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.

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).

Increasing incidence of hypotension in the emergency department; a 12 year population-based cohort study.

BACKGROUND: The epidemiology of hypotension as presenting symptom among patients in the Emergency Department (ED) is not clarified. The aim of this study was to describe the incidence, etiology, and overall mortality of hypotensive patients in the ED. METHODS: Population-based cohort study at an University Hospital ED in Denmark from January 1, 2000, to December 31, 2011. Patients aged ≥18 years living in the hospital catchment area with a first time presentation to the ED with hypotension (systolic blood pressure (SBP) ≤100 mm Hg) were included. Outcomes were annual incidence rates (IRs) per 100,000 person years at risk (pyar) and etiological characteristics by means of the International Classification of Diseases, Tenth Revision (ICD-10), as well as 7-day, 30-day, and 90-day all-cause mortality. RESULTS: We identified 3,268 of 438,198 (1 %) cases with a mean overall IR of 125/100,000 pyar (95% CI: 121-130). The IR increased 28% during the period (from 113 to 152 cases per 100,000 pyar). Patients ≥65 years had the highest IR compared to age <65 years (rate ratio for men 6.3 (95% CI: 5.6-7.1) and for women 4.2 (95% CI: 3.6-4.9)). The etiology was highly diversified with trauma (17%) and cardiovascular diseases (15%) as the most common. The overall 7-day, 30-day and 90-day mortality rates were 15% (95% CI: 14-16), 22 % (95% CI: 21-24) and 28% (95% CI: 27-30) respectively. CONCLUSION: During 2000-2011 the overall incidence of ED hypotension increased and remained highest among the elderly with a diversified etiology and a 90-day all-cause mortality of 28%.

Is Shock Index a Valid Predictor of Mortality in Emergency Department Patients With Hypertension, Diabetes, High Age, or Receipt of ß- or Calcium Channel Blockers?

STUDY OBJECTIVE: Shock index is a widely reported tool to identify patients at risk for circulatory collapse. We hypothesize that old age, diabetes, hypertension, and ß- or calcium channel blockers weaken the association between shock index and mortality. METHODS: This was a cohort study of all first-time emergency department (ED) visits between 1995 and 2011 (n=111,019). We examined whether age 65 years or older, diabetes, hypertension, and use of ß- or calcium channel blockers modified the association between shock index and 30-day mortality. RESULTS: The 30-day mortality was 3.0%. For all patients, with shock index less than 0.7 as reference, a shock index of 0.7 to 1 had an adjusted odds ratio (OR) of 2.9 (95% confidence interval [CI] 2.7 to 3.2) for 30-day mortality, whereas shock index greater than or equal to 1 had an OR of 10.5 (95% CI 9.3 to 11.7). The crude OR for shock index greater than or equal to 1 in patients aged 65 years or older was 8.2 (95% CI 7.2 to 9.4) compared with 18.9 (95% CI 15.6 to 23.0) in younger patients. ß- Or calcium channel-blocked patients had an OR of 6.4 (95% CI 4.9 to 8.3) versus 12.3 (95% CI 11.0 to 13.8) in nonusers and hypertensive patients had an OR of 8.0 (95% CI 6.6 to 9.4) versus 12.9 (95% CI 11.1 to 14.9) in normotensive patients. Diabetic patients had an OR of 9.3 (95% CI 6.7 to 12.9) versus 10.8 (95% CI 9.6 to 12.0) in nondiabetic patients. A shock index of 0.7 to 1 was associated with ORs greater than 1 (range 2.2 to 3.1), with no evident differences within subgroups. The adjusted analyses showed similar ORs. CONCLUSION: Shock index is independently associated with 30-day mortality in a broad population of ED patients. Old age, hypertension, and ß- or calcium channel blockers weaken this association. However, a shock index greater than or equal to 1 suggests substantial 30-day mortality risk in all ED patients.

Increase in hippocampal water diffusion and volume during experimental pneumococcal meningitis is aggravated by bacteremia.

BACKGROUND: The hippocampus undergoes apoptosis in experimental pneumococcal meningitis leading to neurofunctional deficits in learning and memory function. The aim of the present study was 1) to investigate hippocampal apparent diffusion coefficient (ADC) and volume with MRI during the course of experimental pneumococcal meningitis, 2) to explore the influence of accompanying bacteremia on hippocampal water distribution and volume, 3) and to correlate these findings to the extent of apoptosis in the hippocampus. METHODS: Experimental meningitis in rats was induced by intracisternal injection of live pneumococci. The study comprised of four experimental groups. I. Uninfected controls (n = 8); II. Meningitis (n = 11); III. Meningitis with early onset bacteremia by additional i.v. injection of live pneumococci (n = 10); IV. Meningitis with attenuated bacteremia by treatment with serotype-specific anti-pneumococcal antibodies (n = 14). T2 and diffusion weighted MR images were used to analyze changes in hippocampus volume and water diffusion (ADC). The results were correlated to ADC of the cortex, to ventricular volume, and to the extent of hippocampal apoptosis. RESULTS: Both ADC and the volume of hippocampus were significantly increased in meningitis rats compared to uninfected controls (Kruskal-Wallis test, p = 0.0001, Dunns Post Test, p < 0.05), and were significantly increased in meningitis rats with an early onset bacteremia as compared to meningitis rats with attenuated bacteremia (p < 0.05). Hippocampal ADC and the volume and size of brain ventricles were positively correlated (Spearman Rank, p < 0.05), whereas no association was found between ADC or volume and the extent of apoptosis (p > 0.05). CONCLUSIONS: In experimental meningitis increase in volume and water diffusion of the hippocampus are significantly associated with accompanying bacteremia.

A case of human babesiosis in Denmark.

We report the first human case of Babesia microti infection imported to Denmark from the United States by a 64 year old female traveller with fever of unknown origin. The case raises the possibility that Babesia-infections may be under-diagnosed, illustrates the importance of a thorough travel history and discusses important diagnostic pitfalls.