Chronic obstructive pulmonary disease (COPD) is a diverse disease that ranges from bronchitis to lung emphysema. Yet, there is this desire to define the disease state in COPD by simple parameters such as lung function and single soluble inflammatory markers. This has led to some sort of a consensus regarding disease severity embedded in the GOLD initiative.
Unfortunately, COPD cannot be accurately described by general one-dimensional characteristics as the disease is heterogeneous in the lung and is clearly associated by systemic manifestations such as muscle dysfunction, systemic inflammation and metabolic dysfunction.
If we persist in approaching this disease as if it is caused by a single general pathogenetic mechanism these therapeutic strategies are bound to fail.
In addition, the disease is characterized by periods of acute worsening generally referred to as exacerbations. These phases of the disease cause irreversible damage to the lung tissue and are a prime focus for preventive strategies.
A multitude of both clinical and fundamental studies has not lead to a successful therapeutic strategy to treat COPD. In fact, there is an enormous unmet medical need to develop new drugs for this devastating disease that will increase in the coming years to become the third cause of death worldwide. However, if we persist in approaching this disease as if it is caused by a single general pathogenetic mechanism these therapeutic strategies are bound to fail.
Defining systematic inflammation
One of the important unresolved issues in the current literature is the importance of systemic inflammation in the pathogenesis of COPD. This is mainly caused by the lack of a clear definition for systemic inflammation. This has led to a large number of studies that cannot be compared with each other as every study used their own popular mediator and/or disease mechanism.
Systemic inflammation can be defined as the mechanism that transmits local inflammatory disease processes to dysfunction of distant tissues. This rather cryptic definition implies that mediators produced in the lung in COPD can affect distant tissues such as the muscle.
It will be immediately clear that systemic inflammation in COPD is not a single mechanism as signs of dysfunction of distant tissues are very different between COPD patients ranging from pink puffers (‘more wasting phenotype/emphesema’) to blue bloaters (‘more obese/metabolic phenotype/bronchitis’). Recently, even a new phenotype of COPD emerged that is characterized by eosinophilic inflammation. This form of COPD is referred to as asthma COPD overlap syndrome or ACOS.
Also in this field there was the fixed idea to translate systemic inflammation into the occurrence of single mediators such C-reactive protein (CRP) or single cytokines such as interleukin-6 (IL-6) and tumor necrosis factor (TNF). It will be clear from the above that that approach was also doomed to fail.
We approached the problem by an alternative approach and hypothesized that all pro- and anti-inflammatory systemic signals will change the cells expressing the receptors for these mediators.
There are many reasons why single mediators cannot fulfill the desired read-out for systemic inflammation. Important reasons are discussed by us in our recent article in Respiratory Research and include lack of knowledge regarding all mediators found in COPD, cross-talk between the function of mediators, the change in disease mechanisms between stable and instable disease, and the presence or absence of infection. Therefore, only measuring soluble mediators will not likely lead to solving the riddle of the mechanisms underlying systemic inflammation.
We approached the problem by an alternative approach and hypothesized that all pro- and anti-inflammatory systemic signals will change the cells expressing the receptors for these mediators. So these cells integrate all information and will change their phenotype accordingly.
In our study cellular diagnostics by proteomics and flow cytometry was combined with luminex technology that allows multiplex analysis of multiple cytokines in peripheral blood. Our study provides proof-of-principle that cellular diagnostics in stable COPD is able to identify at least two systemic inflammatory processes. These differences were not associated with GOLD stages again pointing at the fact that sterile inflammation is not reflected in the GOLD stages found in the COPD patients.
The study was performed in a small population of stable COPD patients not stratified for clinical or immunological characteristics. Even more types of systemic inflammation will be found when multiple forms of COPD will be compared with each other. Consequently it is not to be expected that the complex mechanism of underlying systemic inflammation in COPD will be identified when we persist in performing studies designed under the assumption that COPD is caused by a single dominant disease mechanism that is caught by simple disease markers.