C-Reactive Protein Levels in Patients with Infectious Mononucleosis

Background: Plasma level of C-reactive protein (CRP) is used as a biomarker of systemic inammation. Differential distributions of CRP levels related to different pathogens aid clinicians in the differential diagnosis of patients. Objectives: To evaluate the distribution of CRP levels in patients with Infectious Mononucleosis (IMN) and its correlation with different pathogen and host characteristics. Methods: A retrospective study conducted on electronic medical records of patients diagnosed clinically and serologically with IMN in a public regional hospital during consecutive ve years. Results: CRP levels were signicantly elevated in patients hospitalized with clinical diagnosis of IMN and serologic evidence of EBV (average 6.8 md/dL) or CMV (average 6.3 md/dL). However, levels of CRP were not signicantly correlated with plasma levels of liver enzymes. Conclusions: Although CRP levels may aid in the differential diagnosis of respiratory syndromes, its distribution in patients infected by hepatotrophic viruses is similar to that in bacterial infections.

Introduction C-reactive protein (CRP) is part of the complementary chain of reactions in response to in ammationprovoking triggers. It is produced in the liver, and secreted to the blood plasma, where its levels are routinely measured.
Due to the statistically higher levels of CRP correlated with bacterial infections relative to respiratory viruses, different cutoffs have been proposed to assist clinicians in the differential diagnosis of systemic in ammation [1][2][3][4].
However, some viral infections and non-infectious states are associated with CRP levels overlapping those induced by bacterial infections [5].
Speci cally, high CRP levels were demonstrated to be in associated with Herpetic and Adenoviral infections. These viruses are hepatotrophic, thus may directly stimulate the production of CRP in the liver.
To further examine the association between hepatotrophic viral infections with elevated CRP levels, we examined its levels in patients with infectious mononucleosis (IMN), caused by Cytomegalovirus (CMV) or Epstein-Barr Virus (EBV), and the correlation between CRP and liver enzymes levels in these patients.

Patients And Methods
The study was conducted retrospectively on electronic health records of inpatients diagnosed with IMN using the combination of clinical symptoms and positive serology between January 2014 and December 2018 in Hillel Yaffe Medical Center, a regional public hospital.
Only records with data regarding CRP and liver enzymes were included, and those with positive bacterial cultures were excluded.

Results
Sixty ve patinets were included in the study, as described in Table 1 The average CRP level was 6.1 mg/dL (CMV patients 6.3 mg/dL, EBV patients 6.0 mg/dL). Twenty four patients (37%) had CRP levels higher than 5 mg/dL, which are considered indicative of bacterial infection in certain clinical scenarios, such as respiratyory infections.
As expected, liver enzymes were elevated in most patients (ALT>35 U/L in 55% of patients, average 94.6 U/L). However, CRP and ALT levels were not signi cantly correlated with each other, nor with age.

Discussion
This study demonstrates that elevated levels of CRP are found in a signi cant portion of patients hospitalized with IMN without bacterial co-infection.
The mechanisms underlying the induction of CRP synthesis in different circumstances are still to be explored. Cytokines such as interleukin-6 and tumor necrosis factor-alpha have been shown to be involved [6-10], but their relation to speci c characteristics of the offending microorganism is unknown.
Since adenovirus and HSV are hepatotrophic viruses, and CRP is synthesized in the liver, our hypothesis was that the distribution of CRP levels would be similarly elevated in patients infected by other hepatotrophic viruses -EBV and CMV. The results presented in the current study support the hypothesis of a general relation between hepatotrophic viral infections and elevated CRP levels, relative to historic cohorts of patients with respiratory virus infections [13], and similar to bacterial infections.
Although CRP may support clinical decisions when the differential diagnosis includes viral and bacterial infections, the extent of its application is controversial [13][14][15][16] due to the relatively high gap between speci city and sensitivity, independent of the threshold used. This gap is the result of overlap between CRP values distribution related to different conditions.
Our results may aid clinicians by suggesting that elevated CRP levels in a clinical context implying infection caused by hepatotrophic viruses (e.g. conjunctivitis for adenovirus, oral aphtha for HSV, rash, lymphadenopthay and/or elevated liver enzymes for IMN) do not necessarily indicate bacterial coinfection, and antibiotic therapy may be withheld.
However, CRP remains important in patients lacking clinical signs and laboratory results implying a possible hepatotrophic viral infection. In the relevant clinical scenarios, such as fever without localizing signs or patients with pneumonia, CRP levels of 5 mg/dL and above support the possibility of bacterial infection and decisions to initiate empirical antibiotic therapy [2,4,13,14].
To the best of our knowledge, this work is the rst to systematically evaluate CRP values in patient with IMN. The retrospective nature of this work and the characteristics of its population preclude de nitive conclusions regarding the distribution of CRP among IMN patients in the community. However, even if the results refer to a subpopulation of IMN patients, the general conclusions and recommendations presented above remain relevant.

Declarations
Ethics approval and consent to participate: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Hillel Yaffe Medical Center . This is an observational study. The Research Ethics Committee has con rmed that informed concent is not required.

Consent for publication:
Not Applicable Availability of data and materials: The dataset will be sent by request.
Competing interests: The authors have no relevant nancial or non-nancial interests to disclose. Funding: