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Buenos Aires, Argentina
Dr. Luna is Associate Professor of Internal Medicine, University of Buenos Aires.
Correspondence to: Carlos M. Luna, MD, PhD, FCCP, Acevedo 1070, Banfield, 1828, Buenos Aires, Argentina; e-mail: cymluna{at}fmed.uba.ar
The initial description of C-reactive protein (CRP) was based on patients with pneumonia. CRP was identified in 1930 and subsequently considered to be an early nonspecific but sensitive marker of inflammation, so called "acute-phase protein."1 An acute-phase protein has been defined as one whose plasma concentration increases (positive acute-phase proteins) or decreases (negative acute-phase proteins) by at least 25% during inflammatory disorders.2 Other acute-phase proteins include proteinase inhibitors and coagulation, complement, and transport proteins; the other major acute-phase protein that displays sensitivity, response speed, and dynamic range comparable to those of CRP is serum amyloid A protein.34 Some acute-phase proteins initiate or sustain inflammation, while other acute-phase proteins may have anti-inflammatory actions. Like other acute-phase proteins, CRP is predominantly synthesized in the liver.
The cytokines produced during the inflammatory processes are the stimulators of the production of acute-phase proteins. These cytokines include interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-
, interferon-
, transforming growth factor-ß, and IL-8. They are produced by cells like macrophages and monocytes at inflammatory sites ready to destroy the invading pathogens. However, excessive cytokine production has deleterious effects, with a systemic inflammatory response (sepsis) that can lead to multiorganic failure and death.5 IL-6 is the chief stimulator of the production of CRP. There is a speculation that changes in plasma concentrations of CRP could be beneficial when recognizing some foreign pathogens and activating the complement system when bound to one of its ligands. It seems likely that CRP has many pathophysiologic roles in the inflammatory process. Plasma concentrations of cytokines and cytokine receptors have been studied in patients with inflammatory conditions. Measuring cytokines in plasma is difficult, partly because of the short plasma half-lives and the presence of blocking factors, and partly because the test is expensive and is not readily available everywhere. Plasma IL-6 concentrations are elevated in patients with many inflammatory diseases, but except for the rapidity with which change occurs, measurement of plasma IL-6 has no apparent advantage over measurement of plasma CRP. Until further studies are available, the high cost, limited availability, and absence of standardization argue against the measurement of plasma cytokines and their receptors in clinical practice.6 The ability to respond to infection varies between individuals and a predisposition to death from infection related to the cytokine response could be genetically determined. There exists a tendency to septic shock and respiratory failure in patients with community-acquired pneumonia and different TNF polymorphism associations.7
An anecdotal but remarkable fact is that CRP was named so because it reacted with the pneumococcal C-polysaccharide in the plasma of patients during the acute phase of pneumococcal pneumonia.1 CRP clearly was born as a laboratory test in the context of patients with pneumonia. Then the test began to be used as a diagnostic tool useful in determining the degree of activity, and as a therapeutic guide of a number of conditions that commonly lead to substantial changes in the plasma concentrations of acute-phase proteins, including rheumatic fever, myocardial infarction, asthma, leprosy, malignancy, congestive heart failure, blood diseases, allergic diseases, kidney diseases, pneumoconiosis, and different infectious diseases (tuberculosis, meningitis, poliomyelitis, infectious mononucleosis, syphilis, etc). Changes in the concentration of CRP have been also described in healthy people after strenuous exercise and during the postoperative and puerperal periods. Interestingly, CRP measurement was not extensively used in patients with pneumonia after its initial description.
The clinical use of CRP measurement had been largely ignored for many years. During the last 15 years, the ready commercial availability of automated CRP immunoassay, with greater sensitivity than those previously in routine use, led to increased application of this test to clinical medicine. The availability of this new technology revealed that increased CRP values, even within the range previously considered normal, strongly predict future coronary events and this triggered widespread interest.8 Also, during recent years, the interest on CRP in pneumonia appeared to be born again.
In this issue of CHEST (see page 1336), Almirall et al assessed the usefulness of serum CRP in community-acquired pneumonia in a population-based, case-control study. They concluded that CRP is useful for establishing the diagnosis of community-acquired pneumonia. Their evidence shows that high plasma levels of CRP are more common when the pathogens are S pneumoniae and Legionella pneumophila or when the illness is more severe. As a consequence, these findings could be useful in deciding whether hospitalization is necessary.
Indeed, because of the wide number of clinical conditions associated with high CRP levels, CRP can never be diagnostic on its own and can only be interpreted at the bedside, in full knowledge of all other clinical and pathologic results. However, it can then contribute powerfully to management, just as recording of the patient’s temperature, an equally nonspecific parameter, is of great clinical utility. About its role in the detection of the etiology, previous publications have recognized that CRP could be useful to predict the pneumococcal etiology9 and differentiate pneumonia from acute bronchitis,10 and also that higher levels were associated with bacteremia in pneumococcal pneumonia.11 In contrast, there had been only one very recent description supporting that L pneumophila is associated with a different way of inflammatory host response leading to a higher level of CRP.12 However, serum CRP was not useful to distinguish between pneumococcal, chlamydial, or viral etiology in 193 pediatric patients with pneumonia in a prospective, population-based study.13 Probably, the relationship of high levels of CRP with some specific etiologies of pneumonia is an age-related phenomenon.14
Concerning the conclusion that higher CRP levels appear to predict severity of illness, Seppa et al15 reported that a CRP level 
100 mg/L is a marker independently associated with higher risk of death in patients with lower respiratory tract infections. Additionally Hedlund16 observed the following: patients with higher CRP levels had longer duration of fever; patients had longer hospital stay; and fewer patients had recovered clinically or radiographically at follow-up 8 weeks after discharge. These findings suggest that CRP could be used together with other clinical, radiographic, and laboratory findings for the risk stratification of patients with pneumonia.
Besides the usefulness as a diagnostic tool for pneumonia, etiologic diagnosis, and outcome marker, there could be some place for CRP in the follow-up of pneumonia. Ninety-nine percent of healthy young adults have a median CRP concentration of < 10 mg/L.17 Following an acute-phase stimulus, values may increase 10,000-fold. Synthesis starts very rapidly after a single stimulus, serum concentrations rising > 5 mg/L by approximately 6 h and peaking at approximately 48 h. The plasma half-life of CRP is approximately 19 h and is constant under all conditions of health and disease, so that the sole determinant of circulating CRP concentration is the synthesis rate.18 When the stimulus for increased production completely ceases, the circulating CRP concentration falls rapidly, at almost the rate of plasma CRP clearance. These characteristics of quick rise and decrease make this parameter an interesting one in the measurement of the evolution on pneumonia that could be used together with other tools in the evaluation of response to therapy and prediction of outcome. Recently, Lauritzen et al,19 in an experimental model of porcine bacterial pneumonia, demonstrated that clinical evidences of infection became apparent 20 h after inoculation. Plasma CRP and IL-6 increased; then, in an antibiotic-treated group of animals, CRP and IL-6 reverted significantly toward normalization within 24 h, while this did not happen in those animals not receiving antibiotics. The relationship between the better outcome of pneumonia and the improvement of the clinical pulmonary infection score, and particularly with the improvement of the PaO2/fraction of inspired oxygen ratio, has been demonstrated recently for ventilator-associated pneumonia.20
The initial selection of an adequate empirical therapy and the evaluation of the response to therapy are two issues that are highly related to outcome of severe community-acquired and hospital-acquired pneumonia. CRP levels may help evaluate patient management and response to antibiotic therapy.
CRP is coming back to be considered a useful tool in pneumonia. The lyrics of the song popularized by Frank Sinatra ("Let me try again. Think of all we had before, let me try once more.") remind us that in medicine there is sometimes a second opportunity for refurbished old practices.
References
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