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- J Feline Med Surg
- v.24(12); 2022 Dec
- PMC10812354
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J Feline Med Surg. 2022 Dec; 24(12): e595–e602.
Published online 2022 Nov 9. doi:10.1177/1098612X221125570
PMCID: PMC10812354
PMID: 36350675
Erdal Matur,1 Mukaddes Özcan,1 Elif Ergül Ekiz,1 Ezgi Ergen,1 Mert Erek,3 Erman Or,2 Banu Dokuzeylül,2 Songül Erhan,3 and Bengü Bilgiç2
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Abstract
Objectives
The aim of this study was to investigate the use of procalcitonin (PCT) as a biomarker in differentiating bacterial infections from viral infections in cats. In addition, the relationship between PCT and mortality rate was also examined.
Methods
Forty-five cats were included in the study. The cats were categorised into two groups: bacterial (n = 20) and viral (n = 25) infection. Serum PCT level and PCT mRNA expression were analysed from blood samples collected before treatment.
Results
Serum PCT level and PCT mRNA expression of the cats with presumed bacterial infection were higher than those with viral infection (P = 0.001 and P = 0.001, respectively). The receiver operating characteristic (ROC) curve analysis revealed an area under the ROC curve value of 0.888 for serum PCT and 0.850 for PCT mRNA expression. There was no statistically significant difference among respiratory, urinary and gastrointestinal tract infections regarding serum PCT level and PCT mRNA expression in the presumed bacterial infection group (P = 0.741 and P = 0.141, respectively). In the presumed bacterial infection group, serum PCT level and PCT mRNA expression in the non-surviving cats were higher than those of the surviving cats (P = 0.021 and P = 0.026, respectively).
Conclusions and relevance
Serum PCT level and PCT mRNA expression were considered efficient biomarkers in cats to distinguish a bacterial infection from a viral infection. Moreover, ROC curve analysis was highly accurate in the discriminative capacity of these two parameters. PCT level and PCT mRNA expression offer substantial assistance in an efficient therapeutic approach and in avoiding unnecessary antibiotic use in feline clinical practice, particularly in emergency patients and those with non-specific clinical signs, decreasing the mortality rate. However, it should be noted that these data are only research data. More detailed future studies are needed.
Keywords: Bacterial infection, mRNA, procalcitonin, ROC analysis, viral infection
Introduction
Procalcitonin (PCT) is the precursor of the hormone calcitonin, synthesised by the parafollicular cells (C cells) of the thyroid gland, encoded by CALC1 on chromosome 11. Once produced, PCT is instantly transformed into intracellular calcitonin, catacalcin and NH2-terminal peptide by the endopeptidases. Therefore, the plasma PCT level is relatively low under physiological conditions.1PCT production follows an entirely different pathway during inflammation or bacterial infection. Endotoxins released by bacteria and proinflammatory cytokines such as tumour necrosis factor alpha, interleukin (IL)-1beta and IL-6 stimulate the parenchymal cells of different organs such as the spleen, liver, pancreas, kidney and colon to produce large amounts of PCT,2–4 which, owing to the lack of endopeptidases in these cells, is directly released into the blood circulation without being converted into calcitonin and other components.5 Thus, the plasma PCT level shows a rapid exponential rise and is sustained at high levels as long as the stimuli are present.6The course of PCT production for viral infections differs compared with bacterial infections. Interferon-gamma (IFN-γ), secreted by T helper cells during a viral infection, inhibits PCT production by the parenchymal cells;7 moreover, IFN-γ blocks PCT production during mixed bacterial and viral infections.8 Therefore, while the serum PCT level is increased in bacterial infections, no significant change is noted in viral and mixed infections, enabling the use of PCT as a clinical biomarker in differentiating bacterial and viral infections in humans.9 Consequently, the US Food and Drug Administration approved the use of PCT as a diagnostic biomarker in lower respiratory tract infections of unknown aetiology to determine whether or not to prescribe antibiotics.10 Apart from the diagnostic value of PCT, assessing serum PCT levels is essential in monitoring a patient’s outcome and response to the treatment protocol. A 30% decline in serum PCT levels 24 h after initiating antibiotic therapy is the threshold of an efficient medical approach.11 PCT is also used to assess the severity of infection and potential mortality.12,13
The upregulation of the CALC1 gene by bacterial endotoxins or proinflammatory cytokines initiates extrathyroidal PCT production; however, increased gene expression does not necessarily result in protein synthesis, and several microRNAs are responsible for silencing genes during the post-transcriptional phase, inhibiting protein synthesis.14 Thus, on particular occasions, PCT production might not be elevated in bacterial infections or during inflammation. Likewise, serum PCT levels have been reported to remain unchanged during severe bacterial infections, including sepsis,15 in which case the measurement of PCT mRNA expression might be required, in addition to serum PCT levels, in order to differentiate between bacterial and viral infections. Furthermore, mononuclear cells are among the primary sources of extrathyroidal PCT in the peripheral blood during bacterial infection or inflammation. A more than 100-fold increase in PCT mRNA expression by mononuclear inflammatory cells is a well-known phenomenon in bacterial infections,16 which raises the question of whether peripheral PCT mRNA expression might be used as a biomarker. To the best of our knowledge, the topic has not been investigated in companion animals, including cats.
