Objectives: This meta-analysis examined the effect of macrolides on resolution of community-acquired pneumonia (CAP) and interpretation of clinical benefit according to microbiology; emphasis is given to data under-reported countries (URCs).Methods: This meta-analysis included 47 publications published between 1994 and 2022. Publications were analysed for 30-d mortality (58 759 patients) and resolution of CAP (6465 patients). A separate meta-analysis was done for the prevalence of respiratory pathogens in URCs. Results: Mortality after 30 d was reduced by the addition of macrolides (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.51-0.82). The OR for CAP resolution when macrolides were added to the treatment regimen was 1.23 (95% CI 1.00-1.52). In the CAP resolution analysis, the most prevalent pathogen was Streptococcus pneumoniae (12.68%; 95% CI 9.36-16.95%). Analysis of the pathogen epidemiology from the URCs included 12 publications. The most prevalent pathogens were S. pneumoniae (24.91%) and Klebsiella pneumoniae (12.90%).Conclusion: The addition of macrolides to the treatment regimen led to 35% relative decrease of 30-d mortality and to 23% relative increase in resolution of CAP.(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

In the ACCESS trial, the addition of clarithromycin to standard-of-care antibiotics (SoC) enhanced early clinical response and attenuated the inflammatory burden in adults with community-acquired pneumonia (CAP) requiring hospitalisation. A post-hoc analysis was performed to investigate the benefit in specific subgroups. The primary endpoint comprised two conditions to be met during the first 72 h: ≥50% decrease in respiratory symptom severity score; and any of ≥30% decrease in sequential organ failure assessment score and favourable change in the kinetics of procalcitonin (PCT, defined as ≥80% PCT decrease or PCT <0.25 ng/mL). In this exploratory post-hoc analysis, achievement of the study composite primary endpoint was compared between the two treatment groups within subsets differentiated by demographic characteristics, comorbidities, CAP severity, baseline laboratory findings and corticosteroid co-administration. The impact of clarithromycin treatment on the need for mechanical ventilation (MV) in all subgroups was also analysed. The addition of clarithromycin significantly increased the proportion of patients achieving the primary endpoint across all subgroups and decreased the need for MV in 19 out of the 37 subgroups studied. For instance, the primary endpoint was attained in 32.7% of placebo-treated patients and in 67% of clarithromycin-treated patients with CURB-65 score ≥2 (P<0.0001), whereas MV was required in 18.8% and 7.4% of patients, respectively (P=0.022). The addition of corticosteroids alone was not as clinically advantageous as the use of clarithromycin alone, when added to SoC. Adding clarithromycin to SoC in the ACCESS trial achieved early clinical anti-inflammatory responses and decreased the need for MV in subgroups of hospitalised patients with CAP.

Early recognition of risk of death in pneumonia and start of precision immunotherapy to improve outcomes is an unmet need. We hypothesized that a precision strategy approach combining early recognition of interleukin (IL)-1 activation coupled with Anakinra treatment may improve pneumonia outcome. INSPIRE is a prospective, double-blind randomized placebo-controlled trial which recruited hospitalized adults with community-acquired or hospital-acquired pneumonia, with qSOFA (quick sequential organ failure assessment) equal to 1 and plasma presepsin (soluble CD14) more than 350 pg/ml. Patients were 1:1 randomised to standard-of-care medication plus either subcutaneous placebo or subcutaneous Anakinra 100 mg once daily for 10 days. The primary endpoint was progression into organ dysfunction defined as meeting at least one of the following two conditions; (i) at least 2-point increase of the baseline SOFA score by day 7 and/or (ii) death by day 90. This was analyzed in the intention-to-treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2022-002390-28) and ClinicalTrials.gov (NCT05785442). Patients were enrolled between March 2023 and June 2024; 30 patients in the placebo arm and 30 patients in the Anakinra arm were the ITT population. The primary endpoint was met in 50·0% (15 patients) of placebo-treated and in 20·0% (6 patients) of Anakinra-treated patients (difference 30·0% [5·9 to 49%]; p: 0·011). 90-day mortality was 43·3% (13 patients) and 20·0% (6 patients) (difference 23·3% [0 to 43·7%]; p: 0·029). The overall incidence of serious treatment-emergent adverse events (TEAEs) in the placebo group was 50% and in the Anakinra group 33·3%. None of the serious TEAEs was judged to be related to treatment assignment. Production of TNFα and ΙFNγ by blood mononuclear cells was decreased. Presepsin-guided Anakinra treatment prevents progression of pneumonia to organ dysfunction and death. The mechanism of benefit is associated with attenuation of cytokine production. 10.13039/501100023710 Hellenic Institute for the Study of Sepsis ; PHC Europe BV; 10.13039/501100012112 Swedish Orphan Biovitrum AB .

