C-reactive protein (CRP) and procalcitonin (PCT) are the most commonly used infection markers in respiratory medicine, guiding the diagnosis and treatment of infectious diseases. The following will mainly introduce the clinical applications of these two infection markers in respiratory medicine.C-reactive Protein (CRP)CRP is an acute-phase inflammatory protein that was first discovered and named in 1930 by Tillet and Francis while studying the serum of patients with pneumococcal infections [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; however, with the 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 begins to rise within 6~8 h after infection, peaks at 24~48 h, and can be several hundred times higher than 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 the baseline CRP level, including age, sex, smoking status, weight, blood lipid levels, and blood pressure [4].
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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 supplement to the clinical predictive diagnosis of pneumonia. When pneumonia is suspected, a CRP ≥ 100 mg/L is a useful indication for completing chest X-rays/CT scans and initiating empirical antibiotic treatment [5]. The guidelines established by the British Thoracic Society recommend that monitoring CRP levels is a useful indicator for evaluating the success or failure of treatment for community-acquired pneumonia (CAP) [6]. A CRP ≤ 100 mg/L has a similar negative predictive effect as CURB-65 and the pneumonia severity index, suggesting that invasive respiratory support and/or vasopressor use is not necessary. Therefore, CAP patients with low CRP levels can be treated safely in outpatient settings. During anti-infective treatment, dynamic monitoring of changes in CRP levels can assist in judging efficacy, with a decrease in CRP to normal being one of the indicators for stopping medication. 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], with a more pronounced increase in CRP levels in patients with Gram-negative infections; Gram-positive infections and parasitic infections typically induce a moderate response, while CRP levels in viral infections may also rise but are often lower than in bacterial infections [10], usually not exceeding 50 mg/L. Additionally, CRP levels help differentiate between bacterial infections and tuberculosis, with a study in Korea showing 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 Correlate with Infection Extent and Severity
When CRP levels are between 10~99 mg/L, they often indicate localized or superficial infections, whereas ≥ 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].
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CRP in Other Site Infections
For patients with potential appendicitis symptoms, those with CRP levels below 25 mg/L after 12 hours of symptom onset can be ruled out for acute appendicitis [13]. Other studies have shown that when clinical symptoms of cholecystitis are present alongside CRP levels exceeding 30 mg/L, the sensitivity for diagnosing cholecystitis can reach 78% [14]. In acute pancreatitis, CRP levels greater than 210 mg/L can differentiate mild from severe cases [15]. Additionally, measuring CRP in cerebrospinal fluid can help differentiate between bacterial meningitis, viral meningitis, and non-infectious patients [16].
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CRP in Other Non-Infectious Diseases
Besides infections, CRP levels are also correlated with other non-infectious diseases.01 CRP and Cardiovascular DiseasesSeveral large studies conducted in asymptomatic populations have shown that baseline CRP levels in seemingly healthy individuals are positively correlated with long-term risks of first myocardial infarction, ischemic stroke, hypertension, peripheral vascular disease, cardiac sudden death, and all-cause mortality [17]. Some studies confirm that baseline CRP levels are strongly positively correlated with future acute coronary events in patients with stable coronary artery disease [18].02 CRP and Rheumatoid ArthritisStudies have proven that patients with rheumatoid arthritis with elevated CRP and ESR are more likely to experience progression of radiological damage (assessed by erosion joint count) [19].03 CRP and Polymyalgia Rheumatica (PMR)CRP is almost always elevated in PMR patients. 99% of patients have elevated serum CRP levels (>5 mg/L) [20,21].04 CRP and Pulmonary EmbolismResearch shows that CRP is associated with right ventricular dysfunction in patients with pulmonary embolism and is a prognostic factor for patients with pulmonary embolism, potentially becoming a biomarker for risk stratification in pulmonary embolism. Some studies suggest that elevated CRP may be related to pulmonary embolism combined with pleural effusion and lung infarction, leading to poor patient prognosis [22,23].Procalcitonin (PCT)PCT is a precursor substance of calcitonin without hormonal activity, first elucidated by Le Moullec et al. in 1984 as a glycoprotein composed of 116 amino acids. French scholars Assicot et al. proposed in 1993 that PCT can serve as a marker for bacterial infections [24]. Under physiological conditions, PCT is primarily synthesized and secreted by the thyroid C cells, and PCT is only released into the bloodstream after being cleaved into its mature form, calcitonin [25], which is generally undetectable in healthy individuals, usually less than 0.05 μg/L [26]. When bacterial infections cause systemic inflammation, PCT is synthesized by almost all tissues and released into the bloodstream. PCT can rise early (2~3 h) during systemic inflammatory responses caused by bacterial infections, peaking at 12~24 h , with concentration positively correlated with infection severity and decreasing predictably as inflammation subsides.
