This study demonstrated: (1) IL-6 and IL-10 concentrations at the time of patient admission reflected, similar to the CRB score, the severity of disease rather than prognosis, which is influenced not only by severity but also by age and co-morbidities of the patients; therefore, high IL-6 and/or IL-10 concentrations were found in patients with high CRB or CRB-65 scores; (2) the biomarkers used were inferior to CRB-65 score, but similar to the CRB score, for predicting a severe course of CAP; (3) the accuracy of both CRB and CRB-65 for predicting a severe course of pneumonia could be increased significantly by including the IL-6 measurements in a statistical model; (4) LBP had some predictive potential in etiology, but individual predictions could not be made.
Current CAP guidelines recommend that patients at increased risk of death should be hospitalized, and that ICU admission should be considered for patients with the highest risk. To date, several different pneumonia severity indexes, such as the pneumonia severity index, CURB, CURB-65, CRB and CRB-65, have been evaluated [16
]. In addition, new biomarkers such as procalcitonin (PCT), proatrial natriuretic peptide (pro-ANP, copeptin), proatrial vasopressin (proAVP), proadrenomedullin (proADM) and proendothelin-1 (proET1) have been found to have similar, additive or superior predictive values for the risk assessment of CAP [19
IL-6 and IL-10 play an important role in regulation of inflammatory reactions. Various studies have shown increased concentrations of these cytokines during pneumonia [21
]. Elevated IL-6 and IL-10 levels have been directly associated with higher mortality, ICU admission and mechanical ventilation [25
Increased LBP concentrations have been found in patients with severe sepsis caused by Gram-negative or Gram-positive bacterial infections or fungal infections [25
]. Data concerning LBP concentration in CAP are scarce [27
In contrast to most of the studies that have been published so far, we investigated the concentrations of IL-6, IL-10 and LBP in comparison with clinical and microbiologic findings in a large and carefully characterized study population, which included a large number of patients with a severe course of CAP; this was defined as mechanical ventilation, ICU treatment and/or death within 30 days of involvement.
In patients with a severe course of pneumonia, we found significantly increased IL-6 and LBP concentrations. In contrast to previous studies, which found new biomarkers such as PCT, pro-ANP, proAVP, proET1 and proADM to be good predictors of the course and the outcome of CAP, and which were similar or superior to CRB-65 score, we found a lower predictive potential for IL-6, IL-10 and LBP. As published recently, the predictive value of CRP was also lower than that of the CRB-65 score [10
]. We were able to confirm these findings by calculating an AUC of 0.663 for differentiation of the combined end point and CRP (data not shown). The combination of CRB-65 score and IL-6 concentration increased the predictive value. This finding may be of limited value for the risk stratification of individual patients as there was a significant overlap in the distribution of IL-6 concentration in different patient groups [29
]. Therefore, to test the value of IL-6 for the improving risk prediction we calculated the NRI for IL-6 in combination with CRB-65 score and compared it with CRB-65 score alone and found a significant net gain in reclassification by including IL-6.
On the other hand, we found a strong association between the IL-6 and IL-10 concentrations and high CRB scores (class 2-3). The operational characteristics of IL-6, IL-10 and CRB with respect to a severe course of CAP were similar to each other.
There are several factors that may reduce the prognostic potential of these parameters. First, the induction of IL-6 secretion precedes that of most other pro-inflammatory cytokines and is strongly controlled by anti-inflammatory cytokines such as IL-10. Second, all cytokines investigated in our study have a short plasma half-life of a few hours. Previous studies have shown that the mean levels of IL-6 and IL-10 decrease rapidly after clinical presentation in response to therapeutic interventions [30
]. Thus, IL-6 and IL-10 are cytokines that characterize the acute clinical condition of patients. Therefore, and with respect to the high negative predictive values of 0.984, 0.981 and 0.978 for IL-6, IL-10 and LBP, respectively, normal cytokine concentrations might be used to identify patients who can be treated as outpatients.
Similar to our results, previous studies have shown that the CRB score fails to predict many severe courses of CAP. Consequently, it has been suggested that age ≥ 65 years should be included to identify patients at high risk because of potential comorbidities [25
]; the resulting CRB-65 score has been shown to useful in characterizing the acute clinical condition and the risk of a severe course of CAP.
Cardiovascular markers such as copeptin (proAVP), proET1 or MR-proANP, or adrenomedullin (MR-proADM) which has multiple effects, reflect at least in part non-pulmonary comorbidities [19
]. These biomarkers have the highest predictive value for death within 30 or 180 days. Inflammatory biomarkers such as PCT, which has a delayed concentration kinetic, have an intermediate predictive value that is comparable with the clinical CRB-65 score. We have shown that inflammatory markers that are rapidly regulated have a low predictive value that is comparable with that of the CRB score. Further studies should answer the questions: (1) does a combination these biomarkers with a cardiovascular marker further improve the prediction of the course of CAP, and (2) can these biomarkers be used to monitor disease progression? The latter question is not addressed within the CAPNETZ study because the timing of the biomarker measurements is not standardized, except that the blood samples were collected within 24 h after presentation at the study center. Under these conditions biomarkers that have short peak concentrations at defined disease states may have lower prognostic values compared with those with long-lasting elevated concentrations.
In CAP, the determination of the etiology of the microbial pathogen is essential to target therapeutic decisions. In our study population the etiology remained unknown in 67.9% of the patients; this is comparable with previous findings [11
]. It has been suggested that diagnostic sensitivity is reduced by antibiotic pretreatment prior to hospital admission. For example, typical pathogens such as S. pneumoniae
are easily missed after a single dose of antimicrobial treatment [11
]. In our study we found no association between antibiotic pretreatment and identification of etiologic microbial pathogen. The identification rate was higher patients with a severe course of pneumonia.
The highest concentrations of LBP, IL-6 and IL-10 were found in patients infected with typical bacteria. In previous studies, elevated IL-6 concentrations were found in patients infected with S. pneumoniae
]. The concentration of the anti-inflammatory IL-10 was increased in parallel to the increase in pro-inflammatory IL-6, and this reflects the amplification of antimicrobial as well as host-protective processes in CAP [35
In our study, the LBP concentration was the best parameter to differentiate between typical and atypical or viral pathogens, and we found significantly higher LBP concentrations in patients with typical bacterial infections. In addition, in our study population, we found significantly higher LBP concentrations in patients with atypical infections compared with patients infected with an unknown pathogen. Masia et al.
found LBP concentrations to be similar in patients infected with unknown pathogens, compared with those with viral and atypical infections [37
]. Within the group of typical bacterial infections, we found higher LBP concentrations in patients infected with Gram-positive bacteria. This supports the previous finding that LBP is a non-specific marker of bacterial infection [25