An increase in serum PCT levels is not always an indicator of bacterial infection. For example, severe trauma, surgical interventions, cardiogenic shock, medullary thyroid carcinoma, small-cell lung cancer, cirrhosis, pancreatitis or ischaemic bowel syndrome might increase PCT production.17 Conversely, a bacterial infection should not necessarily be ruled out if serum PCT remains at a low level, as the PCT level has been documented to remain unchanged during the early phases of infection, in localised infections and in subacute endocarditis.18
Although PCT production and its clinical use have been thoroughly investigated in humans, few studies are available in animals. Infectious and non-infectious inflammatory diseases have been reported to result in an increased expression of CALC1, encoding PCT production in dogs.19,20
Sepsis,21 bacterial infections22 and blood parasites23 increase serum PCT levels. In addition, it has been reported that the PCT level begins to increase 2 h after a lipopolysaccharide injection in dogs, increases significantly over 12 h and returns to baseline after 48 h.24 To the best of our knowledge, infection-associated PCT production in cats has been documented in a single study, which indicated an increase in serum PCT levels during bacterial infections.25 However, PCT’s potential correlation with viral infections, the effect of different bacterial infections on PCT production and PCT’s correlation with mortality have not been investigated in cats. Furthermore, no studies investigating the significance of PCT mRNA expression have been published.
Bacterial and viral infections are highly prevalent in cats and the clinical outcome gradually deteriorates, particularly during the course of viral infections that are not detected early with a simultaneously occurring bacterial infection. Non-specific clinical signs or indistinct alterations in acute-phase reactants are, unlike in dogs, a significant issue in cats.25 Moreover, particular clinical biomarkers widely used in humans or dogs are inefficient in cats,26 impeding diagnosis and the therapeutic approach, and thus increasing the mortality rate. Therefore, novel, reliable biomarkers are required in feline clinical practice.
The main objective of this study was to investigate the potential efficacy of serum PCT levels and PCT mRNA expression as biomarkers in distinguishing between bacterial and viral infections in cats. Furthermore, the effect of infection type on PCT production and the potential correlation between the relevant parameters and mortality were also investigated.
Materials and methods
Animals and groups
The study was approved by the Istanbul University Animal Experiments Local Ethics Committee (approval no: 118-481). Forty-five cats admitted to the Istanbul University-Cerrahpaşa, Faculty of Veterinary Medicine and the Department of Internal Medicine between February and July 2021 were included in the study. Patient medical records were examined and blood samples were collected from those meeting the required criteria after owner consent was obtained. The cats were divided into two groups: bacterial (n = 20) and viral (n = 25) infection. There were no interventions to the animals’ housing, maintenance conditions and treatment protocols during the study.
Patient selection
Cats meeting at least two criteria of systemic inflammatory response syndrome were included in the bacterial group.27 Clinical signs and additional diagnostic test results were also evaluated to confirm the suspected disease. Briefly, eight cats with fever, tachypnoea, lethargy, coughing, sneezing and nasal discharge were diagnosed with presumed bacterial bronchopneumonia. Presumed bacterial enteritis was diagnosed in six cats with acute nausea, watery/bloody diarrhoea, vomiting, anorexia and abdominal distension. Additional diagnostic methods, such as abdominal radiography and ultrasonography, were also performed to confirm clinical diagnosis. Bacterial culture could not be performed in cats with bronchopneumonia and gastroenteritis, as the owners did not agree to sampling by bronchoscopy and endoscopy, respectively. A diagnosis of presumed bacterial urinary tract infection was made in six cats according to the presence of lower urinary tract findings such as haematuria, pollakiuria, pyuria, bacteriuria, stranguria, urine bacterial culture and susceptibility test results. In addition, urine dipstick, urine specific gravity and urine sediment examination were also performed in all cases. As determined by rapid tests (Anigen Rapid FCoV Ab and Anigen Rapid FeLV Ag/FIV Ab [Gentaur]), all cats included in the bacterial group were negative for feline coronavirus (FCoV), feline immunodeficiency virus and feline leukaemia virus (FeLV). In addition, the treatment protocols of these cats were followed to determine whether they responded to antimicrobial therapy.
