSION: Less than half of our study population achieved anti-pneumococcal seroprotective levels following PCV13 and PPV23 immunization. Low pre-vaccination GMC levels were associated with non-response. Further research is required to optimize vaccination strategies that achieve higher seroprotection in this high-risk group.
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Infecciones por VIH , Infecciones Neumocócicas , Humanos , Adulto , Persona de Mediana Edad , Vacunas Conjugadas , Vacunas Neumococicas , Infecciones Neumocócicas/prevención & control , Polisacáridos , Anticuerpos Antibacterianos , Infecciones por VIH/complicacionesRESUMEN
Leptospirosis is a zoonotic bacterial infection that can cause influenza-like symptoms and severe disease. In Denmark, leptospirosis is rare, non-endemic, and most commonly transferred to humans from mice and rats. Cases of human leptospirosis in Denmark are by law notifiable to Statens Serum Institut. This study aimed to describe trends in incidence of leptospirosis in Denmark from 2012 to 2021. Descriptive analyses were used to calculate the incidence, geographical distribution and possible routes of infection, as well as testing capacity and serological trends. The overall incidence rate was 0.23 per 100,000 inhabitants, with the highest annual incidence of 24 cases in 2017. Men between 40-49 years old were the demographic group most commonly diagnosed with leptospirosis. August and September were the months with highest incidence over the entire study period. The most common serovar observed was Icterohaemorrhagiae, although over a third of cases were diagnosed via polymerase chain reaction alone. The most common sources of exposure reported were travel abroad, farming, and recreational contact with fresh water, the latter being a new exposure compared to previous studies. Overall, a One Health approach would ensure better detection of outbreaks and milder disease. Additionally, preventative measures should be expanded to include recreational water sports.
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Leptospirosis , Masculino , Humanos , Animales , Ratones , Ratas , Adulto , Persona de Mediana Edad , Leptospirosis/epidemiología , Zoonosis Bacterianas , Agricultura , Brotes de Enfermedades , Dinamarca/epidemiologíaRESUMEN
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).
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COVID-19 , Humanos , SARS-CoV-2 , Anticuerpos Neutralizantes , Estudios Prospectivos , Anticuerpos AntiviralesRESUMEN
Pertussis toxin (PT) is a unique virulence factor of Bordetella pertussis, and therefore a key component of acellular pertussis vaccines. Although immunity after infection seems to persist longer than after vaccination, the exact mechanisms are not fully known. In this study the overall binding strength (avidity) of anti-PT IgG antibodies was compared after acellular booster vaccination and infection, as a parameter to evaluate long-lasting protection.Danish and Finnish serum samples from a total of 134 serologically confirmed patients and 112 children who received acellular booster vaccines were included in this study. The concentration of anti-PT IgG was first determined by ELISA, followed by two separate ELISAs to evaluate antibody avidity: either with a dilution series of urea as a bond-breaking agent of antibody and antigen binding and a constant anti-PT IgG concentration between the samples or with a constant dilution ratio of sera and detergent. In addition to urea, the use of diethylamine and ammonium thiocyanate as disruptive agents were first compared between each other.A strong Spearman correlation (R > 0.801) was noted between avidity and concentration of anti-PT IgG antibodies if a constant serum dilution method was used, and avidity was noted to be higher in patients in comparison to vaccinees in Denmark, but not in Finland. However, no correlation between antibody concentration and avidity was found if a constant anti-PT IgG concentration was used (R = -0.157). With this method, avidity after vaccination was significantly higher in comparison to that after infection in both Danish and Finnish subjects (p < 0.01). A shorter time since the latest booster vaccination was found to affect avidity positively on the next PT-antigen exposure with either vaccination or infection.
