Calprotectin as a non-invasive biomarker for Acute Noninfectious Granulomatous Anterior Uveitis in Egyptian Patients

doi:10.21203/rs.3.rs-1837222/v1

Purpose

To study the relation between serum calprotectin level and acute noninfectious anterior uveitis in Egyptian patients.

Methods

An observational prospective study carried out at Menoufia University Hospital during the period from march 2021 till June 2022, after informed consent from all studied patients. This study included 20 eyes of patients with Acute Anterior Uveitis (AAU) and 20 eyes healthy individuals matched sex and age as the control group. Full history taking, ophthalmological examination and serum calprotectin levels were performed for both patients and controls.

Results

The majority of AAU patients' eyes (55%) had a moderate grade, followed by a faint grade (30%) and a pronounced grade (15%). Serum calprotectin levels were substantially higher in patients with acute anterior uveitis than in healthy eyes (61.45 ± 7.89 vs. 32.50 ± 11.64; 95% CI: 22.58–35.32; P < 0.001). In comparison to negative previous uveitis and mild to moderate anterior uveitis, serum calprotectin levels were substantially higher with positive previous uveitis (64.75 ± 4.65) and notable grade (67.00 ± 2.65). The serum calprotectin cutoff point for diagnosing AAU was 58.0, with sensitivity of 95% and specificity of 43%. Serum calprotectin had a cutoff value in the prognosis of AAU of 63.0, with a sensitivity of 91.7% and a specificity of 37.5%.

Conclusion

Serum calprotectin levels was significantly higher with positive previous uveitis and marked grade indicating a possible role of calprotectin in the pathogenesis of noninfectious AAU. Finally, we discovered serum calprotectin as a possible biomarker for predicting patients' mortality risk and the likelihood of developing anterior uveitis, whose prompt monitoring may enhance the prognosis of anterior uveitis.

Anterior Uveitis

Biomarkers

serum Calprotectin

Egyptian patients

Uveitis grading scales

Uveitis is regarded as a serious condition that accounts for between 5 and 20 percent of cases of legal blindness and up to 10 percent of the visual impairments linked to occupational disabilities [1]. The most common kind of uveitis in our environment, NIU has been linked to high expenses for both diagnosis and treatment [2].

A variety of illnesses fall under the umbrella term "uveitis." Although most diseases presumably share the same underlying mechanisms that cause ocular inflammation, different treatment responses show that there must also be disease-specific mediators [3]. It is challenging to employ aqueous humour as a daily strategy for assessing disease activity and treatment response in ordinary clinical practice. Unfortunately, there is a lack of serum marker for detecting the degree of inflammation in uveitis [3].

To our knowledge, no multicenter investigation has been carried out in Egypt to ascertain the clinical pattern of uveitis. Uveitis has just recently been recognized in Egypt as an independent ophthalmic subspeciality [4].

The proteins S100A8 [myeloid-related protein 8) and S100A9 [myeloid-related protein 14) combine to make calprotectin, which is primarily produced by activated granulocytes and monocytes in the blood and inflamed tissues [5]. As it binds toll-like receptor 4 (TLR4)-like damage-associated molecular patterns (DAMPs), it is regarded as an endogenous activator of innate immune response, boosting the release of proinflammatory cytokines, [6]. Different inflammatory disorders, such as bacterial infections, certain rheumatic diseases, malignancies, and cystic fibrosis, result in elevated serum calprotectin levels. This protein, which shows innate immune activity, is secreted during the infiltration process of inflamed tissues [7].

Patients with spondylarthritis (SpA) treated with TNF-blockers and patients with rheumatoid arthritis (RA) treated with both conventional and biologic disease-modifying anti-rheumatic drugs may benefit from using circulating calprotectin as a good indicator of clinical response because these treatments cause a rapid drop in the levels of this molecule [8, 9]. In addition to correlating with inflammatory indicators and the generation of autoantibodies, joint and vascular damage in RA, it has also been linked to the advancement of spinal structural deterioration in axial SpA. [10].

Since patients with endogenous posterior uveitis had much higher levels of the protein calprotectin than those with resolving or inactive uveitis or healthy controls, it has been suggested that this protein may be a sensitive predictor of disease activity in these patients [11, 12]. Calprotectin levels were found to be considerably greater in circulating blood than in non-uveitic controls in recent investigations evaluating the relationship between calprotectin and uveitis activity. Additionally, there is a strong association between macular thickness, anterior uveitis activity, and calprotectin levels. [12]. So, the aim of work is to study the relation between serum calprotectin level and anterior uveitis in Egyptian patients.

2.1. Study design and patient enrolment

An observational prospective study carried out at Menoufia University Hospital during the period from march 2021 till June 2022, after informed consent from all studied patients. This study included 20 eyes with Acute Noninfectious Granulomatous Anterior Uveitis (AAU) and 20 healthy individuals' eye matched sex and age as the control group.

2.2. Ethical consideration

After a brief and concise description of the study's goals, either the patient or the patient's legal guardian provided a written informed consent. The consent form was created in compliance with the Helsinki Declaration and Egyptian Ministry of Health Quality and Improvement System standards. The Menoufia Faculty of Medicine's Local Ethical Scientific Committee granted approval for the study plan.

2.3. Patients' criteria

All patients were selected according inclusion and exclusion criteria as follow: Inclusion criteria: Both sex patients with active, non-infectious anterior uveitis and non-uveitis controls, aged 10 to 30, with systemic inflammatory disorders associated with uveitis were recruited.

Exclusion criteria

any patients between the ages of 10 and above 30, diabetic people, patients who have had previous eye surgery, concurrent infectious disorders, systemic inflammatory conditions unrelated to uveitis, or recent ocular truma.

2.4. Measurements examination

Full history taking, ophthalmological examination and serum calprotectin levels were performed for both patients and controls as follow:

Full history taking included Age, sex, family history, medical history, previous uveitis, and uveitis diagnosis are all factors.

The best-corrected visual acuity (BCVA) by decimal chart and fundus examination were both parts of the ophthalmological examination.

Grading of anterior uveitis

According to the suggestions of the Standardization of Uveitis Nomenclature (SUN) Working Group, uveitis was identified and categorized [13]. All of our patients had active uveitis, which was determined to have the presence of inflammatory symptoms such vasculitis, choroiditis, or papillitis for posterior uveitis and an anterior chamber cell grade 1 + for anterior uveitis. For any kind of uveitis, the presence of macular edoema was also thought to be a marker of uveitis activity, [14].

Serum calprotectin levels

According to the manufacturer's instructions, the manufacturer's commercial ELISA kits (SUNLONG BIOTECH CO., LTD, Gongshu District, Hangzhou city, Zhejiang province, Hangzhou, Zhejiang, China) were used to measure the serum calprotectin levels.

Principal of calprotectin ELISA kits

Sandwich-ELISA is the technique used in this ELISA kit. A CALP-specific antibody has been pre-coated on the Microelisa stripplate included in this kit. The appropriate Microelisa stripplate wells are filled with standards or samples, which are then mixed with the designated antibody. Then each Microelisa stripplate well is filled with a Horseradish Peroxidase (HRP)-conjugated antibody that is specific for CALP, and the plate is incubated. Free parts are removed during washing. To each well, the TMB substrate solution is applied. Only the wells containing CALP and the HRP-conjugated CALP antibody will initially appear blue before changing to yellow after the stop solution is added. At a wavelength of 450 nm, the optical density (OD) is measured spectrophotometrically. The relationship between the OD value and CALP concentration is linear.

2.5. Blood sampling

Blood samples were taken from uveitis patients either on the day of the ophthalmologic examination or in the days that followed, but no later than seven days after the flare-up started. Venipuncture was used to obtain blood samples for tri-potassium EDTA tubes. Plasma was extracted from centrifuged blood and kept at -20° C. Using a Fluorescent Enzyme Sandwich Immunoassay, the amount of plasma calprotectin was measured. In this assay, the calprotectin from patient samples binds to the monoclonal antibody coating the wells, and then, after washing away the unbound components, antibodies against human calprotectin are added to form a complex with them.

In order to obtain a final fluorescent signal proportionate to the amount of calprotectin complex present, non-bound conjugate is washed away, and the complex is then incubated with a development solution. The higher the response value, the more calprotectin is present in the specimen. The answers are contrasted with the calibrator calibration curve established for concentration calculations, [15].

2.6. Outcome of the study

Best-corrected visual acuity (BCVA), Slit-lamp biomicroscopy, grading, fundus inspection, macular edoema, and further tests such fluorescein angiography, fundus autofluorescence, and/or OCT where necessary were outcomes of the current study.