Twenty-one cats with FCoV, three with FeLV and one with calicivirus constituted the viral infection group. All cats with FCoV were diagnosed by rapid test kits (Anigen Rapid FCoV Ab and Anigen Rapid FeLV Ag/FIV Ab [Gentaur]) and clinical findings. In addition, a diagnosis of effusive feline infectious peritonitis was made by PCR test from the effusion fluid of cats with ascites; two cats were diagnosed with pleural effusion. Twelve cats had non-effusive FCoV infection with uveitis, ataxia, seizures, vomiting, diarrhoea, lethargy, anorexia, fever and an albumin:globulin ratio <0.4. Three cats were FeLV positive with non-specific clinical signs such as fever, lymphadenomegaly, vomiting and anorexia. The presence of infection in the cat with feline calicivirus infection was diagnosed by RT-PCR.
Blood sampling
Whole blood was harvested from each cat; 0.5 ml of blood was transferred into EDTA tubes (MiniCollect; Kremsmünster) for PCR analysis; 3 ml of blood was collected into anticoagulant-free tubes (Vacutainer; Becton, Dickinson) to measure serum PCT levels. The anticoagulant tubes were then left to clot at room temperature. Sera were separated by 20 mins of centrifugation at 1000 g. Whole-blood samples collected for PCR analysis and serum samples separated for ELISA were stored at −80°C for approximately 6 months until analysis.
Assessment of serum PCT levels
Cat-specific commercial ELISA tests (Abbkine Scientific) were used to measure serum PCT levels. The stock solution (containing 400 ng/l PCT) included in the kit was subjected to a series of dilutions by the sample diluent to obtain the standard solutions. In total, 150 µl of the former diluted solution was transferred to the latter in each dilution step, ensuring the final standard solutions contained a maximum PCT concentration of 200 ng/l and minimum of 12.5 ng/l. Serum samples (50 µl) processed with the standard solutions were subjected to ELISA analysis according to the manufacturer’s instructions. Absorbance was read at a wavelength of 405 nm (RT6000; Rayto). The variability of intra- and inter-assays was <9% and <11%, respectively, according to the manufacturer’s information.
PCR analysis
All RNA isolation and PCR analysis procedures were performed on ice, to prevent degradation. The samples were stored immediately after blood harvesting at −80°C, to prevent RNA degradation. Blood samples of 200 µl were used for total RNA isolation performed by commercially available RNA blood kits (NucleoSpin: Macherey-Nagel), according to the manufacturer’s instructions. All RNA concentrations were measured before the complementary DNA (cDNA) synthesis was synchronised and the ratio of absorbance at 260 nm and 280 nm was used to assess RNA purity. cDNA synthesis was performed with a cDNA synthesis kit (Script; Jena Bioscience) and RT-PCR analysis was carried out with a qPCR Sybr master mix kit (Jena Bioscience). Non-template negative controls were included during the PCR analysis. Beta-actin primary sequences (forward 5′-CAACCGTGAGAAGATGACTCAGA-3′ and reverse 5′-CCCAGAGTCCATGACAATACCA-3′) were used for the reference gene and CALCA primer sequences (forward 5′-GCCACCTGCTGCCTGCT-3′ and reverse 5′-ACTCTCCAGAGCAGACCCTG-3′) for the targeted gene. The results of the RT-PCR were represented as the threshold cycle (Ct) values. CALC1 gene expression was calculated using the ΔΔCt method. Samples were normalised to housekeeping gene beta actin and then ΔΔCt values were calculated concerning the mean value of delta Ct in the control group. Data were presented as the fold changes of gene expression (2-ΔΔCT).
