Guiding therapy and adjunctive treatment in community-acquired pneumonia

Background: Despite the availability of effective antibiotics and vaccines, community-acquired pneumonia (CAP) remains the cause of significant morbidity and mortality worldwide.A major problem is that in absence of full spectrum rapid microbiology diagnostics, the antibiotic treatment at start is empirical what could mean inappropriate treatment in some patients. This thesis adds knowledge on CAP by studying 1) patient characteristics and alternative biomarkers to identify atypical aetiology, 2) novel biomarkers to predict unwanted outcomes and 3) the merits of adjunctive corticosteroid treatment during CAP. Methods: In this thesis different research methods were used: individual patient data meta-analysis to investigate the merits of adjunctive corticosteroid therapy, a randomized controlled trial to investigate bioavailability of oral versus intravenous dexamethasone, post-hoc analysis to study incidence of atypical CAP, costs of CAP and different biomarkers in respect to outcome. Results: Atypical CAP pathogens Chlamydia and Legionella species, Coxiella burnetii and Mycoplasma pneumoniae were more often identified in CAPs occurring from early May to early October, especially in male patients younger than 60 years of age. In this time period two-thirds of CAPs were caused by these atypical pathogens in all patients below 60 years old. Furthermore, we showed that, by routinely performing diagnostics to search for Chlamydia psittaci, incidence of this pathogen in the Netherlands is much higher than previously thought. We investigated the predictive value of respectively proteinuria, cardiac troponin T and the mainly pulmonary markers YKL-40, CCL18, SP-D and CA 15-3 in hospitalised CAP. Proteinuria might reflect the extent of inflammation and thereby serve as a parameter of overall organ damage. Cardiac troponin T (cTNT) proved to be a strong predictor for both short-term and long-term mortality. In 45% of the CAP patients, cTNT levels were elevated. CAP can be seen as a cardiac stress test, in which systemic inflammation with catecholamine release, tachycardia and peripheral vasodilation in combination with low blood oxygenation causes an increased cardiac demand. Of the investigated pulmonary markers especially YKL-40 proved to be useful for prognosis on CAP. The area under the curve of the PSI score was higher, but since this score exist of twenty variables, YKL-40 is easier to use. Chapter 8, on the course of these pulmonary markers during CAP, shows that in CAP caused by atypical pathogens especially CCL18 and YKL-40 levels are lower compared to levels in CAPs caused by other or unknown aetiology. The final part of the thesis concerns the adjunctive therapy of corticosteroids in CAP. In an individual patient data meta-analysis no significant difference in 30-day mortality was found between the corticosteroid and placebo group. A shorter time to clinical stability and shorter length of hospital stay of both one day were found favouring the corticosteroid group. However, incidence of the known side-effect hyperglycaemia and re-hospitalisations were higher in the corticosteroid group. No significant subgroup effects were found