Introduction Limited studies have reported data on the real-world clinical use of extended half-life (EHL) IX products in children and adolescents with haemophilia B, also referred to as people with haemophilia B (PWHB). Aim To examine the real-life experience with EHL factor IX products in PWHB regarding the clinical experience with standard half-life products (SHL). Methods A retrospective review of medical records of PWHB who have been prescribed EHL IX factor concentrates was conducted. Results Fourteen male PWHB were enrolled in the study, all with severe bleeding phenotypes being on prophylaxis (1–6 years old: n = 3, 7–12 years old: n = 5 and 13–18 years old: n = 6). Four of them were previously untreated patients; nine out of fourteen children (64%) had severe, four had moderate, and one child had mild haemophilia B. Median length of follow-up was 45 months (range 16–84 months). Children who transitioned from SHL prophylaxis to EHL prophylaxis experienced changes in their treatment outcomes. The median dosing interval increased from 3.5 days to 7 days, mean trough levels rose from 4.3% to 15.3% among children with severe haemophilia B, and the mean annual bleeding rate (ABR) decreased from 1.8 to 1 (p = 0.3, Wilcoxon test). Significant differences were found in EHL vs. SHL use regarding (a) the factor IX consumption for prophylaxis and bleeds (p = 0.046, t-test), with the EHL consumption (45.6 IU/kg/week) being significantly lower than the SHL consumption (70.3 IU/kg/week), and (b) the factor IX consumption only for prophylaxis (p = 0.022, t-test), with the EHL consumption (37.0 IU/kg/week) being significantly lower than the SHL consumption (66.0 IU/kg/week). There was no inhibitor development. Conclusion This study demonstrates the successful use of EHL prophylaxis in PWHB.

Background: Early detection of joint damage in haemophilia is essential to prevent haemophilic arthropathy. This study longitudinally evaluated joint health in paediatric patients with haemophilia in Greece using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) scoring system. Methods: Children aged 5–18 years with haemophilia of any severity, all receiving prophylaxis, were assessed at baseline and during longitudinal follow-up visits scheduled at 6, 12, 24, and 36 months. Evaluations included HEAD-US and Haemophilia Joint Health Score (HJHS), functional ability (PedHAL), health-related quality of life (HRQoL), and pain (BPI). Results: Forty-seven boys (mean age 11.5 ± 3.7 years) were included (severe 83%, moderate 11%, mild 6%). Baseline HEAD-US scores were low (mean ± SE: 0.22 ± 0.069). No significant overall change was observed over time, although left knee showed significant improvement (p < 0.05). Ankles consistently exhibited higher scores compared to other joints (p < 0.05). Synovitis was the most frequent abnormality, while cartilage damage was infrequent and subchondral bone changes were negligible. HEAD-US detected more abnormalities than HJHS. Conclusions: Joint health was well preserved under prophylaxis, with synovitis representing the earliest detectable change, although interpretation is limited by incomplete long-term follow-up. HEAD-US proved more sensitive than clinical assessment, supporting its role in routine longitudinal monitoring.