Statistical analysis
SPSS for Windows (version 11.5.2.1) was used for the statistical analysis. The Shapiro–Wilk test was used to test whether the data were normally distributed. The Mann–Whitney U-test was performed to assess a potential difference of significance between the cats with bacterial and viral infections and between the survivors and non-survivors regarding serum PCT levels and PCT mRNA expression. The effect of infection type in the bacterial infection group on PCT production was analysed by the Kruskal–Wallis test. For this purpose, cats with respiratory, urinary and gastrointestinal system infections were compared in terms of serum PCT levels and PCT mRNA expression. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the overall data regarding serum PCT levels and PCT mRNA expression in the bacterial and viral infection groups. Sensitivity, specificity, cut-off value and the area under the ROC curve (AUC) were calculated. The cut-off value was determined according to the maximum Youden index.28 The AUC measurements were evaluated according to five different categories: excellent = 0.90–1.00; good = 0.80–0.90; fair = 0.70–0.80; poor = 0.60–0.70; and inefficient = 0.50–0.60.29 Statistical significance was established as a P value of 0.05.
Results
Forty-five cats (25 females and 20 males) were included. There were 37 mixed breed cats, four Scottish Folds, two Persians, one Turkish Angora and one Russian Blue. The median age of the cats in the bacterial infection group was 3 years (interquartile range [IQR] 1–5) and 2 years in cats in the viral infection group (IQR 1–3). According to the Mann–Whitney U-test, no significant difference was noted between groups in terms of age (P = 0.138). Seven patients in the bacterial infection group died and 12 survived, whereas 12 died and nine survived in the viral infection group. A total of 45 cats had been included at the start of the study; however, five cats were lost to follow-up and no data concerning these cats’ mortality or survival status could be obtained.
Serum PCT levels and PCT mRNA expression data are presented in Figure 1. Serum PCT levels and PCT mRNA expression in the bacterial infection group were higher than in the viral infection group (P = 0.001 and P = 0.001, respectively).
Figure 1
(a) Serum procalcitonin (PCT) level of cats with bacterial (n = 20) and viral (n = 25) infections. Cats with bacterial infection had higher serum PCT levels than those with viral infection (P = 0.001). (b) Comparison of PCT mRNA expression in cats with bacterial and viral infections. Cats with bacterial infection showed higher PCT mRNA expression than those with viral infection (P = 0.001). The central lines represent the median, the borders of the boxes represent the interquartile range and the whiskers represent the minimum and maximum values
The ROC curve analysis (Figure 2), performed with a cut-off set at ⩾32.40 ng/l to assess the discriminative ability of PCT, revealed 80% sensitivity and 75% specificity regarding the efficacy of serum PCT levels in distinguishing a bacterial infection from a viral infection. When the cut-off value was set to ⩾1.91 ng/l for PCT mRNA expression, the discriminative potential of PCT mRNA expression showed 80.0% sensitivity and 79.2% specificity. The AUC values for serum PCT and PCT mRNA expression were measured as 0.888 (95% confidence interval [CI] 79.5–98.0) and 0.850 (95% CI 73.2–96.8), respectively, and were categorised as having a ‘good’ level (ie, 0.80–0.90) of discriminative potential as clinical biomarkers for these two parameters in distinguishing a bacterial infection from a viral infection.
Figure 2
Receiver operating characteristic (ROC) curves for the potential efficacy of serum procalcitonin (PCT) levels and PCT mRNA expression to distinguish bacterial infection from viral infection. It was determined that the ability of both parameters to distinguish bacterial infection from viral infection was good (area under the ROC curve 0.888 [95% confidence interval (CI) 79.5–98.0] and 0.850 [95% CI 73.2–96.8], respectively)
To assess the effect of infection type on PCT production, cats with bacterial infections were categorised as having respiratory, digestive and urinary tract infections (Figure 3). No difference was noted regarding serum PCT levels and PCT mRNA expression (P = 0.741 and P = 0.141, respectively) in the cats with respiratory, urinary and gastrointestinal system infections.
Figure 3
Effect of infection type on serum procalcitonin (PCT) level and PCT mRNA expression. There was no significant difference in (a) serum PCT levels and (b) PCT mRNA expression according to the Kruskal–Wallis test in cats with respiratory (n = 8), digestive (n = 6) and urinary tract (n = 6) infections (P = 0.741 and P = 0.141, respectively). The central lines represent the median, the borders of the boxes represent the interquartile range and the whiskers represent the minimum and maximum values. inf. = infection
The potential correlation between serum PCT levels and mRNA expression of the cats measured at the initial admission and mortality was also investigated (Table 1). Serum PCT levels and mRNA expression of the cats of the bacterial infection group that died during the study were higher than those that survived (P = 0.021 and P = 0.026, respectively). No significant difference was noted between the survivors and non-survivors of the viral infection group in terms of serum PCT levels and mRNA expression (P = 0.456 and P = 0.810, respectively).
