The evidence that genetic factors influence the development and outcome of infectious diseases, including pneumonia, is strong. Nevertheless, despite the progress that has been made, the implications of and the clinical applications based on this greater knowledge remain unclear. Although many candidate polymorphisms have been identified, current data are limited by the small numbers of patients that have been studied and by the inconsistent findings by different research groups. The association of genetic factors with an increased risk of death or complications from common infections suggests that the incorporation of genetic risk into vaccination recommendations may be a logical clinical strategy. Nevertheless, no single genetic marker or combination of markers has been demonstrated reproducibly in enough populations to warrant revision of current recommended indications for pneumococcal, meningococcal, and influenza vaccination. A better understanding of the mechanisms of the wide variety of manifestations of the same infection (ie, bacteremic pneumococcal pneumonia) is an additional benefit of recognizing the genetics of serious bacterial infections. Findings such as opposite TNF polymorphism associations for septic shock and respiratory failure in patients with community-acquired pneumonia suggest the need to re-evaluate the pathogenesis of different organ failures in sepsis and may have major implications for targeting immunomodulatory therapies (such as cytokines or cytokine antagonists). Another limitation of current knowledge is that, although no shortage of candidate polymorphisms exists, determination of the polymorphisms that directly affect clinical phenotype and of those that are simply markers of other polymorphisms has not been performed for the vast majority. In vitro studies assessing the functional significance are harder to perform than clinical association studies, and time is needed to sift through the candidates already identified. Given the importance of identifying an association and proving its functional significance, the fact that, despite a decade of research, the influence of the TNF-308 polymorphism on TNF production remains contentious is somewhat depressing. The number and quality of studies addressing genetic influences on pneumonia specifically and sepsis in general has substantially increased. It is apparent that genetic variation in antigen recognition pathways and in pro- and anti-inflammatory pathways is likely to contribute to the overall phenotypic clinical response to specific pathogens. An enormous potential exists for innovative preventative and therapeutic strategies to emerge from this research. Before this potential can be realized, extremely large, well-phenotyped clinical studies assessing many candidate polymorphisms in multiple populations are needed to sort out the real associations from the spurious and to assess their relative importance. Furthermore, basic laboratory science must be carried out to identify which polymorphisms are functional and which are markers for unidentified polymorphisms with which they are in linkage disequilibrium. Only after a core of well-validated genetic markers with proven functional significance is developed will clinicians and patients start seeing the benefits of the genetic studies now being undertaken.
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine