Biomarkers in Community-Acquired Pneumonia (Cardiac and Non-Cardiac)
Pneumology Department, Hospital Universitario y Politécnico La Fe/Instituto de Investigación Sanitaria (IIS) La Fe, 46026 Valencia, Spain; Pneumology Department, Hospital Universitario y Politécnico La Fe, Avda, Fernando Abril Martorell 106, 46026 Valencia, Spain
University of Valencia, Medicine Faculty, 46026 Valencia, Spain
Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain
Pneumology Department, Hospital Germans Trias i Pujol, 08916 Badalona, Spain
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(2), 549; https://doi.org/10.3390/jcm9020549
Received: 7 January 2020 / Revised: 7 February 2020 / Accepted: 10 February 2020 / Published: 18 February 2020
(This article belongs to the Special Issue Diagnosis and Treatment of Pneumonia)
Community-acquired pneumonia (CAP) remains the first cause of morbidity and mortality worldwide due to infection. Several aspects such as severity and host response are related to its clinical course and outcome. Beyond the acute implications that the infection provokes in the host, pneumonia also has long-term negative consequences. Among them, cardiovascular complications and mortality are the most outstanding. Therefore, an adequate recognition and stratification of the risk of complications and mortality is crucial. Many biomarkers have been studied for these reasons, considering that each biomarker mirrors a different aspect. Moreover, the clinical application of many of them is still being deliberated because of their limitations and the heterogeneity of the disease. In this review, we examine some of the most relevant biomarkers that we have classified as cardiac and non-cardiac. We discuss some classic biomarkers and others that are considered novel biomarkers, which are mainly involved in cardiovascular risk.
Community-acquired pneumonia (CAP), with an annual incidence of 3–11 cases per 1000 inhabitants in adult populations, is the first cause of sepsis [1,2]. Despite the progress made in recent decades, pneumonia continues to cause significant mortality worldwide, especially during childhood and in the elderly—mainly in countries with low average incomes. However, mortality in Europe and USA also remains unacceptably high, especially for severe pneumonia.
The impact of CAP does not only occur in the short-term during the acute phase of the infection. For some years now it has been shown that the morbidity and mortality mainly appeared during the first days, and it has been recently recognized that the increased risk for complications remains even years after the acute episode [3,4]. This occurs mostly as a consequence of the cardiovascular damage caused by the infection and the inflammatory host response, capable of leaving chronic sequelae that is predisposed to the occurrence of cardiovascular events and mortality . The underlying pathophysiological mechanisms increase the cardiovascular risk, including inflammation, platelet activation, endothelial dysfunction, hypoxaemia, myocardial invasion, and specific pathogen-associated damage among others [5,6,7].
Stratification of the risk of mortality due to pneumonia, as well as identifying those patients most susceptible to complications in the short and long-term, are key in establishing preventive strategies and optimizing treatment . Biomarkers in CAP could be useful for the diagnosis of infection [9,10], severity assessment , to monitor clinical response and antibiotic duration, and recently, to predict cardiovascular complications . Many biomarkers have been studied for these purposes. The large number of biomarkers analysed reflects the complex pathophysiology of this disease and the heterogeneity of the host response. In this review, we briefly discuss some of the available biomarkers in CAP, including those reflecting cardiovascular damage. To this end, and for better understanding, we have classified the biomarkers as cardiac and non-cardiac. In Table 1, there is an overview of the biomarkers discussed in this issue, and Table 2 has a description of the studies.
2. Cardiac Biomarkers
Cardiac troponins (cTns), cTnI and cTnT, are well known cardiac enzymes because they are sensitive and specific biomarkers of myocardial injury . Their elevation is a consequence of myocardial damage. In CAP, myocardial damage may be produced directly by myocardium bacterial invasion, provoking cardiomyocyte apoptosis and necroptosis with a rise in cardiac enzymes . Animal models show us that the cardiac tropism that some pathogens have, such as Streptococcus pneumoniae, explaining the appearance of CVE during the acute phase of CAP. These pneumococcal inclusions in the myocardium cause tissue damage that eventually develops into fibrous tissue. Other pathogenic mechanisms for myocardial damage in CAP are cardiac overload, reduced contractility, inflammation, and an oxygen supply-demand mismatch resulting in hypoxia over the myocardium [106,107,108]. In fact, AMI appears in around 8% (up to 15% in severe CAP) and it is associated with clinical failure and worse prognoses in CAP patients [3,109].
Troponin determination has been shown to be useful for short and long-term mortality prediction in septic and CAP patients [13,14,15,16]. Moreover, troponins could be used to predict cardiac events during and after CAP. Thus, patients with initial levels of troponin above 21.9 ng/L had a twofold-increased risk of CVE within the first 30 days . However, at day 30 (when myocardial damaged is established and the fibrous tissue has already replaced dead cardiomyocytes) troponin T levels failed to predict CVE beyond that time. Raised levels of troponin in CAP have potential clinical implications because they may guide the prescribing of a cardiovascular rehabilitation program and treatment optimization. Moreover, it could be useful to select CAP patients at a high-risk of cardiovascular events in future trials.
2.2. Natriuretic Peptides
Natriuretic peptides are prohormones produced in numerous tissues. These peptides have multiple biological properties on diverse organs such as the regulation of homeostasis of body fluid volume and water/salt balance, and function as anti-remodelling factors in the heart . The increase in its concentration is related to overload and cardiac stress. Among these biomarkers, midregional pro-atrial (A-type) natriuretic peptide (MR-proANP), N-terminal pro-brain (B-type) natriuretic peptide (NT-proBNP), and B-type natriuretic peptide (BNP) are the most studied.
The different peptides have shown good accuracy in guiding the site of care  and/or prognostic prediction in CAP [19,20,21,22,23]. The three biomarkers that have been studied demonstrate a similar predictive capacity for short and long-term mortality between them and with respect to the Pneumonia Severity Index (PSI) or CURB65 score, although not better results [24,25,26]. The combination of MR-proANP with these scores improves their long-term prognoses . In comparison to inflammatory biomarkers, MR-proANP showed superiority in predicting short and long-term survival in CAP . The usefulness of natriuretic peptides to predict CVE in CAP, specifically MR-proADM, was recently evaluated to identify patients at risk of early and long-term CVE. In that study, those patients with NT-proBNP levels above 1619 pg/mL at day 1 had more than a twofold-increased risk of early CVE, and levels above 315 pg/mL at day 30 day for CV events during one year .
Adrenomedullin (ADM) is a strong vasodilatory prohormone with reliable measurement results being difficult to obtain. Instead, midregional-proadrenomedullin (MR-proADM) is a surrogate marker of ADM that is easier to measure . ADM levels reveal excessive blood volume, inflammation, and cardiac dysfunction, so it could be considered both a cardiac and inflammatory biomarker. Specifically, the increased plasma concentration of ADM is present in patients with heart failure, acute myocardial infarction (AMI), or peripheral arterial occlusive disease [30,31,32]. In the case of MR-proADM, its biological activity is under study, but it seems to have pro and anti-inflammatory activity, inducing local inflammation in the injured heart tissue, but attenuating, exaggerated inflammation . Now, it appears that besides a marker of cardiac damage and inflammation, it may have its own activity.
In CAP, MR-proADM has been found to be useful in improving the capacity of prognostic scales for decision-making in hospital and ICU admission [34,35]. This biomarker alone allows clinicians to estimate short and long-term survival rates in CAP, with a precision comparable to clinical scores, and its combination with the scores improves its accuracy [28,36,37,38,39]. In addition, the survival prediction power of pro-ADM is independent of the microbiological aetiology .
The prognosis in pneumonia is often conditioned by cardiovascular complications. To date, the utility of MR-proADM in CAP has only been evaluated for prognostic purposes. However, recently, this biomarker has been evaluated to predict cardiovascular events (CVE) in hospitalized CAP patients . Menendez et al., in a multicentre study, showed that those patients with initial levels of MR-proADM above 1.2 nmol/L had a twofold-increased the risk of short-term CVE, adjusted for age, prior cardiovascular disease, respiratory failure and sepsis. Furthermore, levels above 0.83 nmol/L at day 30 also increased the risk of long-term CVE events (within one year of follow-up).
Endothelin-1 (ET-1), a peptide that mainly proceeds from endothelial cells, is a stronger vasoconstrictor compared to angiotensin II. ProET-1 is a more stable precursor of ET-1 and is easier to measure . ET-1 causes decreased cardiac output and vasoconstriction in the coronary, pulmonary, renal, and splanchnic circulation . Septic patients show elevated ET-1 plasma levels and its concentration is associated with morbidity and mortality . In CAP, proET-1 levels at admission and their evolution have also demonstrated a good correlation with disease severity (assessed by prognostic scores) and are independently related to short and long-term mortality [28,44,45,46].
In hospitalized CAP, initial high levels (above 104 pmol/L) of proET-1 is a marker that expresses shear stress and exhibited good accuracy in predicting early CVE and levels above 70.7 pmol/L at day 30 for predicting late CVE. Interestingly, the combination of high levels of proET-1 with high levels of IL-6 meant that the remaining inflammation showed the strongest risk of cardiovascular complication after 30 days and one year after CAP diagnosis .
There are other biomarkers that have been evaluated. Carboxy-terminal provasopressin (CT-proAVP), known as copeptin, could also be useful for prognostic prediction [19,25,47,48]. Despite this, its use should be performed with caution because some factors such as antibiotic pre-treatment may influence its concentration in CAP patients . There are no studies that evaluate their predictive role in CVE. Finally, Gutbier et al. published an interesting article demonstrating that angiopoietins, markers of endothelial barrier function and hyperpermeability, are involved in the pathogenesis of CAP and their quantification were useful in predicting short-term mortality .
3. Non-Cardiac Biomarkers
3.1.1. C-Reactive Protein
The C-reactive protein (CRP) is an acute phase protein widely used as a marker of systemic inflammation due to its high sensitivity and early elevation in response to acute damage, but it has low specificity as an infectious biomarker. In CAP, several studies have analysed the usefulness of CRP for diagnosis, severity assessment, and prognostic information [50,51]. Its utility for etiological diagnosis is controversial. Some studies showed high CRP levels in bacterial CAP in comparison to viral CAP [110,111,112]. However, CRP does not allow for optimal discrimination between viral and bacterial aetiology and has no role for treatment purposes. High levels of CRP at admission have been linked to an increased risk of complications and short-term mortality [52,53]. Its combination with PSI and CURB65 scores improves the 30-day short-term mortality prediction . In addition, elevated levels maintained at 3–4 days are related to treatment failure and 30-day mortality [53,54] Regarding pneumonia diagnosis, CRP determination is not specific enough [55,56]. In fact, current European Respiratory Society and American Thoracic Society guidelines do not recommend systematic CRP determination for diagnoses or to guide treatment decisions [113,114], but it could be useful to diagnosis CAP in patients with atypical signs and symptoms or comorbid conditions, which could make other diagnoses more probable . In any case, the correct interpretation of CRP levels can be a complicated issue. Factors, such as the time elapsed since the onset of symptoms, influence CRP kinetics. CPR is more useful in evaluating the inflammatory response of patients at three or more days since the onset of symptoms, because, within the first 48 h, their levels are still raising . Finally, CRP may be useful for cardiovascular risk assessment in healthy women . However, as recently was published, increased CRP levels failed to predict the occurrence of CVE in the short or long-term in CAP patients .
Procalcitonin (PCT) is the active precursor of the hormone calcitonin belonging to the genetic CALC-1 family . While it is mainly useful for detecting sepsis, it is also elevated in other acute inflammation situations such as pancreatitis, appendicitis, burns, polytrauma, and surgery. Interferon gamma, a molecule synthesized in the inflammatory immune response against viral infection, inhibits its synthesis, and therefore their levels are low in these infections. Due to its rapid kinetic in CAP patients within the first 48 h since the onset of CAP symptoms, PCT levels are more useful than CRP that is still mounting .
In contrast to other inflammatory biomarkers such as CRP, PCT has been considered more specific for bacterial infection. However, there is no PCT threshold that totally discriminates against viral and bacterial infection in CAP . In recent studies, the ability of PCT to discriminate between viral and bacterial infection has been questioned. Despite higher levels being found in patients with severe pneumonia, PCT may not be elevated if CAP is caused by Legionella pneumophila or Mycoplasma pneumoniae and in post-influenza or mixed CAP. For this reason, PCT is not accurate enough to be used to determine whether empiric antibiotic therapy for CAP can be withheld because of a presumptive viral pathogen. PCT has been proposed to reduce the use of antibiotics and their duration [58,59]. Nevertheless, the last available studies have not shown that the determination of PCT involves a reduction in antibiotic consumption [60,61].
PCT is also useful as a prognostic biomarker. High levels of PCT at hospital admission for CAP are associated with ICU admission  and short-term mortality [10,63]. Furthermore, the persistence of elevated levels at 72 h before the start treatment is associated with treatment failure and mortality, while PCT being decreased improves the prognostic with a lower risk of shock, ICU admission, invasive mechanical ventilation, and death . Finally, PCT has demonstrated a lack of utility for CVE prediction along, or in combination with, other biomarkers .
Interleukin (IL)-6 is a classic proinflammatory cytokine. In the presence of microorganisms, lL-6 is produced immediately and contributes to host defence through the activation of the acute-phase inflammatory cascade and immune responses . IL-6, IL-8, IL-10, interferon regulatory factor 5 (IRF5), and other inflammatory cytokines were found to be related with CAP severity, treatment failure and poor prognosis [65,66]. However, while a high IL-6 concentration was reported in typical bacterial pneumonia, this cytokine is not accurate enough for etiological purposes. IL-6 levels at days 1 and 3 were independently associated with a higher risk of treatment failure within the first 72 h or later . Yende et al. have also reported that high systemic levels of IL-6 at hospital CAP discharge were associated with all-cause mortality over one year and cause specific mortality that is secondary to cancer, renal failure, infection or cardiovascular disease . Menendez et al. have reported that high levels of IL-6, along with high levels of pro-ADM or proendothelin-1 at day 30, were associated with subsequent CVE (until a year after pneumonia)—as an expression of the deleterious effect of inflammatory persistence .
3.1.4. Tumour Necrosis Factor Alpha
The tumour necrosis factor alpha (TNF-α) is an inflammatory mediator that activated a cellular immune response. Its effect is neutralized by a soluble anti TNF-α receptor. Unlike the inflammatory biomarkers seen previously, it is not studied in CAP. In contrast to CRP, PCT, and IL-6, TNF-α is unable to predict early or late treatment failure in the study by Menendez et al. and it does not improve mortality prediction . However, reduced TNF-α levels are found in patients with low inflammatory systemic response, like COPD patients who developed community-acquired pneumonia . The usefulness of this biomarker to assess cardiovascular risk in patients with CAP has not been analysed.
3.2.1. Absolute Lymphocyte Count
Lymphocytes are the main actors in adaptive immunity. Absolute lymphocyte count (ALC), a biological marker that is cheap and widely available in all clinical settings, has been evaluated for mortality prediction in non-immunosuppressed CAP patients. Lymphopenia was shown to be an independent risk factor of 30 days mortality in two large cohorts of CAP patients . Furthermore, the addition of this item to the CURB65 score improves its accuracy for mortality prediction. These findings have also been found in severe CAP (those admitted to ICU) and in ICU-acquired pneumonia [70,71]. Not only lymphopenia at diagnosis, but also persistent lymphopenia, are markers of poor prognosis . Lymphopenia in CAP, mainly caused by a CD4+ depletion, has been found to be related to a dysregulated immune response with more inflammatory responses . Lymphopenia could be caused by different reasons, including chronic diseases or critical illness, enhanced adhesion to the vascular endothelium, exhaustion, apoptosis or migration to the lungs [7,69]. ALC could also modify the treatment response to corticosteroids in severe CAP. In a post hoc analysis of a randomised clinical trial (RCT) that evaluated the effect of corticosteroids in patients with severe CAP and high inflammatory response, ALC may directly influence systemic inflammation reduction after treatment [73,119]. However, this effect should be prospectively evaluated in larger ad hoc RCTs.
3.2.2. Neutrophil Extracellular Traps
Neutrophil extracellular traps (NETs) are webs formed by DNA, citrullinated histones, and proteases (including myeloperoxidase and neutrophil elastase) capable of snare and kill bacteria . NETs are the result of neutrophil apoptosis (NETosis) in response to different stimuli. In some cases, this process is produced without the death of neutrophils, which preserve phagocytic activity, and are called vital NETosis . Briefly, the triggers for NETs production include the interaction with pathogens , activated platelets , injured/activated endothelium , or reactive oxygen species (ROS) . This interaction may be in the opposite sense and NETs can kill bacteria , activate platelets , damage the endothelium , and enhance inflammation .
The most data about NETs in infection mostly come from animal and in vitro models. There are only two studies in patients with CAP showing NETs as useful prognostic markers or as an endpoint in clinical trials [82,83]. In animal models, NETs have been shown to play a protector role against bacterial dissemination . However, respiratory pathogens have developed evasion methods through the inhibition of release, degradation, and resistance to NETs [85,86]. It is believed that the excess availability of NETs in the tissues and in the bloodstream causes a harmful effect on the body. The main harmful components are the citrullinated histones and neutrophil proteases . The deleterious effect of histones is due to several reasons. The histones have shown to be cytotoxic to lung epithelium and endothelium [88,89]. Another reason is that histones promote thrombosis . This is due to several reasons: first, it is consequence of endothelial activation and damage ; and second, histones and NETs provide a scaffold for thrombi formation . Finally, this causes cytotoxic consequences, ischemic events, and disseminated intravascular coagulation . All this is capable of generating cardiovascular events, a concerning issue in this review. Previously, cardiotoxicity of histones during sepsis has been demonstrated . Histone levels are directly correlated with cardiac troponin levels showing cardiac injury. Despite the data we have so far, there is much more needing to be in this area.
