The treatment of community-acquired pneumonia (CAP) is based on early diagnosis and swift initiation of appropriate antibiotic treatment. Despite effective treatment, CAP is still one of the... Show moreThe treatment of community-acquired pneumonia (CAP) is based on early diagnosis and swift initiation of appropriate antibiotic treatment. Despite effective treatment, CAP is still one of the leading causes of morbidity and mortality due to infectious diseases worldwide. This thesis aimed to identify strategies to optimise the treatment of hospitalised CAP patients outside an intensive care unit (ICU) setting with a focus on corticosteroid treatment. First, this thesis focused on the question whether oral adjunctive corticosteroid treatment improves outcomes in hospitalised CAP patients and tries to identify a subgroup of CAP patients, based on inflammatory status at admission, in whom the beneficial effects of adjunctive corticosteroid treatment outweigh the disadvantages associated with corticosteroid use. Next, this thesis investigated whether obesity and overweight are associated with worse clinical outcomes in a population of hospitalised COVID-19 patients who were all treated with the recommended 6 mg dexamethasone dose. Last, this thesis focused on optimising antibiotic treatment by exploring whether extensive microbiological testing facilitates early antibiotic alterations in CAP patients. Show less
Wittermans, E.; Grutters, J.C.; Moeniralam, H.S.; Ocak, G.; Voorn, G.P.; Bos, W.J.W.; Garde, E.M.W. van de 2022
Objective: A fixed 6 mg dexamethasone dose for 10 days is the standard treatment for all hospitalised COVID-19 patients who require supplemental oxygen. Yet, the pharmacokinetic properties of... Show moreObjective: A fixed 6 mg dexamethasone dose for 10 days is the standard treatment for all hospitalised COVID-19 patients who require supplemental oxygen. Yet, the pharmacokinetic properties of dexamethasone can lead to diminishing systemic dexamethasone exposure with increasing body mass index (BMI). The present study examines whether this translates to overweight and obesity being associated with worse clinical outcomes, defined as ICU admission or in hospital death, in COVID-19 patients treated with fixed-dose dexamethasone. Methods: We conducted a single centre retrospective cohort study in COVID-19 patients who were admitted to a non-ICU ward and were treated with dexamethasone (6 mg once daily for a maximum of ten days) between June 2020 and January 2021. Univariable and multivariable logistic regression analyses were conducted to assess the association between BMI-categories and an unfavourable clinical course (ICU admission and/or in hospital death). Analyses were adjusted for age, comorbidities, inflammatory status, and oxygen requirement at admission. For reference, similar analyses were repeated in a cohort of patients hospitalised before dexamethasone was introduced (March 2020 through May 2020). Results: In patients treated with dexamethasone (n = 385) an unfavourable clinical course was most prevalent in patients with normal weight (BMI < 25) compared to patients with overweight (BMI 25-30) and patients with obesity (BMI >= 30) with percentages of 33, 26 and 21% respectively. In multivariable analyses, there was no association between BMI-category and an unfavourable clinical course (respectively with aORs of 0.81 (0.43-1.53) and 0.61 (0.30-1.27) with normal weight as reference). In the reference cohort (n = 249) the opposite was observed with an unfavourable clinical course being most prevalent in patients with overweight (39% vs 28%; aOR 2.17 (0.99-4.76)). In both cohorts, CRP level at admission was higher and lymphocyte count was lower in patients with normal weight compared to patients with obesity. Conclusions: Overweight and obesity are not associated with an unfavourable clinical course in COVID-19 patients admitted to a non-ICU ward and treated with 6 mg dexamethasone once daily. Show less
Wittermans, E.; Garde, E.M.W. van de; Voorn, G.P.; Aldenkamp, A.F.; Janssen, R.; Grutters, J.C.; ... ; Santeon-CAP Study Grp 2022
Background: It is hypothesised that community-acquired pneumonia (CAP) patients with more severe disease or inflammation might benefit more from adjunctive corticosteroid treatment. Neutrophil... Show moreBackground: It is hypothesised that community-acquired pneumonia (CAP) patients with more severe disease or inflammation might benefit more from adjunctive corticosteroid treatment. Neutrophil count, lymphocyte count and neutrophil-lymphocyte ratio (NLR) have been associated with inflammation and disease severity in CAP. We investigated the interaction between these parameters and adjunctive dexamethasone effects on clinical outcomes in CAP. Methods: We conducted a post hoc analysis of the randomised placebo-controlled Santeon-CAP trial (n = 401), which showed a positive effect of adjunctive oral dexamethasone on length of stay (LOS) in CAP patients. White blood cell (WBC) count, neutrophil count, NLR (highest tertile vs. lowest two tertiles) and lymphocyte count (lowest tertile vs. highest two tertiles) were examined as potential effect modifiers of treatment with dexamethasone on LOS (primary outcome) and ICU-admission, 30-day mortality and hospital readmission. Results: WBC differential counts were available for 354 patients. The effect of dexamethasone on LOS was more pronounced in high WBC count, high neutrophil count or high NLR subgroups (difference in median LOS of 2 days versus zero days in the reference subgroups, p for interaction < 0.05). There was no effect modification for the other outcomes. Patients with low WBC and low neutrophil counts did not benefit from dexamethasone, while hospital readmission rate was higher in those treated with dexamethasone (6% vs. 11%). Conclusions: WBC count and/or neutrophil might be easily available biomarkers to guide selection of CAP patients who are more likely to benefit from adjunctive dexamethasone treatment. Future prospective trials are needed to confirm this predictive potential. Show less
Wittermans, E.; Zee, P.A. van der; Qi, H.C.; Garde, E.M.W. van de; Blum, C.A.; Christ-Crain, M.; ... ; Endeman, H. 2022
Background: Latent class analysis (LCA) has identified subgroups with meaningful treatment implications in acute respiratory distress syndrome. We performed a secondary analysis of three studies to... Show moreBackground: Latent class analysis (LCA) has identified subgroups with meaningful treatment implications in acute respiratory distress syndrome. We performed a secondary analysis of three studies to assess whether LCA can identify clinically distinct subgroups in community-acquired pneumonia (CAP) and whether the treatment effect of adjunctive corticosteroids differs between subgroups. Methods: LCA was performed on baseline clinical and biomarker data from the Ovidius trial (n=304) and the Steroids in Pneumonia (STEP) trial (n=727), both randomised controlled trials investigating adjunctive corticosteroid treatment in CAP, and the observational TripleP cohort (n=201). Analyses were conducted independently in two cohorts (Ovidius-TripleP combined and the STEP trial). In both cohorts, differences in clinical outcomes and response to adjunctive corticosteroid treatment were examined between subgroups identified through LCA. Results: A two-class model fitted both cohorts best. Class 2 patients had more signs of systemic inflammation compared to class 1. In both cohorts, length of stay was longer and in-hospital mortality rate was higher in class 2. In the Ovidius trial, corticosteroids reduced the median length of stay in class 2 (6.5 versus 9.5 days) but not in class 1 (p-value for interaction=0.02). In the STEP trial, there was no significant interaction for length of stay. We found no significant interaction between class assignment and adjunctive corticosteroid treatment for secondary outcomes. Conclusions: In two independent cohorts, LCA identified two classes of CAP patients with different clinical characteristics and outcomes. Given the different response to adjunctive corticosteroids in the Ovidius trial, LCA might provide a useful basis to improve patient selection for future trials. Show less
