Biomarkers in Community-acquired Pneumonia - Page 5 (2025)

Biomarker & Prognosis in CAP

The established risk scores for CAP are the complicated pneumonia severity index and the simple CURB-65 and CRB65 score. However, the scores are validated for the estimation of short-term mortality only. In patients surviving the acute phase of CAP, there is excess mortality long term. Until now, there is no established score and no biomarker for the estimation of long-term prognosis of CAP.

In one CAPNETZ substudy, the prognostic value of the inflammatory markers WBC, CRP and PCT for the prediction of short-term mortality at 28 days was evaluated.[46] In total, 1671 patients with proven CAP were enrolled. PCT, CRP, WBC and CRB-65 scores were determined on admission. Patients were followed-up for 28 days for survival. In 70 patients who died during follow-up, PCT levels on admission predicted the severity and outcome of CAP with a similar prognostic accuracy as the clinical CRB-65 score and a higher prognostic accuracy compared with the established inflammatory biomarkers CRP and WBC. In another study, the new cardiovascular biomarkers Copeptin and proANP were analyzed in 589 patients. The main result was that proANP and Copeptin were at least comparable to the clinical CRB-65 score for the determination of short-term mortality.[47] In other studies from other groups, these results were confirmed for proANP as well as for Copeptin.[48–50] In 300 CAP patients MR-proANP levels were significantly higher in patients with a high PSI risk class (IV–V) than in those with a low PSI risk class (I–III), and in patients that developed complications or died.[51] A CAP study in 173 patients found a positive correlation between PSI and MR-proANP, and C-terminal-proAVP. Nonsurvivors had significantly higher MR-proANP and C-terminal-proAVP levels than survivors.[52] In a selected population of 549 mild CAP patients with low risk of complication, a single ANP measurement was more accurate than CRP and PCT to predict appropriate hospital admission of the patients.[53] In subsequent CAPNETZ studies the prognostic value of biomarkers for the prediction of long-term mortality at 180 days was studied.[54] In the first study 1740 patients with proven CAP were enrolled. ProANP, Copeptin, PCT, CRP, WBC and CRB-65 scores were determined on admission. Patients were followed up for 180 days. ProANP and Copeptin levels increased with increasing severity of CAP. In patients who died within 28 and 180 days, proANP and Copeptin levels were significantly higher compared with levels in survivors. In a ROC analysis for 28- and 180-day survival, AUCs for Copeptin (0.84 and 0.78, respectively) and proANP (0.81 and 0.81, respectively) were superior to the AUC of CRB-65 (0.74 and 0.71) and the inflammatory markers PCT, CRP and WBC. In multivariable Cox proportional hazard regression analyses adjusted for comorbidity and pneumonia severity, proANP and Copeptin were independent and the strongest predictors of short- and long-term mortality.

In other studies, other new biomarkers such as pro-endothelin-1 (proET-1) and pro-adrenomedullin (proADM) were shown to be valuable for the prediction of prognosis in LRTI.[55,56]

There is one study that compared all new biomarkers and the clinical severity score CRB-65 for short- and long-term mortality in patients with CAP on an intraindividual basis to determine which of the new biomarkers would be the most reasonable to use in clinical practice or in biomarker-guided therapeutic intervention studies in CAP.[57] Seven hundred and twenty eight patients were enrolled with a follow-up of 180 days. In patients who died within 28 and 180 days, proADM, proANP, Copeptin, proET-1 and PCT, as well as CRB-65 scores were significantly higher compared with survivors. In Cox regression analysis, proADM had the best performance for the prediction of 28- and 180-day survival. The C-index of proADM for 28-day survival (0.85) was superior to the proANP (0.81), Copeptin (0.78), proET-1 (0.79) and CRB-65 (0.72) scores for the prediction of mortality. For prediction of mortality at 180 days, the C-index of proADM (0.78) was higher than proANP (0.74), Copeptin (0.73), proET-1 (0.76), PCT, CRP and WBC. ProADM was independent of CRB-65 score and added prognostic information for short- and long-term mortality. The main finding of this study was that all new biomarkers were good predictors of short- and long-term mortality, superior to the inflammatory markers PCT, CRP and WBC, and at least comparable to the clinical CRB-65 score. Among the new biomarkers, proADM showed the best performance. A recent Spanish study also found a close correlation of proADM with the PSI- and CURB-65 severity scores, and a high prognostic accuracy of proADM.[40] The results of our study are supported by biomarker studies from the ProHOSP trial.[56] During a 30 day follow-up, 134 serious complications occurred in 925 CAP patients. Both PSI and CURB65 scores overestimated the observed mortality. ProADM and proET1 alone had stronger discriminatory power compared with the PSI and CURB65 scores for the prediction of serious complications. The addition of proADM to the PSI and CURB65 scores significantly improved the prediction of serious complications. In another study proADM also had a good prognostic value. In CAP patients proADM was measured on admission.[58] ProADM showed a good correlation with CAP severity and mortality. With respect to mortality, proADM was comparable to the PSI score and superior to other clinical and laboratory parameters. Again, the combination of proADM and PSI score improved mortality prediction.

