Usefulness of procalcitonin (PCT), C-reactive protein (CRP), and white blood cell (WBC) counts in distinguishing between bacterial and viral infections in acute respiratory tract infections

INTRODUCTION

Around the world, acute respiratory tract infections (ARTIs) are a chief cause of illness, mortality, and lost workdays. Individuals who have immunological suppression, cardiac disease, or both at extreme ages are particularly vulnerable. The introduction of novel antimicrobial medicines and improvements in our knowledge of microbial pathogens notwithstanding, ARTIs continue to be a major source of global health spending. Both illnesses that primarily affect the upper and lower respiratory tracts can be combined to provide an overall category for ARTIs.^[1,2]

Anatomically, the vocal cords act as a barrier between these two regions, with the lower upper respiratory tract (bronchial tree and pulmonary parenchyma) located below the vocal cords and the upper respiratory tract (peritonsillar structures, nasopharynx, sinuses, larynx, and epiglottis) located proximally to the cords. In contrast to other essential organs, the lung is constantly exposed to a significant quantity of airborne microorganisms, increasing susceptibility to infection and inflammation. The respiratory tract has a large surface area (150 m²), a slim, fragile epithelium, and significant blood flow for optimal gas exchange. This structure carries a heavy immunological burden. Many inhaled microorganisms in a healthy lung are held in the mucus layer that covers the upper respiratory tract and nasal epithelium. Once caught, they can be moved to the throat and eaten by ciliary movement. In addition, the innate immune machinery functions locally to aid in the clearance of inhaled pathogens and to regulate inflammatory responses in organisms that elude mucociliary clearance. However, if these respiratory tract defenses are compromised, infection may occur, sometimes resulting in fatality.^[3]

ARTIs account for a significant portion of global disease burden, with an estimated incidence of approximately 5–10% of the population annually. ^[4] The prevalence of ARTIs varies geographically, with higher rates observed in developing regions. Globally, ARTIs are responsible for approximately 15% of all outpatient visits and 20% of hospital admissions.^[5] ARTIs contribute to substantial morbidity worldwide, with approximately 50% of cases occurring in children under 5 years old.^[6] In addition, ARTIs are a leading cause of disability-adjusted life years lost globally, accounting for about 10% of the total burden of disease.^[7] Despite advancements in treatment and prevention, ARTIs remain a significant cause of mortality, responsible for approximately 3 million deaths annually worldwide, with the majority occurring in low- and middle-income countries. Recent studies, such as Yang et al. (2021), have demonstrated the diagnostic utility of combined procalcitonin (PCT), C-reactive protein (CRP), and white blood cell (WBC) in pediatric populations, but data on adult cohorts remain limited.^[8]

In India, ARTIs are prevalent, affecting approximately 6–8% of the population annually.^[9] The prevalence of ARTIs in India varies by region, with higher rates observed in urban areas and during the winter months. Approximately 20% of all outpatient visits in India are due to respiratory infections.^[10] ARTIs are a leading cause of morbidity in India, contributing to about 15–20% of hospital admissions, with pneumonia being the most common manifestation. In India, ARTIs are responsible for approximately 10–15% of all deaths among children under 5 years old.^[11]

CRP, PCT, and WBC counts serve as valuable biomarkers for differentiating between bacterial and viral respiratory tract infections (RTIs) in clinical practice. Elevated CRP levels, typically above a threshold of 20–40 mg/L, are indicative of bacterial infections due to the acute inflammatory response they trigger, although they can also rise in viral infections.^[12] PCT, on the other hand, shows significant elevation in bacterial infections, with levels below 0.25– 0.5 ng/mL often suggesting a viral etiology.^[13] Meta-analyses have shown that PCT-guided algorithms can effectively guide antibiotic therapy in RTIs, leading to reduced antibiotic usage and associated adverse effects. Neutrophilia, reflected by elevated WBC counts, is commonly observed in bacterial infections but is less specific than CRP or PCT. Combining CRP, PCT, and WBC counts can improve diagnostic accuracy, with elevated CRP and PCT levels along with neutrophilia having a high positive predictive value (PPV) for bacterial infections.^[14] These biomarkers, when integrated with clinical assessment, enhance clinicians’ ability to make informed decisions regarding antibiotic therapy in RTIs.

Examining the relationship between the number of inflammatory biomarkers and the duration of the disease is a relatively recent method for understanding the kinetics of inflammation. Biomarkers such as CRP, PCT, and WBC Counts have recently been used to discriminate between viral and bacterial RTIs.^[15]

MATERIALS AND METHODS

RESULTS

Plotting of the receiver operating characteristics (ROC) curve

The ROC curve was plotted under a 95% confidence interval to obtain the area under the curve (AUC). This was done to compare the analytical efficiency of the biomarkers employed in this experiment [Figures 1 and 2]

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Figure 1:

Receiver operating characteristic (ROC) curves for white blood cell, procalcitonin and C-reactive protein for predicting bacterial infection. WBC: White blood cell, CRP: C-reactive protein, PCT: Procalcitonin.

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Figure 2:

Receiver operating characteristic (ROC) curves for white blood cells, procalcitonin and C-reactive protein for detecting viral infections. WBC: White blood cell, CRP: C-reactive protein, PCT: Procalcitonin.

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DISCUSSION

ARTIs are a major clinical concern among adults due to their early onset and chronic complications. Diagnostic confirmation of ARTIs is generally performed through culturing methods, nucleic acid amplification, and antibody detection tests. Since culturing methods are time-consuming, nucleic acid amplification tests and antibody detection tests may yield erroneous results, and additional research on alternative methods has been conducted over the last decade. ^[16-18]

Epidemiological studies across various countries have revealed varying prevalence rates of ARTIs. For instance, research conducted by Berman found a higher prevalence of ARTIs in developing nations compared to developed countries, attributed to factors such as crowded living conditions and limited access to healthcare. Conversely, studies such as those by Bulla and Hitze highlighted the significance of seasonality and climatic factors in influencing ARTI prevalence, with higher rates observed during colder months in temperate regions. ^[19,20]

RTIs represent a significant burden on global healthcare systems, necessitating accurate and timely diagnosis for appropriate management.^[21] Our study investigated the sensitivity and specificity of WBC counts, PCT, and CRP levels as biomarkers for distinguishing between bacterial and viral RTIs. Our study elucidates discernible trends in biomarker upregulation between bacterial and viral infections, offering pertinent implications for clinical management. While biomarker assays are commonly conducted in hospital settings during suspected RTIs, comparative analyses of these biomarkers remain infrequent.^[22] Therefore, our investigation represents a novel endeavor by integrating three specific biomarkers to facilitate precise diagnosis of RTIs, thereby addressing a notable gap in current clinical practices.

In line with previous research, our results indicate that WBC count demonstrates greater sensitivity and specificity in detecting bacterial RTIs compared to CRP and PCT levels. This suggests that WBC count may serve as a reliable biomarker for identifying bacterial etiology in RTIs. Conversely, CRP levels emerge as a more sensitive marker for detecting viral RTIs, exhibiting higher sensitivity albeit lower specificity compared to WBC count. These differential patterns of biomarker elevation underscore the complex immunological responses associated with bacterial and viral infections.^[22]

In a study by Delèvaux et al.,^[23] the patients were split into 2 groups: Group I had a history of fungal or bacterial infections, and group II had an inflammatory bacterial illness. Among the patients in group I, 39/60 (65%) had PCT levels >0.5 ng/mL. In group II, two patients with vasculitis and one patient with crystal arthritis both showed modestly elevated PCT levels (0.7 ng/mL), as did 3 patients with a viral infection (0.7, 0.8, and 1.1 ng/mL). PCT levels in group II were <0.5 ng/mL in every other patient. The study’s marker of bacterial infection was determined to be a PCT concentration >0.5 ng/mL, with 65% sensitivity and 96% specificity. When determining whether an inflammatory process was caused by a bacterial infection, PCT readings were more discriminative than were WBC and CRP measurements. PCT values >1.2 ng/mL in this investigation were consistently indicative of a bacterial infection and the need to begin antibiotic therapy. ^[23]

In a similar study by Li et al.,^[24] when determining whether a child has an acute bacterial infection, the PCT, CRP, and WBC can be used as useful indicators, and the differential diagnostic value of the PCT and CRP levels was greater than that of the WBC. Our findings align with Li et al. (2021), who reported improved diagnostic accuracy using combined biomarkers. However, unlike their pediatric cohort, our adult population showed higher WBC sensitivity in bacterial RTIs, suggesting age-specific variations in biomarker performance.^[24]

In a study conducted by Choi although the probability ratio for a single test value is thought to be a crucial statistic for assessing diagnostic tests, the small sample size makes it difficult to estimate directly from laboratory data. On the other hand, the likelihood ratio for a single test value can be readily determined from the tangent by performing ROC analysis. It is recommended that the ROC analysis software currently in use be updated to provide tangent estimations at different ROC curve locations.^[25]

According to Mandrekar when a test has a value of 1, it is perfectly accurate; when it has a value of 0, it is perfectly inaccurate. An AUC of 0.5 generally indicates no discrimination (i.e., the measurements to analyze people with and without illness or ailment based on the investigation); an AUC of 0.7–0.8 is regarded as acceptable; an AUC of 0.8–0.9 is regarded as exceptional; and an AUC of more than 0.9 is seen as noteworthy.^[26]

Limitations include potential undetected coinfections despite rigorous exclusion criteria, which may influence biomarker levels. Future studies could employ multiplex PCR to comprehensively rule out mixed infections. The simultaneous measurement of procalcitonin (PCT), C-reactive protein (CRP), and white blood cell count (WBC) improves the ability to differentiate bacterial respiratory infections from non-bacterial ones compared to relying on any single marker, yet none of these tests alone offer enough accuracy for a definitive diagnosis. Utilizing these markers together is particularly helpful in the early identification of bacterial infections and can inform antibiotic prescribing decisions. However, physicians should interpret these test results alongside clinical evaluation and other diagnostic methods, rather than relying on them in isolation.

CONCLUSIONS

In discerning bacterial RTIs, WBC count and CRP levels were marginally higher compared to PCT levels. Conversely, CRP and PCT levels were significantly higher than the WBC count in detecting viral RTIs. These findings offer valuable insights for clinical decision-making, facilitating the preliminary differentiation between bacterial and viral RTIs. However, definitive diagnosis necessitates supplementary tests such as blood culture, PCR, and antibody detection assays to ascertain the specific etiology of the infection, enhancing diagnostic precision and therapeutic management.

These biomarkers can be used to obtain the most approximate results to prescribe the right empirical antibiotic to avoid the emergence of antimicrobial resistance and control it to some extent. Combinations of these biomarkers always play a great role in precisely detecting the infection. These findings offer valuable insights for clinical decision making facilitating the preliminary differentiation between bacterial and viral RTIs.