2.7. Statistical Analysis

SPSS V.25 and Microsoft Excel 2019 (Microsoft Corporation, One Microsoft Way Redmond, WA 98052 − 6399 USA) were used to tabulate and statistically analyse the results (IBM Corporation, 1 Orchard Rd, Armonk, NY 10504, USA), Mean (x), median, and standard deviation (SD) were among the descriptive statistics, while the chi-square test (2), Standard Student t-test (t), Mann-Whitney test (U test), Kruskal Wallis test, and ROC curve analysis were among the analytical statistics. Statistical significance was defined as a P value 0.05 or lower.

A CONSORT flow chart of the study population is shown in Fig. 1. Of the 49 eyes of patients with Acute Anterior Uveitis (AAU) and healthy individuals' eye matched sex and age included in this study, they attended to Menoufia University Hospital, 9 eyes excluded from our study, 7 of them did not meet the inclusion criteria and 2 declined consent), 40 eyes of patients were willing to participate and consented for participation in the study. Thus, 40 eyes were analysed (20 eyes with AAU and 20 healthy eyes), 6 eyes of patients had Faint grade (+ 1), 11 eyes had Moderate grade (+ 2) and 3 eyes had Marked grade (+ 3). There were no significantly differences among the studied groups regarding age and gender (P > 0.05), (Table 1).

Table 1

Socio-demographic data among eyes of patients with AAU and healthy eyes.
Variable	Eyes with AAU (20 eyes)		Healthy eyes (20 eyes)		t	P value	Mean Difference	95% CI
Variable	Eyes with AAU (20 eyes)		Healthy eyes (20 eyes)		t	P value	Mean Difference	Lower	Upper
Age/ year Mean ± SD Range	19.15 ± 6.09 10–30		19.55 ± 6.05 10–30		0.208	0.836	0.40	4.28	3.48
Gender Male Female	10 10	50 50	7 13	35 65	X2 = 0.921	0.337	---	---	---

Results in Table 2 shows that, Visual acuity was significantly increased among eyes of patients with Acute Anterior Uveitis (3.10 ± 1.41) than healthy eyes (1.60 ± 0.82) with a significant difference (95%CI: 0.76–2.24, P < 0.001). In this concern, serum calprotectin level significantly increased among eyes of patients with Acute Anterior Uveitis (61.45 ± 7.89) than healthy eyes (32.50 ± 11.64) with a significant difference (95%CI: 22.58–35.32, P < 0.001), (Table 2, Fig. 2).

Table 2

Visual acuity and Serum calprotectin levels among eyes of patients with AAU and healthy eyes.
Variable	Eyes with AAU (20 eyes)	Healthy eyes (20 eyes)	U#	P value	Mean Difference	95% CI
Variable	Eyes with AAU (20 eyes)	Healthy eyes (20 eyes)	U#	P value	Mean Difference	Lower	Upper
Visual acuity Mean ± SD Range Median (IQR)	3.10 ± 1.41 1–4 4 (3)	1.60 ± 0.82 1(3) 1–3	4.111	< 0.001**	1.50	0.76	2.24
Serum calprotectin level Mean ± SD Range Median (IQR)	61.45 ± 7.89 40–72 64 (11)	32.50 ± 11.64 11–50 30 (10)	9.206	< 0.001**	28.95	22.58	35.32
#Mean visual acuity and serum calprotectin level were statistically analogized among cases and healthy groups using Mann-Whitney U test, ^*Significant. CI: Confidence interval for Mean.

In our study, most of eyes of patients with AAU had moderate grade (55%), followed by faint grade (30%), and marked grade (15%), as shown in Fig. 3.

Age, gender, prior uveitis, uveitis diagnosis, and visual acuity did not all significantly correlate with the severity of anterior uveitis (p > 0.05). Neither did previous uveitis or visual acuity. The majority of eyes with moderate grade had positive past uveitis (90.91%), followed by eyes with marked grade by 66.67%, while all of the eyes with faint grade had no prior uveitis (p = 0.001). Previous uveitis was not significantly correlated with the grading of anterior uveitis, as shown in Table 3 and Fig. 4.