To date, the gold standard marker of NETosis or method of NET detection has not been determined . The current methods or markers are as follows: co-localization of neutrophil-derived proteins and extracellular DNA, presence of citrullinated histones, cell-free DNA, myeloperoxidase/neutrophil elastase-DNA complex, image-based flow cytometric detection of NETosis, and flow cytometric detection of cell-appendant NET components. The differences lie in specificity, objectivity, and quantitativity, with advantages and disadvantages in each one. This adds complexity and hinders the translational use of these biomarkers today.
There are other biomarkers that have shown to be useful in pneumonia, but their use still requires further clinical studies. D-dimer, a product derived from fibrin degradation, also has prognostic implications. Low D-dimer levels have low-risk for short-term mortality in CAP patients [95,96], and elevated D-dimer levels are associated with poor outcomes, independently of clinical scores . However, the adrenal function can also influence CAP outcomes . Therefore, cortisol, as a marker of adrenal function, has demonstrated that it may help in prognosis prediction [99,100,101]. In addition, its measurement could identify the response of patients to steroids . Meanwhile, high levels of the fibroblast growth factor 21 (FGF21) have recently been related to poor short-term prognosis in CAP patients from two randomised clinical trials . FGF21 is a metabolic regulator with anti-inflammatory and immunoregulatory properties . Siljan et al. recently evaluated the role of another biomarkers in CAP . Presepsin, calprotectin, and pentraxin 3 (PTX3) are a soluble CD14-subtype molecule (sCD14-ST), a neutrophil biomarker, and a receptor involved in innate immunity, respectively. The study showed the potential use of calprotectin for bacterial aetiology discrimination and long-term prognosis, and a potential use of both presepsin (sCD14-ST) and PTX3 for short-term prognosis [10,122].
4. Limitations and Future Perspectives
While the study of CAP biomarkers has evolved tremendously over the last 25 years, many limitations remain and the search for the ideal biomarker is still open. In fact, the pathogenesis of CAP is an important topic for diagnosis, treatment, and the role of biomarkers. Biomarkers provide information about CAP from different perspectives: severity assessment, host’s immune-inflammatory response, organ failure, cardiovascular complications, and outcome. CAP is a complex disease with a heterogeneous host response depending on multiple factors such as the initial severity, comorbid conditions, and causal microorganism. Thus, this complexity is one of the biggest limitations. Each biomarker may reflect a specific pathophysiological response, but it will hardly cover all the perspectives that occur in pneumonia. For severity assessment, biomarkers improve the prognostic capacity of the scales, however, by themselves, they are not superior to them. Secondly, the technical difficulty in measuring some and the economic cost of others in many cases restricts their clinical use. Another limitation is time and kinetics. Biomarkers are not static and their measurement at a specific time does not give us a complete picture of the condition. Finally, the prior host status, severity, time since onset of infection or other factors can also influence biomarkers [111,116]. Thus far, despite all the information provided by biomarkers, clinical outcomes have not improved. We need more clinical trials with biomarkers involved in the design. This explains both the limited routine use of CAP biomarkers in clinical settings and the limited inclusion in the guidelines today. Nonetheless, biomarkers have their use. The potential utility of cardiac biomarkers has demonstrated, both in patients with previous cardiac disease and in those without . They may guide the design of personalized cardiovascular rehabilitation programs and treatment optimization in patients both with and without known prior cardiac disorders.
The study of biomarkers must be addressed to achieve a more personalized medicine. Regrettably, the perfect biomarker does not exist at the moment. From our humble point of view, an interesting option could be to use a panel of biomarkers that depend on the outcome for evaluation. CRP is cheap, available and useful in monitoring responses, while PCT has a role in antibiotic duration. We consider that PCT is more useful during the first 2–3 days from the onset of symptoms, after this time, CRP seems to be better. Both the PCT and the CRP can be used together with the ALC for short-term survival prediction. For cardiovascular risk, proBNP, proADM, endothelin or troponins, offer similar information. Therefore, as Waterer et al. advocate, the future lies in embracing complexity . In the coming years, it is very likely that the study of omics will bring new biomarkers in order improve the understanding and management of CAP. To this end, basic science has a determining role. Undeniably, a translational approach that combines basic and clinical science in a single effort will be essential in order to take steps in the right direction.
Conceptualization, R.M. (Rosario Menéndez); Writing—Original Draft Preparation, R.M. (Rosario Menéndez), I.A., and R.M. (Raúl Méndez); Writing—Review & Editing, R.M. (Rosario Menéndez), I.A., and R.M. (Raúl Méndez). All authors have read and agreed to the published version of the manuscript.
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
- Menéndez, R.; Torres, A.; Aspa, J.; Capelastegui, A.; Prat, C.; Rodríguez de Castro, F.; Sociedad Española de Neumología y Cirugía Torácica. Community acquired pneumonia. New guidelines of the Spanish Society of Chest Diseases and Thoracic Surgery (SEPAR). Arch. Bronconeumol. 2010, 46, 543–558. [Google Scholar] [CrossRef] [PubMed]
- Schnoor, M.; Hedicke, J.; Dalhoff, K.; Raspe, H.; Schäfer, T. Approaches to estimate the population-based incidence of community acquired pneumonia. J. Infect. 2007, 55, 233–239. [Google Scholar] [CrossRef] [PubMed]
- Violi, F.; Cangemi, R.; Falcone, M.; Taliani, G.; Pieralli, F.; Vannucchi, V.; Nozzoli, C.; Venditti, M.; Chirinos, J.A.; Corrales-Medina, V.F.; et al. Cardiovascular Complications and Short-Term Mortality Risk in Community-Acquired Pneumonia. Clin. Infect. Dis. 2017, 64, 1486–1493. [Google Scholar] [CrossRef]
- Corrales-Medina, V.F.; Alvarez, K.N.; Weissfeld, L.A.; Angus, D.C.; Chirinos, J.A.; Chang, C.-C.H.; Newman, A.; Loehr, L.; Folsom, A.R.; Elkind, M.S.; et al. Association between Hospitalization for Pneumonia and Subsequent Risk of Cardiovascular Disease. JAMA 2015, 313, 264. [Google Scholar] [CrossRef]
- Reyes, L.F.; Restrepo, M.I.; Hinojosa, C.A.; Soni, N.J.; Anzueto, A.; Babu, B.L.; Gonzalez-Juarbe, N.; Rodriguez, A.H.; Jimenez, A.; Chalmers, J.D.; et al. Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling. Am. J. Respir. Crit. Care Med. 2017, 196, 609–620. [Google Scholar] [CrossRef]
- Singanayagam, A.; Singanayagam, A.; Elder, D.H.J.; Chalmers, J.D. Is community-acquired pneumonia an independent risk factor for cardiovascular disease? Eur. Respir. J. 2012, 39, 187–196. [Google Scholar] [CrossRef] [PubMed]
- Lee, K.-Y. A common immunopathogenesis mechanism for infectious diseases: The protein-homeostasis-system hypothesis. Infect. Chemother. 2015, 47, 12–26. [Google Scholar] [CrossRef]
- Aldás, I.; Menéndez, R.; Méndez, R.; España, P.P.; Almirall, J.; Boderías, L.; Rajas, O.; Zalacaín, R.; Vendrell, M.; Mir, I.; et al. Eventos cardiovasculares tempranos y tardíos en pacientes ingresados por neumonía adquirida en la comunidad. Arch. Bronconeumol. 2019. [Google Scholar] [CrossRef]
- Self, W.H.; Balk, R.A.; Grijalva, C.G.; Williams, D.J.; Zhu, Y.; Anderson, E.J.; Waterer, G.W.; Courtney, D.M.; Bramley, A.M.; Trabue, C.; et al. Procalcitonin as a Marker of Etiology in Adults Hospitalized With Community-Acquired Pneumonia. Clin. Infect. Dis. 2017, 65, 183–190. [Google Scholar] [CrossRef]
- Siljan, W.W.; Holter, J.C.; Michelsen, A.E.; Nymo, S.H.; Lauritzen, T.; Oppen, K.; Husebye, E.; Ueland, T.; Molines, T.E.; Aukrust, P.; et al. Inflammatory biomarkers are associated with aetiology and predict outcomes in community-acquired pneumonia: Results of a 5-year follow-up cohort study. ERJ Open Res. 2019, 5. [Google Scholar] [CrossRef]
- Menéndez, R.; Martínez, R.; Reyes, S.; Mensa, J.; Filella, X.; Marcos, M.A.; Martínez, A.; Esquinas, C.; Ramirez, P.; Torres, A. Biomarkers improve mortality prediction by prognostic scales in community-acquired pneumonia. Thorax 2009, 64, 587–591. [Google Scholar]
- Menéndez, R.; Méndez, R.; Aldás, I.; Reyes, S.; Gonzalez-Jimenez, P.; España, P.P.; Almirall, J.; Alonso, R.; Suescun, M.; Martinez-Dolz, L.; et al. Community-Acquired Pneumonia Patients at-risk for Early and Long-term Cardiovascular Events are Identified by Cardiac Biomarkers. Chest 2019, 156, 1080–1091. [Google Scholar] [CrossRef] [PubMed]
- Bessière, F.; Khenifer, S.; Dubourg, J.; Durieu, I.; Lega, J.-C. Prognostic value of troponins in sepsis: A meta-analysis. Intensive Care Med. 2013, 39, 1181–1189. [Google Scholar] [CrossRef] [PubMed]
- Vallabhajosyula, S.; Sakhuja, A.; Geske, J.B.; Kumar, M.; Poterucha, J.T.; Kashyap, R.; Kashani, K.; Jaffe, A.S.; Jentzer, J.C. Role of Admission Troponin—T and Serial Troponin—T Testing in Predicting Outcomes in Severe Sepsis and Septic Shock. J. Am. Heart Assoc. 2017, 6, e005930. [Google Scholar] [CrossRef]
- Lee, Y.J.; Lee, H.; soo Park, J.; Kim, S.J.; Cho, Y.J.; Yoon, H.I.; Lee, J.H.; Lee, C.T.; Park, J.S. Cardiac troponin I as a prognostic factor in critically ill pneumonia patients in the absence of acute coronary syndrome. J. Crit. Care 2015, 30, 390–394. [Google Scholar] [CrossRef]
- Vestjens, S.M.T.; Spoorenberg, S.M.C.; Rijkers, G.T.; Grutters, J.C.; Ten Berg, J.M.; Noordzij, P.G.; Van de Garde, E.M.W.; Bos, W.J.W.; Ovidius Study Group. High-sensitivity cardiac troponin T predicts mortality after hospitalization for community-acquired pneumonia. Respirology 2017, 22, 1000–1006. [Google Scholar] [CrossRef]
- Matsuo, A.; Nagai-Okatani, C.; Nishigori, M.; Kangawa, K.; Minamino, N. Natriuretic peptides in human heart: Novel insight into their molecular forms, functions, and diagnostic use. Peptides 2019, 111, 3–17. [Google Scholar] [CrossRef]
- Claessens, Y.-E.; Mathevon, T.; Kierzek, G.; Grabar, S.; Jegou, D.; Batard, E.; Loyer, C.; Davido, A.; Hausfater, P.; Robert, H.; et al. Accuracy of C-reactive protein, procalcitonin, and mid-regional pro-atrial natriuretic peptide to guide site of care of community-acquired pneumonia. Intensive Care Med. 2010, 36, 799–809. [Google Scholar] [CrossRef]
- Kruger, S.; Ewig, S.; Kunde, J.; Hartmann, O.; Suttorp, N.; Welte, T.; CAPNETZ Study Group. Pro-atrial natriuretic peptide and pro-vasopressin for predicting short-term and long-term survival in community-acquired pneumonia: Results from the German Competence Network CAPNETZ. Thorax 2010, 65, 208–214. [Google Scholar] [CrossRef]
- Christ-Crain, M.; Breidthardt, T.; Stolz, D.; Zobrist, K.; Bingisser, R.; Miedinger, D.; Leuppi, J.; Tamm, M.; Mueller, B.; Mueller, C. Use of B-type natriuretic peptide in the risk stratification of community-acquired pneumonia. J. Intern. Med. 2008, 264, 166–176. [Google Scholar] [CrossRef]
- Lin, S.-C.; Tsai, Y.-J.; Huang, C.-T.; Kuo, Y.-W.; Ruan, S.-Y.; Chuang, Y.-C.; Yu, C.J. Prognostic value of plasma N-terminal pro B-type natriuretic peptide levels in pneumonia patients requiring intensive care unit admission. Respirology 2013, 18, 933–941. [Google Scholar] [CrossRef] [PubMed]
- Chang, C.L.; Mills, G.D.; Karalus, N.C.; Jennings, L.C.; Laing, R.; Murdoch, D.R.; Chambers, S.T.; Vettise, D.; Tuffery, C.M.; Hancox, R.J. Biomarkers of Cardiac Dysfunction and Mortality from Community-Acquired Pneumonia in Adults. PLoS ONE 2013, 8, e62612. [Google Scholar] [CrossRef] [PubMed]
- Akpınar, E.E.; Hoşgün, D.; Akpınar, S.; Ateş, C.; Baha, A.; Gülensoy, E.S.; Ogan, N. Do N-terminal pro-brain natriuretic peptide levels determine the prognosis of community acquired pneumonia? J. Bras. Pneumol. 2019, 45, e20180417. [Google Scholar] [CrossRef] [PubMed]
- Nowak, A.; Breidthardt, T.; Christ-Crain, M.; Bingisser, R.; Meune, C.; Tanglay, Y.; Heinisch, C.; Reiter, M.; Drexler, B.; Arenja, N.; et al. Direct Comparison of Three Natriuretic Peptides for Prediction of Short- and Long-term Mortality in Patients With Community-Acquired Pneumonia. Chest 2012, 141, 974–982. [Google Scholar] [CrossRef]
- Krüger, S.; Papassotiriou, J.; Marre, R.; Richter, K.; Schumann, C.; von Baum, H.; Morgenthaler, N.G.; Suttorp, N.; Welte, T.; CAPNETZ Study Group. Pro-atrial natriuretic peptide and pro-vasopressin to predict severity and prognosis in community-acquired pneumonia. Intensive Care Med. 2007, 33, 2069–2078. [Google Scholar] [CrossRef] [PubMed]
- Viasus, D.; Del Rio-Pertuz, G.; Simonetti, A.F.; Garcia-Vidal, C.; Acosta-Reyes, J.; Garavito, A.; Carratalà, J. Biomarkers for predicting short-term mortality in community-acquired pneumonia: A systematic review and meta-analysis. J. Infect. 2016, 72, 273–282. [Google Scholar] [CrossRef] [PubMed]
- Alan, M.; Grolimund, E.; Kutz, A.; Christ-Crain, M.; Thomann, R.; Falconnier, C.; Hoess, C.; Henzen, C.; Zimmerli, W.; Mueller, B.; et al. Clinical risk scores and blood biomarkers as predictors of long-term outcome in patients with community-acquired pneumonia: A 6-year prospective follow-up study. J. Intern Med. 2015, 278, 174–184. [Google Scholar] [CrossRef]
- Krüger, S.; Ewig, S.; Giersdorf, S.; Hartmann, O.; Suttorp, N.; Welte, T.; German Competence Network for the Study of Community Acquired Pneumonia (CAPNETZ) Study Group. Cardiovascular and Inflammatory Biomarkers to Predict Short- and Long-Term Survival in Community-acquired Pneumonia. Am. J. Respir. Crit. Care Med. 2010, 182, 1426–1434. [Google Scholar] [CrossRef]
- Morgenthaler, N.G.; Struck, J.; Alonso, C.; Bergmann, A. Measurement of Midregional Proadrenomedullin in Plasma with an Immunoluminometric Assay. Clin. Chem. 2005, 44, 571–577. [Google Scholar] [CrossRef]
- Nishikimi, T.; Saito, Y.; Kitamura, K.; Ishimitsu, T.; Eto, T.; Kangawa, K.; Matsuo, H.; Omae, T.; Matsuoka, H. Increased plasma levels of adrenomedullin in patients with heart failure. J. Am. Coll. Cardiol. 1995, 26, 1424–1431. [Google Scholar] [CrossRef]
- Miyao, Y.; Nishikimi, T.; Goto, Y.; Miyazaki, S.; Daikoku, S.; Morii, I.; Matsumoto, T.; Takishita, S.; Miyata, A.; Matsuo, H.; et al. Increased plasma adrenomedullin levels in patients with acute myocardial infarction in proportion to the clinical severity. Heart 1998, 79, 39–44. [Google Scholar] [CrossRef]
- Suzuki, Y.; Horio, T.; Hayashi, T.; Nonogi, H.; Kitamura, K.; Eto, T.; Kangawa, K.; Kawano, Y. Plasma adrenomedullin concentration is increased in patients with peripheral arterial occlusive disease associated with vascular inflammation. Regul. Pept. 2004, 118, 99–104. [Google Scholar] [CrossRef] [PubMed]
- Hinrichs, S.; Scherschel, K.; Krüger, S.; Neumann, J.T.; Schwarzl, M.; Yan, I.; Warnke, S.; Ojeda, F.M.; Zeller, T.; Karakas, M.; et al. Precursor proadrenomedullin influences cardiomyocyte survival and local inflammation related to myocardial infarction. Proc. Natl. Acad. Sci. USA 2018, 115, E8727–E8736. [Google Scholar] [CrossRef] [PubMed]
- España, P.P.; Capelastegui, A.; Mar, C.; Bilbao, A.; Quintana, J.M.; Diez, R.; Esteban, C.; Bereciartua, E.; Unanue, U.; Uranga, A. Performance of pro-adrenomedullin for identifying adverse outcomes in community-acquired pneumonia. J. Infect. 2015, 70, 457–466. [Google Scholar] [CrossRef] [PubMed]
- Renaud, B.; Schuetz, P.; Claessens, Y.-E.; Labarère, J.; Albrich, W.; Mueller, B. Proadrenomedullin Improves Risk of Early Admission to ICU Score for Predicting Early Severe Community-Acquired Pneumonia. Chest 2012, 142, 1447–1454. [Google Scholar] [CrossRef]
- Christ-Crain, M.; Morgenthaler, N.G.; Stolz, D.; Müller, C.; Bingisser, R.; Harbarth, S.; Tamm, M.; Struck, J.; Bergmann, A.; Müller, B. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia. Crit. Care 2006, 10, R96. [Google Scholar] [CrossRef]
- Huang, D.T.; Angus, D.C.; Kellum, J.A.; Pugh, N.A.; Weissfeld, L.A.; Struck, J.; Delude, R.L.; Rosengart, M.R.; Yealy, D.M. Midregional proadrenomedullin as a prognostic tool in community-acquired pneumonia. Chest 2009, 136, 823–831. [Google Scholar] [CrossRef]
- Albrich, W.C.; Dusemund, F.; Rüegger, K.; Christ-Crain, M.; Zimmerli, W.; Bregenzer, T.; Irani, S.; Buergi, U.; Reutlinger, B.; Mueller, B.; et al. Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: Derivation of a clinical algorithm. BMC Infect. Dis. 2011, 11, 112. [Google Scholar] [CrossRef]
- Liu, D.; Xie, L.; Zhao, H.; Liu, X.; Cao, J. Prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with community-acquired pneumonia: A systematic review and meta-analysis. BMC Infect. Dis. 2016, 16, 232. [Google Scholar] [CrossRef]
- Bello, S.; Lasierra, A.B.; Mincholé, E.; Fandos, S.; Ruiz, M.A.; Vera, E.; de Pablo, F.; Ferrer, M.; Menendez, R.; Torres, A. Prognostic power of proadrenomedullin in community-acquired pneumonia is independent of aetiology. Eur. Respir. J. 2012, 39, 1144–1155. [Google Scholar] [CrossRef]
- Papassotiriou, J.; Morgenthaler, N.G.; Struck, J.; Alonso, C.; Bergmann, A. Immunoluminometric Assay for Measurement of the C-Terminal Endothelin-1 Precursor Fragment in Human Plasma. Clin. Chem. 2006, 52, 1144–1151. [Google Scholar] [CrossRef] [PubMed]
- Wanecek, M.; Weitzberg, E.; Rudehill, A.; Oldner, A. The endothelin system in septic and endotoxin shock. Eur. J. Pharmacol. 2000, 407, 1–15. [Google Scholar] [CrossRef]
- Pittet, J.-F.; Morel, D.R.; Hemsen, A.; Gunning, K.; Lacroix, J.-S.; Suter, P.M.; Lundberg, J.M. Elevated Plasma Endothelin-1 Concentrations Are Associated with the Severity of Illness in Patients with Sepsis. Ann. Surg. 1991, 213, 261–264. [Google Scholar] [CrossRef] [PubMed]
- Schuetz, P.; Stolz, D.; Mueller, B.; Morgenthaler, N.G.; Struck, J.; Mueller, C.; Bingisser, R.; Tamm, M.; Christ-Crain, M. Endothelin-1 precursor peptides correlate with severity of disease and outcome in patients with community acquired pneumonia. BMC Infect. Dis. 2008, 8, 22. [Google Scholar] [CrossRef] [PubMed]
- Schuetz, P.; Wolbers, M.; Christ-Crain, M.; Thomann, R.; Falconier, C.; Widmer, I.; Neidert, S.; Fricker, T.; Blum, C.; Schild, U.; et al. Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit. Care 2010, 14, R106. [Google Scholar] [CrossRef] [PubMed]
- Schuetz, P.; Christ-Crain, M.; Zimmerli, W.; Mueller, B. Repeated measurements of endothelin-1 precursor peptides predict the outcome in community-acquired pneumonia. Intensive Care Med. 2011, 37, 970–980. [Google Scholar] [CrossRef]
- Masia, M.; Papassotiriou, J.; Morgenthaler, N.G.; Hernandez, I.; Shum, C.; Gutierrez, F. Midregional Pro-A-Type Natriuretic Peptide and Carboxy-Terminal Provasopressin May Predict Prognosis in Community-Acquired Pneumonia. Clin. Chem. 2007, 53, 2193–2201. [Google Scholar] [CrossRef]
- Kolditz, M.; Halank, M.; Schulte-Hubbert, B.; Bergmann, S.; Albrecht, S.; Höffken, G. Copeptin predicts clinical deterioration and persistent instability in community-acquired pneumonia. Respir. Med. 2012, 106, 1320–1328. [Google Scholar] [CrossRef]
- Kruger, S.; Ewig, S.; Kunde, J.; Hanschmann, A.; Marre, R.; Suttorp, N.; Welte, T.; CAPNETZ Study Group. C-terminal provasopressin (copeptin) in patients with community-acquired pneumonia--influence of antibiotic pre-treatment: Results from the German competence network CAPNETZ. J. Antimicrob. Chemother. 2009, 64, 159–162. [Google Scholar] [CrossRef]
- Almirall, J.; Bolíbar, I.; Toran, P.; Pera, G.; Boquet, X.; Balanzó, X.; Sauca, G.; Community-Acquired Pneumonia Maresme Study Group. Contribution of C-Reactive Protein to the Diagnosis and Assessment of Severity of Community-Acquired Pneumonia. Chest 2004, 125, 1335–1342. [Google Scholar] [CrossRef]
- Van Vugt, S.F.; Broekhuizen, B.D.L.; Lammens, C.; Zuithoff, N.P.A.; de Jong, P.A.; Coenen, S.; Ieven, M.; Butler, C.C.; Goossens, H.; Little, P.; et al. Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: Diagnostic study. BMJ 2013, 346, f2450. [Google Scholar] [CrossRef] [PubMed]
- Hohenthal, U.; Hurme, S.; Helenius, H.; Heiro, M.; Meurman, O.; Nikoskelainen, J.; Kotilainen, P. Utility of C-reactive protein in assessing the disease severity and complications of community-acquired pneumonia. Clin. Microbiol. Infect. 2009, 15, 1026–1032. [Google Scholar] [CrossRef] [PubMed]
- Chalmers, J.D.; Singanayagam, A.; Hill, A.T. C-Reactive Protein Is an Independent Predictor of Severity in Community-acquired Pneumonia. Am. J. Med. 2008, 121, 219–225. [Google Scholar] [CrossRef]
- Menéndez, R.; Cavalcanti, M.; Reyes, S.; Mensa, J.; Martinez, R.; Marcos, M.A.; Filella, X.; Niederman, M.; Torres, A. Markers of treatment failure in hospitalised community acquired pneumonia. Thorax 2008, 63, 447–452. [Google Scholar] [CrossRef] [PubMed]
- Le Bel, J.; Hausfater, P.; Chenevier-Gobeaux, C.; Blanc, F.-X.; Benjoar, M.; Ficko, C.; Ray, P.; Choquet, C.; Duval, X.; Claessens, Y.E.; et al. Diagnostic accuracy of C-reactive protein and procalcitonin in suspected community-acquired pneumonia adults visiting emergency department and having a systematic thoracic CT scan. Crit. Care 2015, 19, 366. [Google Scholar] [CrossRef] [PubMed]
- Falk, G.; Fahey, T. C-reactive protein and community-acquired pneumonia in ambulatory care: Systematic review of diagnostic accuracy studies. Fam. Pract. 2009, 26, 10–21. [Google Scholar] [CrossRef]
- Whicher, J.; Bienvenu, J.; Monneret, G. Procalcitonin as an Acute Phase Marker. Ann. Clin. Biochem. Int. J. Biochem. Lab. Med. 2001, 38, 483–493. [Google Scholar] [CrossRef]
- Schuetz, P.; Wirz, Y.; Sager, R.; Christ-Crain, M.; Stolz, D.; Tamm, M.; Bouadma, L.; Luyt, C.E.; Wolff, M.; Chastre, J.; et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst. Rev. 2017, 10, CD007498. [Google Scholar] [CrossRef]
- Schuetz, P.; Wirz, Y.; Sager, R.; Christ-Crain, M.; Stolz, D.; Tamm, M.; Bouadma, L.; Luyt, C.E.; Wolff, M.; Chastre, J.; et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: A patient level meta-analysis. Lancet Infect. Dis. 2018, 18, 95–107. [Google Scholar] [CrossRef]
- Huang, D.T.; Yealy, D.M.; Filbin, M.R.; Brown, A.M.; Chang, C.-C.H.; Doi, Y.; Donnino, M.W.; Fine, J.; Fine, M.J.; Fischer, M.A.; et al. Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection. N. Engl. J. Med. 2018, 379, 236–249. [Google Scholar] [CrossRef]