Table 1
Comparison of serum procalcitonin (PCT) levels and PCT mRNA expression in surviving and non-surviving cats
| Serum PCT level (ng/l) | PCT mRNA expression | |
|---|---|---|
| Bacterial infection | ||
| Survivors (n = 12) | 51.4 (30.3–137.1) | 4.4 (0.61–5.85) |
| Non-survivors (n = 7) | 146.2 (118.8–282.9) | 10.9 (5.24–12.3) |
| P = 0.021 | P = 0.026 | |
| Viral infection | ||
| Survivors (n = 9) | 20.3 (17.7–33.8) | 0.34 (0.17–1.84) |
| Non-survivors (n = 12) | 28.3 (19.2– 44.4) | 0.35 (0.13–2.07) |
| P = 0.456 | P = 0.810 | |
Open in a separate window
Data are presented as median and interquartile range
Discussion
Serum PCT level has been suggested as a clinical biomarker to differentiate between bacterial and viral infections,30,31 although one study has shown the inefficiency of the distinctive potential of PCT.32 Moreover, studies have indicated that PCT is more efficient than other biomarkers such as C-reactive protein, IL-6 and IFN-alpha.33 In the present study, we investigated the potential of PCT in distinguishing bacterial infections from viral infections in cats. The data obtained showed a distinct elevation in serum PCT levels in cats with bacterial infections. To date, only one study has investigated this topic, and indicated an increase in serum PCT levels in cats.25 Likewise, serum PCT levels were higher in dogs with sepsis than in healthy controls.24 However, viral infections were not evaluated in previous studies. In a recent study, our research team indicated the applicability of PCT as a clinical biomarker to differentiate between bacterial and viral infections in dogs.34 To the best of our knowledge, no other study has investigated the potential of PCT as a biomarker in other animal species, including cats. Our findings explicitly demonstrated the efficacy of serum PCT levels as a clinical biomarker in distinguishing between bacterial and viral infections in cats.
Our findings revealed a significant elevation in PCT mRNA expression, as well as in serum PCT levels, in bacterial infections (Figure 1), allowing for differentiation between bacterial and viral infections (Figure 2). A limited number of studies have been conducted on this subject in cats, making comparison of our results with other studies difficult. Kuzi et al19 reported that infectious diseases stimulated mRNA expression in dogs; however, they did not determine whether there was a difference between bacterial and viral infection.
Upregulation of the CALC1 gene initiates extrathyroidal PCT production; however, the increase in gene expression may not necessarily result in protein synthesis.14 Therefore, it might be inappropriate to rely solely on serum PCT levels in relevant cases. In such cases, monitoring potential changes in PCT mRNA expression may also facilitate discrimination of bacterial infections that do not result in PCT synthesis.
It is crucial to differentiate precisely the aetiology of suspected infections in cats referred to hospital polyclinics. Thus, the data were analysed by the ROC curves to determine the distinctive ability of PCT in distinguishing between bacterial and viral infections. No research was found regarding the phenomenon in companion animals. A meta-analysis performed in humans indicated that PCT’s specificity and sensitivity were insufficient for a biomarker, and a simultaneous assessment of other diagnostic parameters was required to differentiate between bacterial and viral infections.31 However, other studies have found that the ability of PCT to distinguish a bacterial infection from a viral one is sufficient.32–35 Likewise, our study revealed satisfactory findings in terms of AUC values, which were categorised under a good level of discriminative ability for serum PCT levels and PCT mRNA expression (0.836 for PCT and 0.822 for mRNA). Thus, these were considered efficient parameters for differentiating between bacterial and viral infections in feline clinical practice.