Table 3

Grading of anterior uveitis in relation to age, gender, Previous uveitis, Uveitis diagnosis and visual acuity.
Variable	Grading of anterior uveitis			X²	P value
Variable	Faint grade (+ 1) (N = 6 eyes)	Moderate grade (2+) (N = 11 eyes)	Marked grade (3+) (N = 3 eyes)	X²	P value
Age/year Mean ± SD Range	19.00 ± 7.24 10–30	20.27 ± 6.17 10–30	15.33 ± 1.53 14–17	K= 0.758	0.484
Gender Male Female	4 (66.67%) 2 (33.33%)	5 (45.45%) 6 (54.55%)	1 (33.33%) 2 (66.67%)	1.09	0.580
Previous uveitis Negative Positive	6 (100.0%) 0 (0.0%)	1 (9.09%) 10 (90.91%)	1 (33.33%) 2 (66.67%)	13.43	0.001*
Uveitis diagnosis Juvenile idiopathic arthritis in children Crohn’s disease Bechet's disease Rheumatoid arthritis	2 (33.33%) 0 (0.00%) 3 (50.00%) 1 (16.67%)	4 (36.36%) 5 (45.45%) 1 (9.09%) 1 (9.09%)	1 (33.33%) 1 (33.33%) 1 (33.33%) 0 (0.00%)	5.97	0.426
Visual acuity 6/60 6/36 6/24	4 (66.67%) 0 (0.00%) 2 (33.33%)	5 (45.45%) 4 (36.36%) 2 (18.18%)	1 (33.33%) 1 (33.33%) 1 (33.33%)	3.15	0.533
X²: Chi-square test, K: Kruskal Wallis test, *Significant. CI: Confidence interval for Mean.

Data represented in Table 4 revealed that, previous uveitis and grading of anterior uveitis were statistically significant relation with serum calprotectin levels (p < 0.05). Serum calprotectin significantly higher with positive previous uveitis (64.75 ± 4.65) and marked grade (67.00 ± 2.65) as compared negative previous uveitis and faint and moderate anterior uveitis (Figs. 5, 6). While, gender, uveitis diagnosis and visual acuity did not show any relation with serum calprotectin level (P > 0.05), (Table 4).

Table 4

Serum calprotectin levels in relation to gender, previous uveitis, uveitis diagnosis, grading of anterior uveitis and visual acuity.
		Serum calprotectin level		Sig. test		95% CI
	No.	Mean ± SD	Range	U	P value	Lower	Upper
Gender Males Females	10 10	60.60 ± 9.89 62.30 ± 5.66	10–72 10–71	0.472	0.644	-9.41	-6.01
Previous uveitis Negative Positive	8 12	56.50 ± 9.39 64.75 ± 4.65	40–67 55–72	2.30	0.046*	-16.31	-0.185
Uveitis diagnosis Juvenile idiopathic arthritis in children Crohn’s disease Bechet's disease Rheumatoid arthritis	7 6 5 2	62.71 ± 7.11 63.16 ± 4.35 58.80 ± 13.02 58.50 ± 4.94	52–71 55–67 40–72 55–62	K= 0.394	0.759	57.75	65.14
Grading of anterior uveitis Faint grade (+ 1) Moderate grade (2+) Marked grade (3+)	6 11 3	53.17 ± 8.38 64.45 ± 4.63 67.00 ± 2.65	40–66 55–72 65–70	K= 8.849	0.002*	57.76	65.14
Visual acuity 6/60 6/36 6/24	10 5 5	58.40 ± 8.19 66.20 ± 3.76 62.80 ± 8.75	40–65 62–72 52–71	K= 1.887	0.182	57.75	65.14
U: Mann-Whitney U test, K: Kruskal Wallis test, *Significant. CI: Confidence interval for Mean.

Regarding the diagnosis of acute anterior uveitis, ROC curve analysis showed that the cutoff point of serum calprotectin in diagnosis of AAU was ≥ 58.0, with sensitivity of 95%, specificity of 43% at AUC of 0.986, with reached to significant level (p < 0.001), (Table 5, Fig. 7).

Table 5

Cut off point of serum calprotectin in diagnosis of acute anterior uveitis.
Area	Std. Error	P value	Cut off≥	Sens.	Spec.	95% CI
Area	Std. Error	P value	Cut off≥	Sens.	Spec.	Lower	Upper
0.986	0.015	< 0.001*	58.0	95%	43%	0.96	1.00
*Significant. CI: Confidence interval for Mean.