- Montassier, E.; Javaudin, F.; Moustafa, F.; Nandjou, D.; Maignan, M.; Hardouin, J.-B.; Annoot, C.; Ogielska, M.; Orer, P.L.; Schotté, T.; et al. Guideline-Based Clinical Assessment Versus Procalcitonin-Guided Antibiotic Use in Pneumonia: A Pragmatic Randomized Trial. Ann. Emerg. Med. 2019, 74, 580–591. [Google Scholar] [CrossRef] [PubMed]
- Self, W.H.; Grijalva, C.G.; Williams, D.J.; Woodworth, A.; Balk, R.A.; Fakhran, S.; Zhu, Y.; Courtney, D.M.; Chappell, J.; Anderson, E.J.; et al. Procalcitonin as an Early Marker of the Need for Invasive Respiratory or Vasopressor Support in Adults with Community-Acquired Pneumonia. Chest 2016, 150, 819–828. [Google Scholar] [CrossRef] [PubMed]
- Zhydkov, A.; Christ-Crain, M.; Thomann, R.; Hoess, C.; Henzen, C.; Werner, Z.; Mueller, B.; Schuetz, P.; ProHOSP Study Group. Utility of procalcitonin, C-reactive protein and white blood cells alone and in combination for the prediction of clinical outcomes in community-acquired pneumonia. Clin. Chem. Lab. Med. 2015, 53, 559–566. [Google Scholar] [CrossRef]
- Tanaka, T.; Narazaki, M.; Kishimoto, T. Interleukin (IL-6) Immunotherapy. Cold Spring Harb. Perspect. Biol. 2018, 10, a028456. [Google Scholar] [CrossRef] [PubMed]
- Zobel, K.; Martus, P.; Pletz, M.W.; Ewig, S.; Prediger, M.; Welte, T.; Bühling, F.; CAPNETZ study group. Interleukin 6, lipopolysaccharide-binding protein and interleukin 10 in the prediction of risk and etiologic patterns in patients with community-acquired pneumonia: Results from the German competence network CAPNETZ. BMC Pulm. Med. 2012, 12, 6. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Guo, J.; Wang, Y.; Xiao, Y.; Wang, L.; Hua, S. Expression Levels of Interferon Regulatory Factor 5 (IRF5) and Related Inflammatory Cytokines Associated with Severity, Prognosis, and Causative Pathogen in Patients with Community-Acquired Pneumonia. Med. Sci. Monit. 2018, 24, 3620–3630. [Google Scholar] [CrossRef]
- Yende, S.; D’Angelo, G.; Kellum, J.A.; Weissfeld, L.; Fine, J.; Welch, R.D.; Kong, L.; Carter, M.; Angus, D.C.; GenIMS Investigators. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am. J. Respir. Crit. Care Med. 2008, 177, 1242–1247. [Google Scholar] [CrossRef]
- Crisafulli, E.; Menéndez, R.; Huerta, A.; Martinez, R.; Montull, B.; Clini, E.; Torres, A. Systemic inflammatory pattern of patients with community-acquired pneumonia with and without COPD. Chest 2013, 143, 1009–1017. [Google Scholar] [CrossRef]
- Bermejo-Martin, J.F.; Cilloniz, C.; Mendez, R.; Almansa, R.; Gabarrus, A.; Ceccato, A.; Torres, A.; Menendez, R.; NEUMONAC group. Lymphopenic Community Acquired Pneumonia (L-CAP), an Immunological Phenotype Associated with Higher Risk of Mortality. EBioMedicine 2017, 24, 231–236. [Google Scholar] [CrossRef]
- Güell, E.; Martín-Fernandez, M.; De la Torre, M.C.; Palomera, E.; Serra, M.; Martinez, R.; Solsona, M.; Miró, G.; Vallès, J.; Fernández, S.; et al. Impact of Lymphocyte and Neutrophil Counts on Mortality Risk in Severe Community-Acquired Pneumonia with or without Septic Shock. J. Clin. Med. 2019, 8, 754. [Google Scholar] [CrossRef]
- Ceccato, A.; Panagiotarakou, M.; Ranzani, O.T.; Martin-Fernandez, M.; Almansa-Mora, R.; Gabarrus, A.; Bueno, L.; Cilloniz, C.; Liapikou, A.; Ferrer, M.; et al. Lymphocytopenia as a Predictor of Mortality in Patients with ICU-Acquired Pneumonia. J. Clin. Med. 2019, 8, 843. [Google Scholar] [CrossRef] [PubMed]
- Méndez, R.; Menéndez, R.; Amara-Elori, I.; Feced, L.; Piró, A.; Ramírez, P.; Sempere, A.; Ortega, A.; Bermejo-Martín, J.F.; Torres, A. Lymphopenic community-acquired pneumonia is associated with a dysregulated immune response and increased severity and mortality. J. Infect. 2019, 78, 423–431. [Google Scholar] [CrossRef] [PubMed]
- Torres, A.; Ceccato, A.; Ferrer, M.; Gabarrus, A.; Sibila, O.; Cilloniz, C.; Mendez, R.; Menendez, R.; Bermejo-Martin, J.; Niederman, M.S. Effect of Corticosteroids on C-Reactive Protein in Patients with Severe Community-Acquired Pneumonia and High Inflammatory Response: The Effect of Lymphopenia. J. Clin. Med. 2019, 8, 1461. [Google Scholar] [CrossRef] [PubMed]
- Brinkmann, V.; Reichard, U.; Goosmann, C.; Fauler, B.; Uhlemann, Y.; Weiss, D.S.; Weinrauch, Y.; Zychlinsky, A. Neutrophil Extracellular Traps Kill Bacteria. Science 2004, 303, 1532–1535. [Google Scholar] [CrossRef] [PubMed]
- Yipp, B.G.; Kubes, P. NETosis: How vital is it? Blood 2013, 122, 2784–2794. [Google Scholar] [CrossRef]
- Ullah, I.; Ritchie, N.D.; Evans, T.J. The interrelationship between phagocytosis, autophagy and formation of neutrophil extracellular traps following infection of human neutrophils by Streptococcus pneumoniae. Innate Immun. 2017, 23, 413–423. [Google Scholar] [CrossRef]
- Clark, S.R.; Ma, A.C.; Tavener, S.A.; McDonald, B.; Goodarzi, Z.; Kelly, M.M.; Patel, K.D.; Chakrabarti, S.; MvAvoy, E.; Sinclair, G.D.; et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 2007, 13, 463–469. [Google Scholar] [CrossRef]
- Gupta, A.K.; Joshi, M.B.; Philippova, M.; Erne, P.; Hasler, P.; Hahn, S.; Resink, T.J. Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death. FEBS Lett. 2010, 584, 3193–3197. [Google Scholar] [CrossRef]
- Wang, Y.; Wang, Y.; Wu, J.; Liu, C.; Zhou, Y.; Mi, L.; Zhang, Y.; Wang, W. PRAK Is Required for the Formation of Neutrophil Extracellular Traps. Front. Immunol. 2019, 10, 1252. [Google Scholar] [CrossRef]
- Gould, T.J.; Vu, T.T.; Swystun, L.L.; Dwivedi, D.J.; Mai, S.H.C.; Weitz, J.I.; Liaw, P.C. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler. Thromb. Vasc. Biol. 2014, 34, 1977–1984. [Google Scholar] [CrossRef]
- Folco, E.J.; Mawson, T.L.; Vromman, A.; Bernardes-Souza, B.; Franck, G.; Persson, O.; Nakamura, M.; Newton, G.; Luscinskas, F.W.; Libby, P. Neutrophil Extracellular Traps Induce Endothelial Cell Activation and Tissue Factor Production Through Interleukin-1α and Cathepsin G. Arterioscler. Thromb. Vasc. Biol. 2018, 38, 1901–1912. [Google Scholar] [CrossRef]
- Ebrahimi, F.; Giaglis, S.; Hahn, S.; Blum, C.A.; Baumgartner, C.; Kutz, A.; van Breda, S.V.; Mueller, B.; Schuetz, P.; Christ-Crain, M.; et al. Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: Secondary analysis of a randomised controlled trial. Eur. Respir. J. 2018, 51, 1701389. [Google Scholar] [CrossRef] [PubMed]
- Sapey, E.; Patel, J.M.; Greenwood, H.; Walton, G.M.; Grudzinska, F.; Parekh, D.; Mahida, R.Y.; Dancer, R.C.A.; Lugg, S.T.; Howells, P.A.; et al. Simvastatin Improves Neutrophil Function and Clinical Outcomes in Pneumonia: A Pilot Randomised Controlled Clinical Trial. Am. J. Respir. Crit. Care Med. 2019, 200, 1282–1293. [Google Scholar] [CrossRef]
- McDonald, B.; Urrutia, R.; Yipp, B.G.; Jenne, C.N.; Kubes, P. Intravascular Neutrophil Extracellular Traps Capture Bacteria from the Bloodstream during Sepsis. Cell Host Microbe 2012, 12, 324–333. [Google Scholar] [CrossRef]
- Storisteanu, D.M.L.; Pocock, J.M.; Cowburn, A.S.; Juss, J.K.; Nadesalingam, A.; Nizet, V.; Chilvers, E.R. Evasion of Neutrophil Extracellular Traps by Respiratory Pathogens. Am. J. Respir. Cell Mol. Biol. 2017, 56, 423–431. [Google Scholar] [CrossRef]
- Martinez, P.J.; Farhan, A.; Mustafa, M.; Javaid, N.; Darkoh, C.; Garrido-Sanabria, E.; Fisher-Hoch, S.P.; Briles, D.E.; Kantarci, A.; Mirza, S. PspA facilitates evasion of pneumococci from bactericidal activity of neutrophil extracellular traps (NETs). Microb. Pathog. 2019, 136, 103653. [Google Scholar] [CrossRef]
- Wildhagen, K.C.A.A.; Wiewel, M.A.; Schultz, M.J.; Horn, J.; Schrijver, R.; Reutelingsperger, C.P.M.; van der Poll, T.; Nicolaes, G.A. Extracellular histone H3 levels are inversely correlated with antithrombin levels and platelet counts and are associated with mortality in sepsis patients. Thromb. Res. 2015, 136, 542–547. [Google Scholar] [CrossRef]
