BackgroundInvasive meningococcal disease (IMD) is a highly lethal disease. Diagnosis is commonly performed by culture or Realtime-PCR (qPCR).AimsOur aim was to evaluate, retrospectively, whether culture positivity correlates with higher bacterial load and fatal outcome. Our secondary aim was to compare culture and qPCR sensitivity.MethodsThe National Register for Molecular Surveillance was used as data source. Cycle threshold (CT), known to be inversely correlated with bacterial load, was used to compare bacterial load in different samples.ResultsThree-hundred-thirteen patients were found positive for Neisseria meningitidis by qPCR, or culture, or both; 41 died (case fatality rate 13.1%); 128/143 (89.5%) blood samples and 138/144 (95.8%) CSF were positive by qPCR, 37/143 (25.9%) blood samples and 45/144 (31.2%) CSF were also positive in culture. qPCR was 3.5 times (blood) or 3.1 times (CSF) more sensitive than culture in achieving a laboratory diagnosis of IMD (OR 24.4; 95% CI 12.2–49.8; p < .10−4; Cohen’s κ 0.08 for blood and OR 49.0; 95% CI 19.1–133.4; p<10−4; Cohen’s κ 0.02; for CSF). Positivity of culture did not correlate with higher bacterial loads in blood (mean CT 27.7±5.71, and CT 28.1±6.03, p = 0.739 respectively in culture positive or negative samples) or in CSF (mean CT 23.1±4.9 and 24.7±5.4 respectively in positive or negative CSF samples, p = 0.11).CT values in blood from patients who died were significantly lower than in patients who survived (respectively mean 18.0, range 14–23 and mean 29.6, range 16–39; p<10−17). No deaths occurred in patients with CT in blood over 23. Positive blood cultures were found in 10/25 (40%) patients who died and in 32/163 (19.6%) patients who survived, p = 0.036, OR 2.73; 95% CL 1.025–7.215), however 60% of deaths would have remained undiagnosed with the use of culture only.ConclusionsIn conclusion our study demonstrated that qPCR is significantly (at least 3 times) more sensitive than culture in the laboratory confirmation of IMD. The study also demonstrated that culture negativity is not associated with lower bacterial loads and with less severe cases. On the other side, in patients with sepsis, qPCR can predict fatal outcome since higher bacterial load, evaluated by qPCR, appears strictly associated with most severe cases and fatal outcome. The study also showed that molecular techniques such as qPCR can provide a valuable addition to the proportion of diagnosed and serotyped cases of IMD.
BackgroundEnrichment strategies from clinical trials for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) have been partly successful but have not been tested in a real life cohort.ObjectivesAnalyse the efficacy, representativeness and feasibility of enrichment strategies in SSc-ILD patients from the EUSTAR cohort.MethodsWe applied the inclusion criteria of major recent SSc-ILD trials (focuSSced, SLS II and SENSCIS) in SSc-ILD patients and assessed progressive ILD, defined as absolute change in forced vital capacity (FVC) and as significant progression (FVC decline >10%) over time. Data were compared to all patients and patients not fulfilling any inclusion criteria.ResultsIn total, 2258 SSc-ILD patients were included, with 31.2% meeting SENSCIS, 5.8% SLS II, 1.6% focuSSced criteria and 1529 (67.7%) not meeting any criteria (Table 1). In the first 12+/-3 months, a slow FVC% decline of –0.1% was seen in the total, unselected cohort and in patients fulfilling SENSCIS criteria. Patients fulfilling criteria from focuSSced showed a strong FVC decline of –3.7%. Notably, patients enriched for SLS II criteria showed FVC improvement of +2.3% (Figure 1). Similarly, compared to the total unselected cohort, the number of significant progressive events was numerically higher in patients fulfilling focuSSced criteria, the same for SENSCIS criteria and even slightly lower for patients fulfilling the SLS2 criteria.Table 1.Demographics and baseline clinical characteristics of EUSTAR patientsNot fulfilling any criteria (n=1529)focuSSced (n=36)SLS II (n=132)SENSCIS (n=704)Age, years (SD)58.4 (2.9)51.5 (12.2)†51.2 (12.7) †54.2 (13.8) †Male, n (%)231 (15.1)7 (19)35 (27)**156 (21)*Disease duration, months (SD)156.3 (99.4)16.1 (13.9)†40.7 (25.2) †39.4 (23.9) †DcSSc, n (%)597 (43.8)36 (100) †85 (65) †35 (52) †ATA, n (%)735 (51.1)24 (67)*85 (69) †370 (56)mRSS, mean (SD)9.5 (8.3)21 (6.5)*13 (9.6)*11 (9.2)GERD, n (%)1002 (65.9)25 (69)92 (70)430 (62)ESR, mean (SD)27 (20.5)43.1 (23) †29.6 (19.6) †24.7 (20.7)MMF, n (%)75 (16.5)0 (0) †0 (0) †52 (22) †MTX, n (%)42 (9.2)0 (0) †2 (5)20 (9)FVC % predicted, mean (SD)85.7 (22.5)88 (13.6)*66 (9.1) †88 (19.8)DLCO% predicted, mean (SD)58.9 (21.5)61 (12.7)49(14.6)†59 (14.2)NYHA class, n (%)3261 (17.8)6 (19)28 (21)72 (10)*440 (2.7)0 (0)3 (2)4 (1)**P-value: 0.001–0.05; †P<0.001, between focuSSced, SENSCIS or SLS compared with not fulfilling any study criteria.In the second 12 months period, SENSCIS enriched patients had a further