What is the explanation for the fact that cardiovascular biomarkers are better for the prediction of short- and long-term mortality compared with inflammatory biomarkers? Inflammatory markers PCT, CRP and WBC are predominantly useful for the diagnosis of infection, whereas the new cardiovascular biomarkers reflect different aspects of CAP. There are various underlying mechanisms for this phenomenon. First, all of these new cardiovascular markers are elevated in sepsis as one of the main causes of short-term death in the acute phase of CAP. Second, Copeptin, proANP, proET-1 and proADM are increased in patients with cardiac failure. The elevation of these biomarkers in CAP may be due to underlying pre-existing cardiac disease or septic cardiomyopathy. However, in the cited study Copeptin, proANP and proADM were independent of pre-existing diagnosis of chronic heart disease or heart failure.[57] As a result, CAP may aggravate underlying, previously unknown cardiovascular or renal disease due to acute inflammatory activation. The fact that proADM seems to be superior to the other cardiovascular markers proANP, Copeptin and proET-1 could be explained by the multiple functions of adrenomedullin. In contrast to ANP, AVP and endothelin with predominant cardiovascular actions, adrenomedullin possesses not only cardiovascular activity but also anti-inflammatory and antibacterial functions.

So what should be the implications for the practical management of CAP as a consequence of these studies? Several investigations have consistently shown that long-term mortality is excessive after an acute phase of CAP compared with an age-matched cohort.[55,59–63] After 180 days, the mortality rate is double compared with short-term mortality after 28 days. The highest impact of CAP on long-term mortality is in the first year after the initial CAP episode, but the association with excess long-term mortality, could be demonstrated for at least 5 years. The main causes of death after a CAP episode are cardiovascular diseases and cancer, but chronic lower respiratory disease, renal failure and infection can also play an important role. In many patients who die at long-term after CAP of cardiovascular disease, cancer and renal failure, the presence of these underlying diseases is unknown prior to the occurrence of CAP and even after the CAP episode. This supports the traditional hypothesis that in many cases, especially in the elderly, CAP could be a sentinel event for an underlying life-limiting disease. New cardiovascular biomarkers could become new and useful additional prognostic markers for short- and long-term risk assessment in CAP. Elevated levels of these new cardiovascular biomarkers in CAP identify a high-risk population. As a consequence, increased attention to possible cardiovascular disease, chronic lung disease and cancer, and closer medical follow-up may be indicated. If this results in an improved long-term outcome in CAP, patients remains to be evaluated in future prospective randomized controlled studies, with inclusion of these new biomarkers into the treatment algorithm.

For the determination of prognosis, the kinetics of inflammatory parameters play a role over time. In patients with severe CAP higher PCT values were found within 48 h in those patients with a positive bacteriological result and complications such as septic shock or organ failure.[64] Serial PCT measurements in CAP patients on admission and on day 3 demonstrated that PCT values in survivors were lower on admission compared with those who died, and that survivors showed a decrease of PCT values on day 3, whereas those who died had an increase of PCT on day 3.[65] In multivariate analysis, relevant factors for mortality included mechanical ventilation (OR: 9.9), multilobar infiltrations (OR: 5.6), increasing PCT values (OR: 4.5) and an increase in the multiorgan failure score. Low PCT values on day 3 indicated a low mortality risk, while CRP had no predictive value. Another study including 394 hospitalized CAP patients evaluated whether PCT and CRP reflect clinical stability after 72 h of treatment.[66] They found that patients with clinical stability after 72 h had significantly lower levels of CRP. When clinical stability was achieved within 72 h and PCT was below 0.25 µg/ml and CRP was below 3 mg/dl, no severe complications occurred. In a recent study in 925 patients with CAP, pro-ET1 levels on admission and proET-1 changes from baseline to day 3 were independent predictors of mortality and ICU admission, and significantly improved the prognostic value of the PSI score.[67] From the same trial 1359 LRTI patients, including 925 with CAP, were analyzed with respect to MR-proANP. Mortality risk at days 30 and 180 significantly increased with increasing MR-proANP quartiles, which was true for low-risk as well as high-risk patients.[50] A comparable result was found in a study including 75 CAP patients, with levels of PCT, CRP and MR-proANP being higher in patients developing complications or dying. MR-proANP and PCT remained elevated in serial measurements in patients developing complications.[68]

Expert Rev Resp Med.2012;6(2):203-214.©2012 Expert Reviews Ltd.

Biomarkers in Community-acquired Pneumonia - Page 5 (2025)
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