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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, so PCT values can be used to roughly differentiate between viral and bacterial infections, with an accuracy of 65%~70% [28]. However, not all bacteria cause elevated PCT; typical bacteria such as Streptococcus pneumoniae or Haemophilus influenzae often cause a greater degree of PCT elevation than atypical bacteria [28-30]. A multicenter study found that pneumonia patients caused by typical bacteria had higher median PCT levels compared to those caused by atypical bacteria or viruses (2.5 μg/L, 0.20 μg/L, and 0.09 μg/L) [28]. Among atypical bacteria, Legionella can cause mild PCT elevation [31,32], while Mycoplasma and Chlamydia may not cause detectable PCT elevation [28,33]. Some studies have also mentioned that in sepsis caused by different pathogens, PCT elevation is more pronounced in Gram-negative bacterial infections than in Gram-positive ones [34]. A meta-analysis showed that severe invasive fungal infections can lead to mild to moderate PCT elevation, generally around 1 μg/L [35], while other pulmonary fungal infections do not elevate PCT levels or only cause mild elevation, typically below 0.25 μg/L [36,37].
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PCT Can Assess Infection Severity
PCT can serve as a biomarker for diagnosing sepsis and identifying severe bacterial infections; PCT is often normal or mildly elevated in localized bacterial infections. When PCT concentration rises 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 concentration exceeds 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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PCT Can Assess Prognosis in Sepsis Patients
If anti-infective treatment is effective, PCT in sepsis patients can decrease by about 50% after 24 hours; if PCT continues to rise or remains elevated, it indicates poor prognosis [12]. Some studies have shown that if PCT levels in sepsis patients decrease by more than 80% after effective treatment for 3 days, the negative predictive value for mortality is 90%. If PCT continues to rise or does not decrease, the positive predictive value for mortality is 50% [39].
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PCT’s Value in Antibiotic Use
01 Initiation of AntibioticsAccording to the guidelines of the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA), it is not recommended to use PCT to guide the initiation or withholding of antibiotics in CAP patients. For any confirmed or suspected CAP patients with sepsis or critical illness, antibiotic treatment should not be delayed regardless of the initial PCT level.02 Discontinuation of Antibiotics
- Stable Patients:
When PCT remains < 0.25 μg/L in stable patients, if the initial diagnosis of community-acquired pneumonia is uncertain and there are other non-infectious disease diagnoses, or if viral pneumonia is considered, it is generally recommended to discontinue antibiotics. For confirmed or suspected bacterial CAP patients who have received appropriate antibiotic treatment for at least 5 days, if clinical condition improves and PCT < 0.25 μg/L or decreases ≥ 80% from peak, antibiotic discontinuation can be considered. If PCT levels decrease but remain ≥ 0.25 μg/L, continuing antibiotic treatment is recommended. It is important to note that PCT < 0.25 μg/L or a decrease of ≥ 80% from peak is not a necessary condition for antibiotic discontinuation [40].
- Critical Patients:
If CAP patients have sepsis or critical illness at diagnosis, it is recommended to discontinue antibiotics when PCT drops to < 0.5 μg/L; if the initial PCT value is > 5 μg/L, it should be discontinued when compared to peak values with a decrease of ≥ 80% [41].
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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. Some autoimmune diseases such as Kawasaki disease and Wegener’s granulomatosis can elevate PCT levels [42], but most immune system diseases do not, such as rheumatoid arthritis or systemic lupus erythematosus [43]. Additionally, some medications exceeding conventional doses may also cause elevated PCT, such as vancomycin, imipenem, cefotaxime, norepinephrine, dopamine, dobutamine, heparin, and furosemide [12].Comparison of Clinical Applications of CRP and PCT01 Distinguishing Autoimmune Diseases with InfectionIn distinguishing whether autoimmune diseases are complicated by infections, PCT is more meaningful than CRP, with PCT sensitivity and specificity both at 75%, while CRP sensitivity is 95% with only 8% specificity [43].02 CRP and PCT in Distinguishing Different Bacterial InfectionsCRP and PCT can be used to distinguish different bacterial infections. Meta-analysis shows that PCT and CRP levels in patients with G- bacterial infections are higher than those in patients with G+ bacterial infections and fungal infections. The CRP concentration in the G+ bacterial infection group is higher than that in the fungal infection group, while the difference in PCT between G+ bacterial infections and fungal infections is statistically insignificant. Some articles suggest that a PCT of 10 μg/L can serve as a critical value to distinguish G- bacterial infections from G+ bacterial infections or fungal infections. For CRP, 70~80 mg/L can serve as a critical value to distinguish G- bacteria from G+ bacteria [44].03 CRP and PCT in Distinguishing Bacterial Pneumonia from TuberculosisResearch results show that CRP and PCT levels in patients with bacterial pneumonia are significantly higher than those in patients with tuberculosis, thus CRP and PCT levels help distinguish bacterial pneumonia from tuberculosis, but there is no difference in the ability of CRP and PCT to distinguish bacterial pneumonia from tuberculosis [11,45].04 CRP and PCT in Distinguishing COVID-19 from CAPThe PCT and CRP levels in the COVID-19 group are significantly lower than those in the CAP group, with a statistically significant difference (p < 0.05). In the critical, severe, and common patient subgroups, the CRP level comparisons all show statistical significance (p < 0.05). However, there is no significant difference in PCT among the three subgroups [46].Reviewed by: Senior Physician, Department of Respiratory and Critical Care Medicine, PLA General Hospital, Jiankang Han
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