C-Reactive Protein (CRP) is an acute phase inflammatory protein that was first discovered and named by Tillet and Francis in 1930 while studying the serum of patients infected with Streptococcus pneumoniae.[1]CRP is primarily synthesized in hepatocytes, initially produced as a monomer and then assembled into a pentamer in the endoplasmic reticulum of the source cell. In a quiescent (non-inflammatory) state, CRP is slowly released from the endoplasmic reticulum, but with an increase in inflammatory cytokine levels, CRP is rapidly secreted.[2]The stimulation of CRP synthesis mainly occurs in response to pro-inflammatory cytokines, most notably IL-6, followed by IL-1 and tumor necrosis factor-alpha (TNF-α).[3]CRP levels begin to rise 6 to 8 hours after the onset of infection, peaking at 24 to 48 hours, potentially increasing several hundred times above normal values, with the degree of increase positively correlated with the severity of infection or inflammation. The normal reference value is <5 mg/L, and many factors can alter baseline CRP levels, including age, sex, smoking status, weight, blood lipid levels, and blood pressure.[4].
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Application of CRP in Lower Respiratory Tract Infections
Lower respiratory tract infections are common diseases in respiratory medicine, and CRP plays an important role in the diagnosis and treatment of these diseases. Research has shown that CRP levels may be a valuable adjunct in the clinical predictive diagnosis of pneumonia. When pneumonia is suspected, a CRP level ≥ 100 mg/L is a useful indication for further chest X-ray/CT examination and empirical antibiotic treatment.[5]The guidelines established by the British Thoracic Society recommend monitoring CRP levels as a useful indicator for evaluating the success or failure of treatment for community-acquired pneumonia (CAP).[6].A CRP level ≤ 100 mg/L has a similar negative predictive effect as CURB-65 and the pneumonia severity index, indicating that invasive respiratory support and/or the use of vasopressors may not be necessary. Therefore, CAP patients with low CRP levels can be treated safely on an outpatient basis. During anti-infective treatment, dynamic monitoring of changes in CRP levels can assist in assessing efficacy, with a decrease in CRP to normal levels serving as one of the indicators for stopping treatment. However, CRP is not an effective predictor of mortality.[7,8].
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CRP Helps Differentiate Types of Infectious Pathogens
In patients with CRP > 100 mg/L, 80% have bacterial infections.[9]Among them, CRP levels are more significantly elevated in patients with Gram-negative bacterial infections, while Gram-positive bacterial infections and parasitic infections typically cause a moderate response. Viral infections may also elevate CRP levels, but the degree of elevation is often lower than that seen in bacterial infections.[10]Typically, it does not exceed 50 mg/L.Moreover, CRP levels also help distinguish between bacterial infections and tuberculosis infections. A study in Korea found that the median CRP concentration in patients with bacterial CAP was 14.58 mg/dL (range 0.30–36.61), while the median CRP concentration in patients with pulmonary tuberculosis was 5.27 mg/dL (range 0.24–13.22) (p < 0.001).[11].
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CRP Levels are Related to the Extent and Severity of Infection
When CRP levels are between 10 and 99 mg/L, they often indicate localized or superficial infections, while ≥100 mg/L typically suggests sepsis or invasive infections. However, its predictive value for severe infections and bloodstream infections is not as strong as that of procalcitonin (PCT).[12].Procalcitonin (PCT) is a precursor substance of calcitonin that lacks hormonal activity, first elucidated by Le Moullec et al. in 1984 as a glycoprotein composed of 116 amino acids. French scholar Assicot et al. first proposed in 1993 that PCT could serve as a marker for bacterial infections.[24].Under physiological conditions, PCT is primarily synthesized and secreted by thyroid C cells, and PCT is only released into the bloodstream after being cleaved into its mature form, calcitonin.[25]It is generally undetectable in healthy individuals, usually less than 0.05 μg/L.[26]During systemic inflammation caused by bacterial infections, PCT is induced in nearly all tissues and released into the bloodstream.PCT levels can rise early (2–3 hours) in response to systemic inflammation caused by bacterial infections, peaking at 12–24 hours post-infection, with PCT concentration positively correlated with the severity of infection. As inflammation subsides, PCT levels decrease rapidly at a predictable rate.
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PCT in Bacterial, Viral, and Fungal Infections
In bacterial infections, increases in endotoxins or IL (such as IL-1β) can lead to elevated PCT levels.[27]In viral infections, PCT typically does not rise, thus PCT values can be used to roughly differentiate between viral and bacterial infections, with an accuracy of 65% to 70%.[28.However, not all bacteria cause an increase in PCT; typical bacteria such as Streptococcus pneumoniae or Haemophilus influenzae often lead to a greater increase in PCT than atypical bacteria.[28-30]A multicenter study found that patients with pneumonia caused by typical bacteria had a higher median PCT than those with pneumonia caused by atypical bacteria or viruses (2.5 μg/L, 0.20 μg/L, and 0.09 μg/L, respectively).[28].Among atypical bacteria, Legionella can cause a mild increase in PCT, while Mycoplasma and Chlamydia may not lead to detectable increases in PCT.[28,33]Some studies have also mentioned that in sepsis caused by different pathogens, the increase in PCT is more significant in Gram-negative bacterial infections than in Gram-positive bacterial infections.[34].A meta-analysis showed that in severe invasive fungal infections, PCT can be mildly to moderately elevated, generally around 1 μg/L, while other pulmonary fungal infections do not elevate PCT levels or only cause mild increases, typically below 0.25 μg/L.[36,37].
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PCT Can Assess the Severity of Infection
PCT can serve as a biomarker for diagnosing sepsis and identifying severe bacterial infections. PCT levels are often normal or mildly elevated in localized bacterial infections. When PCT concentrations rise to 2–10 μg/L, it is highly likely to indicate sepsis, severe sepsis, or septic shock, with a high risk of organ dysfunction; when PCT concentrations exceed 10 μg/L, it strongly suggests severe bacterial sepsis or septic shock, often accompanied by organ failure and a high risk of mortality.[38].
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Other Causes of Elevated PCT
Common clinical causes that can lead to elevated PCT include cardiac arrest or circulatory shock, intracranial hemorrhage, pancreatitis, ischemic bowel disease, pulmonary edema, severe trauma, surgery, heat shock, and medullary thyroid carcinoma. Patients with end-stage renal disease may have elevated PCT, possibly related to decreased clearance of biomarkers. Certain autoimmune diseases such as Kawasaki disease and Wegener’s granulomatosis can elevate PCT levels, but most immune system diseases do not, such as rheumatoid arthritis or systemic lupus erythematosus.[42]Additionally, when some medications exceed normal dosages, they can also cause elevated PCT, such as vancomycin, imipenem, cefotaxime, norepinephrine, dopamine, dobutamine, heparin, and furosemide.[12].
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