- Saffarzadeh, M.; Juenemann, C.; Queisser, M.A.; Lochnit, G.; Barreto, G.; Galuska, S.P.; Lohmeyer, J.; Preissner, K.T. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: A predominant role of histones. PLoS ONE 2012, 7, e32366. [Google Scholar] [CrossRef] [PubMed]
- Grailer, J.J.; Ward, P.A. Lung inflammation and damage induced by extracellular histones. Inflamm. cell Signal. 2014, 1, e131. [Google Scholar] [CrossRef]
- Semeraro, F.; Ammollo, C.T.; Morrissey, J.H.; Dale, G.L.; Friese, P.; Esmon, N.L.; Esmon, C.T. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: Involvement of platelet TLR2 and TLR4. Blood 2011, 118, 1952–1961. [Google Scholar] [CrossRef]
- Fuchs, T.A.; Brill, A.; Duerschmied, D.; Schatzberg, D.; Monestier, M.; Myers, D.D.; Wrobleski, S.K.; Wakefield, T.W.; Hartwig, J.H.; Wagner, D.D. Extracellular DNA traps promote thrombosis. Proc. Natl. Acad. Sci. USA 2010, 107, 15880–15885. [Google Scholar] [CrossRef]
- Abrams, S.T.; Morton, B.; Alhamdi, Y.; Alsabani, M.; Lane, S.; Welters, I.D.; Wang, G.; Toh, C.H. A Novel Assay for Neutrophil Extracellular Traps (NETs) Formation Independently Predicts Disseminated Intravascular Coagulation and Mortality in Critically Ill Patients. Am. J. Respir. Crit. Care Med. 2019, 134, 440. [Google Scholar]
- Alhamdi, Y.; Abrams, S.T.; Cheng, Z.; Jing, S.; Su, D.; Liu, Z.; Lane, S.; Welters, I.; Wang, G.; Toh, C.H. Circulating Histones Are Major Mediators of Cardiac Injury in Patients with Sepsis. Crit. Care Med. 2015, 43, 2094–2103. [Google Scholar] [CrossRef] [PubMed]
- Masuda, S.; Nakazawa, D.; Shida, H.; Miyoshi, A.; Kusunoki, Y.; Tomaru, U.; Ishizu, A. NETosis markers: Quest for specific, objective, and quantitative markers. Clin. Chim. Acta 2016, 459, 89–93. [Google Scholar] [CrossRef] [PubMed]
- Chalmers, J.D.; Singanayagam, A.; Scally, C.; Hill, A.T. Admission D-dimer Can Identify Low-Risk Patients with Community-Acquired Pneumonia. Ann. Emerg. Med. 2009, 53, 633–638. [Google Scholar] [CrossRef]
- Snijders, D.; Schoorl, M.; Schoorl, M.; Bartels, P.C.; van der Werf, T.S.; Boersma, W.G. D-dimer levels in assessing severity and clinical outcome in patients with community-acquired pneumonia. A secondary analysis of a randomised clinical trial. Eur. J. Intern Med. 2012, 23, 436–441. [Google Scholar] [CrossRef]
- Querol-Ribelles, J.M.; Tenias, J.M.; Grau, E.; Querol-Borras, J.M.; Climent, J.L.; Gomez, E.; Martinez, I. Plasma d-Dimer Levels Correlate With Outcomes in Patients With Community-Acquired Pneumonia. Chest 2004, 126, 1087–1092. [Google Scholar] [CrossRef]
- Kolditz, M.; Halank, M.; Schulte-Hubbert, B.; Höffken, G. Adrenal function is related to prognosis in moderate community-acquired pneumonia. Eur. Respir. J. 2010, 36, 615–621. [Google Scholar] [CrossRef]
- Salluh, J.I.F.; Bozza, F.A.; Soares, M.; Verdeal, J.C.R.; Castro-Faria-Neto, H.C.; LapaeSilva, J.R.; Bozza, P.T. Adrenal Response in Severe Community-Acquired Pneumonia. Chest 2008, 134, 947–954. [Google Scholar] [CrossRef]
- Mueller, C.; Blum, C.A.; Trummler, M.; Stolz, D.; Bingisser, R.; Mueller, C.; Tamm, M.; Mueller, B.; Schuetz, P.; Christ-Crain, M. Association of Adrenal Function and Disease Severity in Community-Acquired Pneumonia. PLoS ONE 2014, 9, e99518. [Google Scholar] [CrossRef]
- Kolditz, M.; Höffken, G.; Martus, P.; Rohde, G.; Schütte, H.; Bals, R.; Suttorp, N.; Pletz, M.W.; CAPNETZ Study Group. Serum cortisol predicts death and critical disease independently of CRB-65 score in community-acquired pneumonia: A prospective observational cohort study. BMC Infect. Dis. 2012, 12, 90. [Google Scholar] [CrossRef]
- Urwyler, S.A.; Blum, C.A.; Coslovsky, M.; Mueller, B.; Schuetz, P.; Christ—Crain, M. Cytokines and Cortisol—predictors of treatment response to corticosteroids in community—acquired pneumonia? J. Intern Med. 2019, 286, 75–87. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Wang, N.; Khoso, M.H.; Shen, C.; Guo, M.; Pang, X.; Li, D.; Wang, W. FGF-21 Elevated IL-10 Production to Correct LPS-Induced Inflammation. Inflammation 2018, 41, 751–759. [Google Scholar] [CrossRef] [PubMed]
- Gutbier, B.; Neuhauß, A.-K.; Reppe, K.; Ehrler, C.; Santel, A.; Kaufmann, J.; Scholz, M.; Weissmann, N.; Morawietz, L.; Mitchell, T.J.; et al. Prognostic and Pathogenic Role of Angiopoietin-1 and -2 in Pneumonia. Am. J. Respir. Crit. Care Med. 2018, 198, 220–231. [Google Scholar] [CrossRef] [PubMed]
- Thygesen, K.; Alpert, J.S.; Jaffe, A.S.; Simoons, M.L.; Chaitman, B.R.; White, H.D. Third Universal Definition of Myocardial Infarction. Circulation 2012, 126, 2020–2035. [Google Scholar] [CrossRef] [PubMed]
- Vita, J.A.; Treasure, C.B.; Yeung, A.C.; Vekshtein, V.I.; Fantasia, G.M.; Fish, R.D.; Ganz, P.; Selwyn, A.P. Patients with evidence of coronary endothelial dysfunction as assessed by acetylcholine infusion demonstrate marked increase in sensitivity to constrictor effects of catecholamines. Circulation 1992, 85, 1390–1397. [Google Scholar] [CrossRef]
- Moammar, M.Q.; Ali, M.I.; Mahmood, N.A.; DeBari, V.A.; Khan, M.A. Cardiac troponin I levels and alveolar-arterial oxygen gradient in patients with community-acquired pneumonia. Heart Lung Circ. 2010, 19, 90–92. [Google Scholar] [CrossRef]
- Frencken, J.F.; van Baal, L.; Kappen, T.H.; Donker, D.W.; Horn, J.; van der Poll, T.; van Klei, W.A.; Bonten, M.J.M.; Cremer, O.L.; Members of the MARS Consortium. Myocardial Injury in Critically Ill Patients with Community-acquired Pneumonia. A Cohort Study. Ann. Am. Thorac. Soc. 2019, 16, 606–612. [Google Scholar] [CrossRef]
- Ramirez, J.; Aliberti, S.; Mirsaeidi, M.; Peyrani, P.; Filardo, G.; Amir, A.; Moffet, B.; Gordon, J.; Blasi, F.; Bordon, J. Acute Myocardial Infarction in Hospitalized Patients with Community—Acquired Pneumonia. Clin. Infect. Dis. 2008, 47, 182–187. [Google Scholar] [CrossRef]
- Krüger, S.; Ewig, S.; Papassotiriou, J.; Kunde, J.; Marre, R.; von Baum, H.; Suttor, N.; Welte, T.; CAPNETZ Study Group. Inflammatory parameters predict etiologic patterns but do not allow for individual prediction of etiology in patients with CAP: Results from the German competence network CAPNETZ. Respir. Res. 2009, 10, 65. [Google Scholar] [CrossRef]
- Menéndez, R.; Sahuquillo-arce, J.M.; Reyes, S.; Martínez, R.; Polverino, E.; Cillóniz, C.; Córdoba, J.G.; Montull, B.; Torres, A. Cytokine activation patterns and biomarkers are influenced by microorganisms in community-acquired pneumonia. Chest 2012, 141, 1537–1545. [Google Scholar] [CrossRef] [PubMed]
- Ten Oever, J.; Tromp, M.; Bleeker-Rovers, C.P.; Joosten, L.A.B.; Netea, M.G.; Pickkers, P.; van de Veerdonk, F.L. Combination of biomarkers for the discrimination between bacterial and viral lower respiratory tract infections. J. Infect. 2012, 65, 490–495. [Google Scholar] [CrossRef]
- Woodhead, M.; Blasi, F.; Ewig, S.; Huchon, G.; Ieven, M.; Leven, M.; Ortqvist, A.; Schaberg, T.; Torres, A.; van der Heijden, G.; et al. Guidelines for the management of adult lower respiratory tract infections. Eur. Respir. J. 2005, 26, 1138–1180. [Google Scholar] [CrossRef] [PubMed]
- Metlay, J.P.; Waterer, G.W.; Long, A.C.; Anzueto, A.; Brozek, J.; Crothers, K.; Cooley, L.A.; Dean, N.C.; Fine, M.J.; Flanders, S.A.; et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am. J. Respir. Crit. Care Med. 2019, 200, e45–e67. [Google Scholar] [CrossRef] [PubMed]
