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Anke Bruns

Friday 24 September 2010

Individualized treatment strategies in community-acquired pneumonia

Promotor: Prof.dr I.M. Hoepelman
Defence: 24 September 2010
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Despite the progress in healthcare the past decades, community-acquired pneumonia continues to exert extremely high human and economic costs. Moreover, treatment of respiratory tract infections largely contributes to the global burden of antibiotic resistance. In present thesis, we explored options for individualized treatment of community-acquired pneumonia, in a spectrum from initial inflammatory response to long-term prognosis. We hope these studies may serve as targets for progress the coming decades.

Genetic risk for community-acquired pneumonia
We provide an overview of the enormous amount of genetics variations (polymorphisms) in diverse inflammatory genes, identified as candidates to explain genetic variability in susceptibility to pulmonary infections and outcomes. Furthermore, we studied an indivdualized approach in selecting patients most likely to benefit from anticoagulant treatment for severe pneumonia based on genetic variations. We identified a functional variation in the Tisse factor pathway inhibitor (TPFI) gene (rs6434222), associated with a beneficial response to adjuvant treatment with rTFPI. Results suggest that the polymorphism may contribute to an excessive hypercoagulable response in severe pneumococcal disease, leading to an increased risk for mortality. Counteracting this hypercoagulable state with adjuvant anticoagulant agents as rTFPI may improve outcomes in carriers of the variation.

Biomarkers of the inflammatory response
Biomarkers of the inflammatory response may reflect the inter-individual variation in the immune responses based on variable genetic backgrounds, comorbidities, and causative pathogens. For that reason, biomarkers may aid in diagnosing bacterial infections, reducing antibiotic overuse and determining response to treatment and prognosis.
We systematically evaluated the additional value of PCT to clinical practice. In hospital care setting, we show that routine use of PCT as biomarker for diagnosis of bacterial community-acquired pneumonia is not indicated since clinical judgment based on medical history, physical examination, clinical scores, and chest radiography still seems to outweigh the diagnostic value of PCT. In a primary care setting, a setting with relative large antibiotic overuse, prescribing antibiotics based on a point-of-care PCT testing is a promising strategy to better select individuals in necessitating antibiotics and hereby reduce antibiotic prescriptions. Yet, the introduction of newer inflammatory markers such as PCT stresses the need to clarify the position of the older and less costly markers, such a C-reactive protein (CRP). We show that patients with a decline of less than 60% in CRP levels in 3 days or a decline of less than 90% in 7 days after admission to the hospital have an four- to sevenfold increased risk of having recieved inappropriate antibiotic treatment. Therefore, consecutive CRP measurements seem useful in the first week of follow-up to assist the physician in monitoring efficacy of empiric antibiotic therapy.

Antimicrobial treatment
The optimal empirical antibiotic regime for patients hospitalized because of severe community-acquired pneumonia remains an important topic of debate. Dutch guidelines advise several empiric strategies, which are all regarded equally. However, equality of empiric antibiotic strategies for in-hospital treatment of community-acquired pneumonia in terms of selection for Clostridium difficile (C. difficile) is unclear. Our studies show no significant differences in acquisition rates for C. difficile were identified between the three empirical antibiotic strategies advised by Dutch guidelines. Intravenous antibiotic treatment >7 days and previous hospitalization in the past 3 months but not one particular agent, are identified as risk factors for C. difficile carriership. Therefore, we concluded that screening on admission for C. difficile in individual high-risk patients and management strategies as minimizing duration of antibiotic treatment and early switch to oral treatment allowing early discharge, seem more likely to reduce nosocomial acquisition rates of C. difficile than bannig one particular antimicrobial agent.
Minimzing time to first antibiotic dose to less than 4 hours was adopted in international guidelines and as quality measurement in 2004. Though, it can be questioned if all patients with community-acquired pneumonia will benefit from minimizing TFAD or in example only those necessitating treatment in the intensive care unit (ICU) directly. We concluded that clinical parameters on admission other than TFAD predict early clinical outcome in patients with severe community-acquired pneumonia admitted to general wards. In contrast to severe community-acquired pneumonia necessitating treatment in the ICU directly, in case of admission to general wards one can take time to establish a reliable diagnosis before administration of antibiotics.

Follow-up of treatment and long-term prognosis
Unless the additional value to clinical practice has never been established, follow-up chest and radiographs prior to discharge are frequently scheduled to evaluate response to treatment in patients hospitalized with community-acquired pneumonia. To improve the scheduling of these follow-up chest radiographs, we studied patterns of resolution of chest radiographic abnormalities. In patients with with severe community-acquired pneumonia, resolution of pneumonia related abnormalities on the chest radiograph occurred in 25% of patients at day 7 and in 56% of the patients at day 28. In patients with mild to moderate community-acquired pneumonia, the radiological clearance rate is about 30% after 10 days and 70% after one month. Our findings indicate that monitoring a favorable disease process by means of routine short-term follow-up chest radiography in patients with mild to severe community-acquired pneumonia leads to unnecessary resource use and has no additional value above clinical decisions based on a patientís clinical symptoms.
Finanally we privied insights into cause-specific long-term mortality rates of patients hospitalized in general wards for an episode of pneumonia as compared to the general population are provided. Long-term mortality rates after initial recovery are high; up to 53% after 7 years and considerably higher than in an age- and sex matched general population cohort. Causes of death in the years following an episode of community-acquired pneumonia are mostly co-morbidity related and not due to recurrent pneumonia; no excess mortality from (recurrent) pneumonia is observed in ex-pneumonia patients as compared to the general population. Therefore, optimizing treatment of co-morbidities an initial episode of community-acquired pneumonia seems a good target to improve long-time survival.