absolute FVC% decline as described for the total cohort. In contrast, patients fulfilling the focuSSced and SLS II inclusion criteria showed numerical improvement of lung function in the second period (Figure 1). There were no significant associations of enrichment criteria and ILD progression in the second period.Over the mean observation period of 2.3 years, patients not fulfilling any inclusion criteria showed the same FVC decline of –0.9 (12.1) as observed for the total cohort (–0.9% (12.6)). There were numerical differences in FVC changes in the enriched patient cohorts, varying from –2.8% FVC decline in patients fulfilling the focuSSced criteria to +3.4% FVC improvement with SLS II criteria.ConclusionApplication of enrichment criteria from previous clinical trials showed enrichment for progression with variable success but led to selected patient populations reducing feasibility of recruitment. These findings are important for future clinical trial design and interpretation of the results of published trials.AcknowledgementsWe thank all EUSTAR collaborators.Disclosure of InterestsAnna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Cathrine Brunborg: None declared, Paolo Airò Speakers bureau: Bristol-Myers-Squibb, Boehringer Ingelheim, Consultant of: Bristol-Myers-Squibb, Grant/research support from: Bristol-Myers-Squibb, Roche, Jannsen, CSL Behring, Lidia P. Ananyeva Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, László Czirják Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion (now GSK), MSD, Novartis, Pfizer, Roche, Lilly, Grant/research support from: Boehringer Ingelheim, Actelion (now GSK), MSD, Novartis, Pfizer, Serena Guiducci: None declared, Eric Hachulla Speakers bureau: GSK, Roche-Chugai, Johnson & Johnson, Boehringer Ingelheim, Consultant of: CSL Behring, GSK, Roche-Chugai, Johnson & Johnson, Boehringer Ingelheim, Grant/research support from: CSL Behring, Boehringer Ingelheim, GSK, Roche-Chugai, Sanofi Genzyme, Mengtao Li: None declared, Carina Mihai Speakers bureau: MEDtalks Switzerland, Mepha, Grant/research support from: Roche, Boehringer Ingelheim, Janssen, Gabriela Riemekasten Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Petros Sfikakis Consultant of: Boehringer Ingelheim, Gabriele Valentini Consultant of: Boehringer Ingelheim, Sanofi, Grant/research support from: BMS, Otylia Kowal-Bielecka Speakers bureau: Boehringer Ingelheim, Novartis, Pfizer, Gilead Sciences, Janssen-Cilag, MEDAC, MSD, Abbvie, Sandoz, Consultant of: Boehringer Ingelheim, Health Care system Navigator, CSL Behring, MSD, Novartis, Grant/research support from: CSL Behring, Boehringer Ingelheim, Abbvie, Roche, MEDAC, Yannick Allanore Speakers bureau: Boehringer, Abbvie, Consultant of: Boehringer, Bayer, Astra-Zeneca, Prometheus, Sanofi, Genentech/Roche, Boehringer, Grant/research support from: Alpine Immunosciences, OSE Immunotherapeutics, Medsenic, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur, Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim
Background: Enrichment strategies from clinical trials for progressive systemic sclerosisassociated interstitial lung disease (SSc-ILD) have not been tested in a real-life cohort.Research Question: Do enrichment strategies for progressive ILD impact efficacy, representativeness and feasibility in SSc-ILD patients from the European Scleroderma Trials and Research (EUSTAR) database?Study design and methods: We applied the inclusion criteria of major recent SSc-ILD trials (focuSSced, SLS II and SENSCIS) and assessed progressive ILD, defined as absolute change in forced vital capacity (FVC) and as significant progression (FVC decline ≥10%). Data were compared to all patients and patients not fulfilling any inclusion criteria. Results:In total, 2258 SSc-ILD patients were included, with 31.2% meeting SENSCIS, 5.8% SLS II, 1.6% focuSSced and 1529 (67.7%) not meeting any criteria. In the first 12+/-3 months, the absolute FVC decline in all and in patients fulfilling criteria from SENSCIS was -0.1%, from focuSSced -3.7%, and from SLS II 2.3%, with accompanying more progressors in focuSSced. The patient populations fulfilling the different study inclusion criteria significantly differed in various clinical parameters. In the second 12 months period, SENSCIS enriched patients had a further absolute FVC% decline as described for the total cohort. In contrast, patients fulfilling the focuSSced and SLS II criteria showed numerical improvement of lung function. There were no significant associations of enrichment criteria and ILD progression. Interpretation:The application of enrichment criteria from previous clinical trials showed enrichment for progression with variable success, leading to selected patient populations reducing feasibility of recruitment. These findings are important for future clinical trial design and interpretation of the results of published trials.
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