- Severiche-Bueno, D.; Parra-Tanoux, D.; Reyes, L.F.; Waterer, G.W. Hot topics and current controversies in community-acquired pneumonia. Breathe 2019, 15, 216–225. [Google Scholar] [CrossRef] [PubMed]
- Méndez, R.; Menéndez, R.; Cillóniz, C.; Amara-Elori, I.; Amaro, R.; González, P.; Posadas, T.; Gimeno, A.; España, P.P.; Almirall, J.; et al. Initial Inflammatory Profile in Community-Acquired Pneumonia Depends on Time since Onset of Symptoms. Am. J. Respir. Crit. Care Med. 2018, 198, 370–378. [Google Scholar]
- Ridker, P.M.; Hennekens, C.H.; Buring, J.E.; Rifai, N. C-Reactive Protein and Other Markers of Inflammation in the Prediction of Cardiovascular Disease in Women. N. Engl. J. Med. 2000, 342, 836–843. [Google Scholar] [CrossRef]
- Drewry, A.M.; Samra, N.; Skrupky, L.P.; Fuller, B.M.; Compton, S.M.; Hotchkiss, R.S. Persistent Lymphopenia After Diagnosis of Sepsis Predicts Mortality. Shock 2014, 42, 383–391. [Google Scholar] [CrossRef]
- Torres, A.; Sibila, O.; Ferrer, M.; Polverino, E.; Menendez, R.; Mensa, J.; Gabarrús, A.; Sellarés, J.; Restrepo, M.; Anzueto, A.; et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: A randomized clinical trial. JAMA 2015, 313, 677–686. [Google Scholar] [CrossRef]
- Zhang, Y.; Guan, L.; Yu, J.; Zhao, Z.; Mao, L.; Li, S.; Zhao, J. Pulmonary endothelial activation caused by extracellular histones contributes to neutrophil activation in acute respiratory distress syndrome. Respir. Res. 2016, 17, 155. [Google Scholar] [CrossRef]
- Ebrahimi, F.; Wolffenbuttel, C.; Blum, C.A.; Baumgartner, C.; Mueller, B.; Schuetz, P.; Meier, C.; Kraenzlin, M.; Christ-Crain, M.; Betz, M.J. Fibroblast growth factor 21 predicts outcome in community-acquired pneumonia: Secondary analysis of two randomised controlled trials. Eur. Respir. J. 2019, 53, 1800973. [Google Scholar] [CrossRef] [PubMed]
- Liu, B.; Yin, Q.; Chen, Y.-X.; Zhao, Y.-Z.; Li, C.-S. Role of Presepsin (sCD14-ST) and the CURB65 scoring system in predicting severity and outcome of community-acquired pneumonia in an emergency department. Respir. Med. 2014, 108, 1204–1213. [Google Scholar] [CrossRef] [PubMed]
- Waterer, G.; Chalmers, J. The Elusive Hunt for a Reliable Biomarker in Community-acquired Pneumonia. Are We Searching for Something That Can’t Exist? Am. J. Respir. Crit. Care Med. 2018, 198, 300–302. [Google Scholar] [CrossRef] [PubMed]
Table 1. Main cardiac and non-cardiac biomarkers in community-acquired pneumonia patients.
|Biomarker||Main Pathophysiological Mechanisms Involved||Main Potential Clinical Uses in CAP||Usefulness for Cardiovascular Risk Assessment in CAP||Main References|
|Troponins||Myocardial injury||Short-term survival|
|Natriuretic peptides||Body fluid volume|
|Copeptin||Body fluid volume|
|ALC||Adaptive immune response||Short-term survival|
Treatment response to corticosteroids
|D-dimer||Thrombus degradation||Short-term survival||NA||[95,96,97]|
|Cortisol||Adrenal function||Short-term survival|
Treatment response to corticosteroids
|Calprotectin||Neutrophil inflammation||Bacterial aetiology discrimination|
|Presepsin||Bacterial recognition||Short-term survival||NA|||
|PTX3||Innate immune response||Short-term survival||NA|||
|Angiopoietins||Endothelial barrier function||Short-term survival||NA|||
ALC: absolute lymphocyte count; CAP: community-acquired pneumonia; CRP: C-reactive protein; FGF21: fibroblast growth factor 21; ICU: intensive care unit; IL-6: interleukin-6; MR-proADM: midregional-proadrenomedullin; NA: not assessed; NETs: neutrophil extracellular traps; PCT: procalcitonin; PTX3: pentraxin 3; TNF-α: tumour necrosis factor alpha.
Table 2. Cardiac biomarkers, type of studies, design, and outcomes are evaluated.
|Biomarker||Studies||Design||Number of Participants||Outcomes|
|Troponins||Menéndez R et al.|
|Prospective, observational and multicentre in CAP||730||Short-term cardiovascular events|
|Bessière F et al.|
|Meta-analysis in sepsis||1227||Short-term mortality|
|Vallabhajosyula S et al.|
|Retrospective in severe sepsis and septic shock||944||Short and long-term mortality|
|Lee YJ et al.|
|Retrospective in severe pneumonia||152||ICU mortality|
|Vestjens SMT et al.|
|Post hoc analysis of a clinical trial on adjunctive dexamethasone treatment in CAP||295||Short and long-term mortality|
|Natriuretic peptides||Menéndez R et al.|
|Prospective, observational and multicentre in CAP||730||Short and long-term cardiovascular events|
|Claessens Y-E et al.|
|Prospective, observational and multicentre in mild CAP||549||Guide site of care|
|Kruger S et al.|
|Prospective, observational and multicentre in CAP||1740||Short and long-term mortality|
|Christ-Crain M et al.|
|Prospective, observational and single-centre in CAP||302||Treatment failure and short-term mortality|
|Lin S-C et al.|
|Prospective, observational and single-centre in severe CAP||216||Short-term mortality|
|Chang CL et al.|
|Prospective, observational and bicentric in severe CAP||474||Short-term mortality|
|Akpinar EE et al.|
|Prospective, observational and single-centre in CAP||179||ICU admission and short-term mortality|
|Nowak A et al.|
|Prospective, observational and single-centre in CAP||341||Short and long-term mortality|
|Kruger S et al.|
|Prospective, observational and multicentre in CAP||589||Short-term mortality|
|Viasus D et al.|
|Systematic review and meta-analysis||10319||Short-term mortality|
|Alan M et al.|
|Prospective, observational and multicentre in CAP||925||Long-term mortality|
|Kruger S et al.|
|Prospective, observational and multicentre in CAP||728||Short and long-term mortality|
|MR-proADM||Menéndez R et al.|
|Prospective, observational and multicentre in CAP||730||Short and long-term cardiovascular events|
|Kruger S et al.|
|Prospective, observational and multicentre in CAP||728||Short and long-term mortality|
|España PP et al.|
|Prospective, observational and single-centre in CAP||491||Guide site of care|
|Renaud B et al.|
|Prospective, observational and multicentre in CAP||877||ICU admission|
|Christ-Crain M et al.|
|Prospective, observational and single-centre in CAP||302||Short-term mortality|
|Huang DT et al.|
|Prospective, observational and multicentre in CAP||1653||Short-term mortality|
|Albrich WC et al.|
|Prospective, observational and multicentre in LRTI||1359||Composite outcome: ICU admission, short-term mortality, and complications|
|Liu D et al.|
|Systematic review and meta-analysis||4119||Short-term mortality|
|Bello S et al.|
|Prospective, observational and multicentre in CAP||228||Short-term mortality|
|Endothelin-1||Menéndez R et al.|
|Prospective, observational and multicentre in CAP||730||Short and long-term cardiovascular events|
|Schuetz P et al.|
|Prospective, observational and single-centre in CAP||281||ICU admission and short-term mortality|
|Schuetz P et al.|
|Prospective, observational and multicentre in CAP and LRTI||925||Composite outcome: ICU admission, short-term mortality, and complications|
|Copeptin||Kruger S et al.|
|Prospective, observational and multicentre in CAP||1740||Short and long-term mortality|
|Kruger S et al.|
|Prospective, observational and multicentre in CAP||589||Short-term mortality|
|Masia M et al.|
|Prospective, observational and single-centre in CAP||173||Short-term mortality|
|Kolditz M et al.|
|Prospective, observational and single-centre in CAP||51||Composite outcome: ICU admission, short-term mortality, and clinical instability|
CAP: community-acquired pneumonia; ICU: intensive care unit; LRTI: lower respiratory tract infections; MR-proADM: midregional-proadrenomedullin.
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).