Regarding the prognosis of acute anterior uveitis, the cutoff point for serum calprotectin in predicting the development of AAU was determined by ROC curve analysis to be 63.0, with sensitivity of 91.7% and specificity of 37.5% at an AUC of 0.708, reaching a significant level of 0.012 (Table 6, Fig. 8).

Table 6

Cut off point of serum calprotectin for prognosis of anterior uveitis grades.
Area	Std. Error	P value	Cut off≥	Sens.	Spec.	95% CI
Area	Std. Error	P value	Cut off≥	Sens.	Spec.	Lower	Upper
0.708	0.137	0.012*	63.0	91.7%	37.5%	0.439	0.977
*Significant. CI: Confidence interval for Mean.

Worldwide, uveitis and its aftereffects continue to be a leading cause of blindness. Many times, there is no known cause [16]. Although uveitis frequently occurs alone, it is not a single disease. Uveitis can be a part of numerous distinct disease processes, much like arthritis can. [17]. Uveitis develops as a failure of the ocular immune system, and the condition is characterized by inflammation and tissue damage [18]. Importantly, leukocyte migration, activation, and retention in inflamed ocular tissue are mediated by chemokines and their receptors, which may represent potential therapeutic targets. [19]. calprotectin is proteins that have been extensively researched in inflammatory disease [20]. So, the aim of this work is to investigate the correlation between serum calprotectin level and anterior uveitis in Egyptian patients.

In our study, compared to healthy eyes, patients with acute anterior uveitis had considerably higher serum calprotectin levels. Calprotectin has previously been investigated in systemic illness of various clinical phenotypes with overall uveitis presentation. When compared to patients with idiopathic anterior uveitis and healthy individuals, patients with juvenile idiopathic arthritis-associated uveitis had elevated serum calprotectin levels, and systemic conditions appeared to interfere with the calprotectin. Additionally, Behçet's disease (BD) patients were found to have elevated serum levels of calprotectin, and faecal calprotectin may be useful in assessing the intestinal involvement of BD, [21]. To ascertain its precise function in the condition, calprotectin expression in uveitis should be examined as a single entity. Olson et al. [22]16 reported early in 1996 that calprotectin was elevated in endogenous posterior uveitis, but only enrolled 27 patients, and no additional linkage between calprotectin and clinical parameters was carried out due to the small sample size. In the same line Pascual et al. [23] found age and gender did not substantially differ across the groups under study. Results showed that patients' groups' serum calprotectin levels were significantly higher than those of the control groups.

Another study by Gazim, et al. [24] concluded that, the clinician may be able to categorise the causes of anterior uveitis with the aid of faecal calprotectin levels. SpA-associated uveitis is difficult to diagnose in some cases because some rheumatological findings are absent or insufficient [25]. SpA may also present itself initially as uveitis. Finding high faecal calprotectin levels could be another piece of information that contributes to this classification. To fully comprehend the significance of faecal calprotectin levels in the diagnosis of SpA in individuals presenting with anterior uveitis, more research is required. Despite the fact that none of our patients had Behçet's illness, it is important to note that this condition is similarly linked to intestinal inflammation and high amounts of faecal calprotectin [26]. The relevance of calprotectin levels in the differential diagnosis of these two diseases may be clarified by further research comparing the calprotectin levels in uveitis patients with SpA and Behçet's disease.

In the present study, serum calprotectin levels were significantly elevated with positive previous uveitis and marked grade indicating a possible role of calprotectin in the pathogenesis of IAAU. These findings support Song et al. [3] observation that uveitis activity grading in individuals with idiopathic acute anterior uveitis correlated positively with serum calprotectin levels. Pascual et al. [23] could not find a link between plasma calprotectin and anterior uveitis activity grading or a statistically significant difference in calprotectin levels when uveitis was cleared, in contrast to these most recent data. The fact that there is a great deal of variation in activity grading assessment could be one explanation for the lack of association with anterior chamber cellularity, which is reflected in the study of Kempen et al. in which interobserver agreement in grading intraocular inflammation is found to be moderate [27]. In a previous study by Szepessy et al. [28] showed that, Uveitis grading revealed a favourable correlation between higher calprotectin levels and ocular inflammation. It was noted that the degree of inflammation in acute anterior uveitis was linked with macular alterations assessed by OCT. In uveitic eyes evaluated by OCT, a linear association between the level of inflammation and central foveal thickness was found; the latter can, to some extent, represent uveitis activity [29]. While macular thickness measuring by OCT also required specific technique, serum detection of calprotectin was more accurate and objective than uveitis grading using anterior chamber cells and anterior chamber flare. All of these contribute to the understanding of serum calprotectin as a novel, practical, quantitative biomarker for uveitis activity evaluation.

