Viral or Bacterial Etiology? Old Question, New Methods...

Can We Always Rely on Diagnostic Standards?

CRP

CRP is an acute-phase protein that responds to bacterial infection within 6–9 hours of its onset, peaking at 24–48 hours. Levels normalize within 3–7 days. The concentration in the blood of a completely healthy individual is usually < 1 mg/l. (1) However, CRP levels can also increase in the following situations: 

• Postoperative states
• Systemic diseases
• Inflammations other than bacterial etiology
• Cancers

CRP levels also correlate with the activity of autoimmune inflammations, complicating its use in diagnosing infections in patients with autoimmune diseases such as asthma. (2)

Procalcitonin

Compared to CRP, procalcitonin is considered a more sensitive acute-phase reactant with higher sensitivity and specificity, and it exhibits faster and earlier dynamics. Significant increases in its concentrations occur within 6–8 hours of the initial stimulus. In newborns, physiologically elevated procalcitonin values are observed in the first 72 hours of life, peaking between 18 and 30 hours. Procalcitonin values do not significantly increase in viral infections, localized or superficial infections, autoimmune diseases, early postoperative states, or cancers. Its use is therefore appropriate in immunocompromised individuals, including those with corticosteroid-induced immunosuppression or severe liver insufficiency. However, its cost and indication limitations restrict its use in outpatient settings.

Interleukin 6

Interleukin 6 (IL-6) is a very early marker that, compared to CRP and procalcitonin, exhibits faster dynamics, preceding the rise of CRP by 4–6 hours and clinical symptoms by at least one day. Short-term nonspecific increases in IL-6 occur due to muscle exertion, and it also increases nonspecifically in obesity and diabetes. (1)

Studies on IL-6 in children are not entirely consistent. While some indicate higher sensitivity and specificity compared to CRP, others show the opposite. It appears that IL-6 levels in children are higher in gram-negative bacteremia compared to gram-positive. (2) 

Where is the Research Heading?

New methods for differentiating infection etiology are based on identifying host- or pathogen-derived biomarkers—including various proteins, enzymes, or metabolites—and genetic markers are also being investigated. Bronchoalveolar lavage or blood is considered a suitable source for samples in diagnosing lower respiratory tract infections, aiming to eliminate contamination from upper respiratory tract pathogens. (2)

Proteome from Bronchoalveolar Lavage 

A study investigating the proteome from bronchoalveolar lavage in children was conducted at the University of Edinburgh. Differences in the proteome of children with viral versus bacterial infections were identified. The results were compared with parallel studies conducted in mouse models. Haptoglobin, angiotensinogen, polymeric immunoglobulin receptor (PIGR), and annexin A2 were identified as potential markers for further research. (3)

CD35 and CD64 Expression

Determining the ratio of CD64 and CD35 on neutrophils also seems to be a useful tool in distinguishing bacterial from viral infections. A study involving 104 children found significant differences in this ratio in viral and bacterial infections compared to a healthy control group. (4)

Combined Tests

In the future, combined tests evaluating multiple biomarkers simultaneously could further enhance diagnostic accuracy. (2)

Careful Indication of Antibiotics is Important Not Only Because of Resistance

Timely differentiation of viral and bacterial infection etiology in children is crucial, not only due to the risk of developing antibiotic resistance. Research indicates that frequent use of antibiotics in early childhood may also increase the incidence of adverse long-term consequences such as diabetes and obesity. (2)

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Sources:
1. Laboratory Indicators of Inflammation. Thomayer University Hospital. Available at: www.ftn.cz/upload/ftn/Kliniky/okb/Dokumenty/prirucka/HVEZDAAAES.htm
2. Tsao Y. T., Tsai Y. H., Liao W. T. et al. Differential markers of bacterial and viral infections in children for point-of-care testing. Trends Mol Med 2020; 26 (12): 1118–1132, doi: 10.1016/j.molmed.2020.09.004.
3. Twynam-Perkins J., Karagianni A., Saha S. et al. Proteomics of paediatric airway secretions to identify potential biomarkers to guide antibiotic decision making in LRTI. Eur Respir J 2022; 60 (Suppl. 66): 873, doi: 10.1183/13993003.congress-2022.873.
4. Lu L., Jin X., Zhang Q. CD35 and CD64 of neutrophils can differentiate between bacterial and viral infections in children by simultaneous quantitative analysis. Med Sci Monit 2019; 25: 7728–7734, doi: 10.12659/MSM.914527.