An elevation in PCT production, depending on the type of the bacterial infection, has been monitored in humans. Higher serum PCT levels were found in certain infectious diseases such as bronchitis, chronic obstructive pulmonary disease, pneumonia and septic shock than in urinary tract infections, meningitis and endocarditis.36 Therefore, PCT is used in human medicine to distinguish a bacterial infection from a viral one, and to assess the type of bacterial infection.37 Likewise, we detected a higher increase in PCT production for certain types of infections in dogs.30 However, in the present study, no statistically significant difference was noted among different bacterial infections in cats, despite the higher levels of serum PCT and PCT mRNA expression in the bacterial infection group than in the viral infection group. Therefore, PCT was considered ineffective at assessing the type of bacterial infection. However, the relatively low number of individuals for all infection types might have been a hindrance to an accurate evaluation, and a further study is required with a larger cat population in which the infectious agents have already been isolated.
Serum PCT levels at initial hospital admission were shown to be a significant parameter in assessing mortality, regardless of the underlying type of infection in humans.38 However, one study has indicated that serum PCT levels are not correlated with mortality.39 PCT concentration at the initial admission was suggested to indicate organ dysfunction, septic shock and mortality in dogs.40 In a recent study, prolonged recovery was monitored in dogs with a high PCT level.22 To the best of our knowledge, no data are available regarding this topic in cats; therefore, we investigated the potential correlation between serum PCT levels measured at the initial admission before the treatment protocol and the mortality rates. The serum PCT levels of cats with bacterial infections that died during the study were higher than those that survived. However, the same argument was invalid for viral infections (Table 1), for which no difference was noted between those that died and the survivors in terms of serum PCT levels and mRNA expression. Considering the increased risk of mortality in patients with high serum levels might enable veterinary practitioners to take immediate precautions and determine treatment priorities.
The study had certain limitations. The serum PCT level was only measured once, at the beginning of the study. Instead, it might have been assessed at certain intervals during the course of the infection or recovery to monitor the potential changes in extrathyroidal production status. Furthermore, cats with mixed infections (bacterial and viral) might also have been included in the study. The lack of bacterial isolation in the cases of pneumonia and gastroenteritis is considered another limitation of the research.
Conclusions
On most occasions, the likelihood of distinguishing between a bacterial and a viral infection based on clinical signs is poor in cats. An accurate diagnostic approach allowing differentiation between bacterial and viral infection is crucial, particularly in emergency patients and those with non-specific clinical signs, to initiate an efficient treatment protocol and avoid the prescription of unnecessary antibiotics. In the present study, based on the results of the ROC curve analysis, the results indicated that serum PCT levels and PCT mRNA expression might be used as clinical biomarkers to distinguish bacterial infection from viral infections in cats, with a high level of reliability. However, the type of bacterial infection did not affect PCT production and elevated levels of PCT at the initial admission posed a high risk for mortality. Based on the data obtained, assessing serum PCT levels and PCT mRNA expression offers substantial assistance to an efficient therapeutic approach, and avoids unnecessary antibiotic use in feline clinical practice, particularly in emergency patients and those with non-specific clinical signs, reducing the mortality rate. However, it should be noted that these data are only research data that have potential as a basis for future work. In the future, carefully designed studies to determine the possible clinical value of measuring serum PCT and PCT mRNA expression are needed.
Acknowledgments
We would like to express our gratitude to Evren Eraslan, Pınar Ertör Akyazı and Nurcan Erözkan Dusak for their technical support.
Footnotes
Accepted: 25 August 2022
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: This work was supported by Scientific Research Projects Coordination Unit of Istanbul University-Cerrahpaşa. Project number: TSA-2019-33240.
Ethical approval: The work described in this manuscript involved the use of non-experimental (owned or unowned) animals and procedures that differed from established internationally recognised high standards (‘best practice’) of veterinary clinical care for the individual patient. The study therefore had prior ethical approval from an established (or ad hoc) committee as stated in the manuscript.
Informed consent: Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers) for all procedure(s) undertaken (prospective or retrospective studies). For any animals or people individually identifiable within this publication, informed consent (verbal or written) for their use in the publication was obtained from the people involved.
ORCID iD: Erdal Matur 
https://orcid.org/0000-0003-0737-8148
Mukaddes Özcan https://orcid.org/0000-0003-1135-4448
Elif Ergül Ekiz https://orcid.org/0000-0003-2931-3257
Ezgi Ergen https://orcid.org/0000-0001-8655-7384
Mert Erek https://orcid.org/0000-0002-2625-897X
Erman Or https://orcid.org/0000-0002-8764-1956
Banu Dokuzeylül https://orcid.org/0000-0003-3086-4726
Songül Erhan https://orcid.org/0000-0003-0189-7924
Bengü Bilgiç https://orcid.org/0000-0002-6952-2937
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