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Tos Ferina , Niño , Humanos , Toxina del Pertussis , Tos Ferina/prevención & control , Afinidad de Anticuerpos , Anticuerpos Antibacterianos , Inmunoglobulina G , Vacuna contra la Tos Ferina , Vacunación/métodosRESUMEN
This study aimed to estimate the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPV23) against invasive pneumococcal disease (IPD) among individuals ≥ 65 years of age. We used Danish nationwide databases to obtain information on PPV23 vaccination, covariates, and IPD and linked data on an individual level using a unique personal identifier. A total of 948,263 individuals were included and followed between June 15, 2020, and September 18, 2021 (58.6% were vaccinated during follow-up). The adjusted vaccine effectiveness was 42% (95% confidence interval (CI): 9-63%) for all-serotype IPD and 58% (95% CI: 21-78%) for PPV23-serotype IPD, using no vaccination as the reference.
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Infecciones Neumocócicas , Vacunas Neumococicas , Humanos , Estudios de Cohortes , Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/prevención & control , Serogrupo , Dinamarca/epidemiologíaRESUMEN
Background: Introduction of the Omicron variant caused a steep rise in SARS-CoV-2 infections despite high vaccination coverage in the Danish population. We used blood donor serosurveillance to estimate the percentage of recently infected residents in the similarly aged background population with no known comorbidity. Methods: To detect SARS-CoV-2 antibodies induced due to recent infection, and not vaccination, we assessed anti-nucleocapsid (anti-N) immunoglobulin G (IgG) in blood donor samples. Individual level data on SARS-CoV-2 RT-PCR results and vaccination status were available. Anti-N IgG was measured fortnightly from January 18 to April 3, 2022. Samples from November 2021 were analysed to assess seroprevalence before introduction of the Omicron variant in Denmark. Findings: A total of 43 088 donations from 35 309 Danish blood donors aged 17-72 years were screened. In November 2021, 1·2% (103/8 701) of donors had detectable anti-N IgG antibodies. Adjusting for test sensitivity (estimates ranging from 74%-81%) and November seroprevalence, we estimate that 66% (95% confidence intervals (CI): 63%-70%) of the healthy, similarly aged Danish population had been infected between November 1, 2021, and March 15, 2022. One third of infections were not captured by SARS-CoV-2 RT-PCR testing. The infection fatality rate (IFR) was 6·2 (CI: 5·1-7·5) per 100 000 infections. Interpretation: Screening for anti-N IgG and linkage to national registers allowed us to detect recent infections and accurately assess assay sensitivity in vaccinated or previously infected individuals during the Omicron outbreak. The IFR was lower than during previous waves. Funding: The Danish Ministry of Health.
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BACKGROUND: Pneumococcal prime-boost vaccination is recommended for solid organ transplant recipients and candidates. The long-term durability of the antibody (AB) response is unknown. The same applies to a dose-dependent immune response. METHODS: We studied the durability of the vaccine response after 18 months in kidney transplant recipients (KTRs) and patients on the kidney transplant waiting list (WLPs). Both groups received either a normal dose (ND) or a double dose (DD) of the 13-valent pneumococcal conjugate vaccine and the 23-valent pneumococcal polysaccharide vaccine. The average pneumococcal AB geometric mean concentration (GMC) was evaluated. A level ≥ 1 mg/L was considered protective against invasive pneumococcal disease (IPD). RESULTS: Sixty WLPs and 70 KTRs were included. The proportion of participants protected declined from 52% to 33% in WLPs and from 29% to 16% in KTRs, with the previously significant dose-effect in WLPs no longer present (40% DD vs. 27% ND; p = 0.273). Average pneumococcal AB GMCs remained significantly above baseline levels (all groups p ≤ 0.001). Drug-induced immunosuppression diminished the vaccine dose-effect. CONCLUSIONS: At follow-up, the pneumococcal prime-boost vaccination still provided significantly elevated average pneumococcal AB GMCs in both populations. Though the proportion of participants protected against IPD in WLP-DD and WLP-ND were statistically comparable, a DD may still be recommended for WLPs (EudraCT: 2016-004123-23).
