CRP body fluid analysis in COPD

A literature review conducted over the past 30 years (web of science: COPD, biomarkers, C-reactive protein, serum, sputum, BAL, exhaled breath, electronic nose, urine, saliva) of studies using various body fluids to measure CRP levels in COPD patients these are described below under their particular medium.

1.9.1.1.1. Serum

The most extensively investigated body-fluid for CRP analysis in COPD patients is blood.

Baseline median serum CRP levels in COPD subjects have been shown to range between 3.00 to 8.75mg/L (Aksu et al., 2013, Pinto-Plata et al., 2006, de Torres et al., 2006, Chan et al., 2010, Silva et al., 2015). COPD patients have been shown to have significantly higher serum CRP concentrations compared to healthy controls in the stable phase of their disease and serum CRP levels appear to increase from moderate to severe disease (Zhang et al., 2012). The evidence for increased baseline serum CRP levels resulting in an accelerated longitudinal decline in FEV1 is conflicting. Several studies have demonstrated that serum CRP levels are associated with an accelerated decline in FEV1 (Gan et al., 2004, Man et al., 2006, Higashimoto et al., 2009). However, a large cross-sectional analysis of approximately 1000 patients in

et al., 2007, Deng et al., 2014). Relationships have also been demonstrated between PROs and serum CRP levels in stable COPD patients; with increasing CRP levels significantly correlating to a worsening in MRC score (Garrod et al., 2007).

Several studies have demonstrated an increase in serum CRP (greater than 10ng/ml) during an acute exacerbation of COPD (Kostikas et al., 2013, Hurst et al., 2006, Stolz et al., 2007b), with simultaneously elevated serum levels of CRP, fibrinogen and leucocytes associated with an increased risk of frequent exacerbations (Thomsen et al., 2013). Further elevated levels of serum CRP (greater than 15mg/L) also appear to distinguish community acquired pneumonia from an acute exacerbation of COPD (Huerta et al., 2013). Serum CRP levels greater than 50mg/L during an acute exacerbation in conjunction with a positive smoking history, at least 2 co-morbidities and confusion may assist in the identification of patients with a higher risk of mortality (Ruiz-Gonzalez et al., 2008). Significantly higher serum CRP concentration (8.8 mg/L compared to 3.4mg/L) 14 days after an index exacerbation have also been demonstrated in a group of COPD patients who had a re-exacerbation, compared with those who remained exacerbation free over 50 days (Perera et al., 2007). A relationship however has not been established between annual exacerbation frequency and stable baseline serum CRP levels in COPD patients (Gompertz et al., 2001).

1.9.1.1.2. Sputum

Two studies have investigated the levels of CRP in sputum. Out of these studies one is written in Chinese although the English abstract concludes that CRP may be secreted from the local respiratory tract (Wu et al., 2005). The other study demonstrates no correlation between sputum and serum CRP levels in same-subjects (Broekhuizen et al., 2005).

1.9.1.1.3. Exhaled breath condensate (EBC)

As described in Section 1.7.1.2, Page 42, it is not possible to make comparisons between different laboratories for the levels of biomarkers quantified in EBC. Only one study has investigated CRP in EBC of COPD patients and the text is in Russian. However the abstract highlights elevated levels of EBC CRP in COPD patients compared to healthy subjects (Dotsenko et al., 2008).

1.9.1.1.4. Saliva

No studies have yet been published investigating salivary CRP levels in COPD patients.

However numerous works are now being published for salivary CRP in other disease states.

There have been studies on unstimulated saliva that demonstrate elevated levels in patients with periodontal disease (Pederson et al., 1995, Christodoulides et al., 2005); however this conflicts with another small cohort study showing reduced CRP levels in patients with chronic periodontitis compared to healthy controls (Aurer et al., 2005). More recent work supports a significant association between salivary CRP concentrations and periodontitis (Shojaee et al., 2013). Salivary CRP has also been investigated in haemodialysis patients (Pallos et al., 2015) and acute urticaria (Rao et al., 2011).

Salivary levels of CRP have been found to be elevated in patients who have suffered an acute myocardial infarction (Floriano et al., 2009). Within this study a panel of salivary biomarkers including an electrocardiogram were found to have an excellent diagnostic accuracy comparable to the best serum multi-marker panels. This demonstrates saliva’s reflection of

The current consensus is that whilst salivary CRP levels could mirror systemic events, design of meaningful clinical studies such as in patients with COPD should consider the co-existent presence of periodontitis as this could affect measured CRP levels and thus interpretation of salivary CRP should account for the co-variate effect of periodontitis (gum disease).

1.9.2. Procalcitonin (PCT)

PCT is a peptide precursor of the hormone calcitonin (Figure 1.7) discovered in 1975 by Moya et al. It is composed of 116 amino acids and is produced by the neuroendocrine parafollicular cells of the thyroid gland during health.

Figure 1.7: Molecular structure of Procalcitonin (PCT).

This figure (ribbon diagram) represents the 3-dimensional structure of PCT. PCT is composed of 116 amino acids with a molecular weight of 13kDa (Maruna et al., 2000).

Circulating levels of PCT in healthy subjects are undetectable (Maruna et al., 2000). Elevated levels in bacterial infection were first reported by Assicot et al. (Assicot et al., 1993) and since then it has become an important protein in the detection of bacterial inflammatory states (Maruna et al., 2000). Importantly, localised bacterial infections do not result in a significant increase in PCT alongside viral and non-infectious inflammation for example, autoimmune

production believed to switch to the neuroendocrine cells of the lungs and/or intestine. (Müller et al., 2001).

The most elevated levels of serum PCT levels are invariably found in acute severe bacterial infections, sepsis, and severe inflammation (Becker et al., 2010). PCT has been demonstrated to be more accurate than CRP in differentiating bacterial from non-infective causes of inflammation with a sensitivity of 88% compared to 75% and a specificity of 81% compared to 67% (Simon et al., 2004). In the same study Simon et al., also found PCT superior in distinguishing between bacterial and viral aetiology causes of inflammation with a sensitivity of 92% compared to 86% but a more comparable specificity of 73% compared to 70%. A 2012 Cochrane review found no increase in mortality or treatment failure when serum PCT levels were used to guide initiation and duration of antibiotic treatment in patients with acute respiratory infections compared to healthy controls (Schuetz et al., 2012). Importantly serum PCT time-dependent decay is not affected by steroids (Perren et al., 2008).