Our results showed that, the serum calprotectin cut-off point for diagnosing AAU was 58.0, with sensitivity of 95% and specificity of 43%. Serum calprotectin had a cut-off point in the prognosis of AAU of 63.0, with sensitivity of 91.7 and specificity of 37.5%. In a study by Song et al. [3] found that, according to the results of ROC analysis, serum calprotectin is more effective at differentiating IAAU from healthy controls. The area under the curve for serum calprotectin for screening IAAU was 0.935 at the optimal cut-off value of 13.3 ng/ml, with corresponding sensitivity and specificity of 88.9% and 87.5%, and facilitating future application of serum calprotectin in clinical practise.

Furthermore, Pato et al., [7] reported that, a disease activity index for patients with uveitis (UVEDAI) comprising the pertinent areas was developed relatively recently and needs further validation in addition to the currently available scoring methods for uveitis grading. The uveitis community will need to assess these sensitive and discriminatory tools for objective quantification of anterior chamber inflammation against the current subjective clinical estimates as new forms of quantitative imaging in uveitis are proposed, and come to a new understanding on how disease activity in uveitis should be measured [30].

In this respect Song et al. [3]. showed that, the data from various organisations and research might be readily compared if there were a uniform set of standards for rating the four features of intraocular inflammation. However, a number of variables, including semiquantitative parameters like beam height and width, illumination angle, light intensity, and magnification, are likely to have an impact on the accuracy and precision of such scoring schemes. There were differences in opinions among uveitis doctors while determining whether to regularly count the number of cells and utilise laser flare photometry or not [30].

Most of the studied patients with AAU had moderate grade, Patients with acute anterior uveitis had higher serum calprotectin levels. Serum calprotectin levels was significantly elevated with positive previous uveitis and marked grade indicating a possible role of calprotectin in the pathogenesis of non-infectious AAU. The serum calprotectin cut-off points for diagnosing AAU were 58.0, with sensitivity of 95% and specificity of 43%. Serum calprotectin had a cut-off point in the prognosis of AAU of 63.0, with sensitivity of 91.7 and specificity of 37.5%. Finally, we identified serum calprotectin as a potential biomarker for prediction of anterior uveitis risk and patients' mortality risk, whose timely monitoring might improve the prognosis of non-infectious anterior uveitis. Further investigation with large sample size is needed to assess the relationship between calprotectin and uveitis activity.

Acute Anterior Uveitis (AAU)

Noninfectious uveitis (NIU)

Toll-like receptor 4 (TLR4

damage-associated molecular patterns (DAMPs

spondylarthritis (SpA)

best-corrected visual acuity (BCVA)

Standardization of Uveitis Nomenclature (SUN)

Behçet's disease (BD)

Horseradish Peroxidase (HRP)

Optical coherence tomography (OCT)

Author Contribution Conceptualization: Sara A. Nage. Investigation, methodology, and data curation: Sara A. Nage and Ahmed Esmail. Preparing original draft: Sara A. Nage. Review and final editing: Sara A. Nage and Ahmed Esmail. All authors read and approved the final manuscript.

Funding Open access funding will be provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).

Availability of Data and Material All data and materials included in this work are available.

Code Availability Not applicable.

Ethics Approval Not applicable

Consent to Participate Not applicable.

Consent for Publication Not applicable.

Conflict of Interest The authors declare no competing interests.

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No competing interests reported.

Calprotectin as a non-invasive biomarker for Acute Noninfectious Granulomatous Anterior Uveitis in Egyptian Patients

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

1. Introduction

2. Patients And Methods

2.1. Study design and patient enrolment

2.2. Ethical consideration

2.3. Patients' criteria

2.4. Measurements examination

2.5. Blood sampling

2.6. Outcome of the study

2.7. Statistical Analysis

3. Results

4. Discussion

5. Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1