RESUMEN
Virus neutralization assays provide a means to quantitate functional antibody responses that block virus infection. These assays are instrumental in defining vaccine and therapeutic antibody potency, immune evasion by viral variants, and post-infection immunity. Here we describe the development, optimization and evaluation of a live virus microneutralization assay specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this assay, SARS-CoV-2 clinical isolates are pre-incubated with serial diluted antibody and added to Vero E6 cells. Replicating virus is quantitated by enzyme-linked immunosorbent assay (ELISA) targeting the SARS-CoV-2 nucleocapsid protein and the standardized 50% virus inhibition titer calculated. We evaluated critical test parameters that include virus titration, assay linearity, number of cells, viral dose, incubation period post-inoculation, and normalization methods. Virus titration at 96 hours was determined optimal to account for different growth kinetics of clinical isolates. Nucleocapsid protein levels directly correlated with virus inoculum, with the strongest correlation at 24 hours post-inoculation. Variance was minimized by infecting a cell monolayer, rather than a cell suspension. Neutralization titers modestly decreased with increasing numbers of Vero E6 cells and virus amount. Application of two different normalization models effectively reduced the intermediate precision coefficient of variance to <16.5%. The SARS-CoV-2 microneutralization assay described and evaluated here is based on the influenza virus microneutralization assay described by WHO, and are proposed as a standard assay for comparing neutralization investigations.
Asunto(s)
COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Ensayo de Inmunoadsorción Enzimática , Humanos , Pruebas de Neutralización/métodos , Proteínas de la Nucleocápside , Glicoproteína de la Espiga del CoronavirusRESUMEN
Functional antibody deficiency is clinically assessed from antibody responses to vaccination. However, diagnostic vaccination is complex and may fail in practice. We hypothesized that the levels of naturally occurring antibodies against galactose-α-1,3-galactose (αGal) may represent alternative markers of functional antibody capacity. We included data from 229 patients with suspected primary immunodeficiency in a retrospective study. Antibody levels against αGal and twelve pneumococcal serotypes were determined with solid-phase immunoassays. Pneumococcal vaccinations and treatment with normal human immunoglobulin were assessed from medical records. Anti-αGal antibody levels correlated positively with anti-pneumococcal antibody levels measured before and after pneumococcal vaccination. Contrary to the anti-pneumococcal antibody levels, the anti-αGal antibody level showed potential for predicting subsequent immunoglobulin treatment - a marker of disease severity. Naturally occurring antibodies may reflect the functional capacity tested by diagnostic vaccination but add more useful clinical data. The clinical utility of this easy test should be evaluated in prospective studies.
Asunto(s)
Anticuerpos Antibacterianos , Enfermedades de Inmunodeficiencia Primaria , Galactosa , Humanos , Inmunoglobulina G , Vacunas Neumococicas , Estudios Prospectivos , Estudios Retrospectivos , VacunaciónRESUMEN
BACKGROUND: The SARS-CoV-2 pandemic has resulted in massive testing by Rapid Antigen Tests (RAT) without solid independent data regarding clinical performance being available. Thus, decision on purchase of a specific RAT may rely on manufacturer-provided data and limited peer-reviewed data. METHODS: This study consists of two parts. In the retrospective analytical part, 33 RAT from 25 manufacturers were compared to RT-PCR on 100 negative and 204 positive deep oropharyngeal cavity samples divided into four groups based on RT-PCR Cq levels. In the prospective clinical part, nearly 200 individuals positive for SARS-CoV-2 and nearly 200 individuals negative for SARS-CoV-2 by routine RT-PCR testing were retested within 72 h for each of 44 included RAT from 26 manufacturers applying RT-PCR as the reference method. RESULTS: The overall analytical sensitivity differed significantly between the 33 included RAT; from 2.5% (95% CI 0.5-4.8) to 42% (95% CI 35-49). All RAT presented analytical specificities of 100%. Likewise, the overall clinical sensitivity varied significantly between the 44 included RAT; from 2.5% (95% CI 0.5-4.8) to 94% (95% CI 91-97). All RAT presented clinical specificities between 98 and 100%. CONCLUSION: The study presents analytical as well as clinical performance data for 44 commercially available RAT compared to the same RT-PCR test. The study enables identification of individual RAT that has significantly higher sensitivity than other included RAT and may aid decision makers in selecting between the included RAT. FUNDING: The study was funded by a participant fee for each test and the Danish Regions.