Clinical Characteristics of Hospitalized Patients with COVID-19 in Sofia,Bulgaria

Abstract

Introduction:

SARS-CoV-2 infection is spreading around the world, including countries from Southeastern Europe. The purpose of the study was to present the clinical manifestations of COVID-19 patients admitted to the Military Medical Academy, Sofia, Bulgaria.

Materials and Methods:

A retrospective study was conducted for a period of 3 months from March 2020 to June 2020 on this infection in our hospital. All participants were laboratory confirmed cases of COVID-19. RT-PCR was performed for etiological diagnosis. The hospitalized patients were divided into two groups on admission, that is, nonsevere and severe.

Results:

One hundred thirty-eight COVID-19 patients were hospitalized and analyzed during the study period. The mean age was 52.9 years. Male was the dominant sex (sex ratio: male/female = 1/0.6). The leading clinical signs were fever, fatigue, cough, and headache. On comparative analysis of both groups (nonsevere and severe) was measured significant elevation of white blood cells (odds ratio [OR] = 1.238; p value = 0.006), C-reactive protein (OR = 1.021; p < 0.001), creatinine (OR = 1.037; p < 0.001), aspartate aminotransferase (OR = 1.014; p = 0.040), lactate dehydrogenase (OR = 1.004; p < 0.001), ferritin (OR = 1.002; p < 0.001), fibrinogen (OR = 2.028; p < 0.001), and d-dimer (OR = 2.162; p = 0.002) in severe group than in nonsevere group. Interleukin 6 was tested in 17.4% of patients and high value was found—38.6 pg/mL (95% confidence interval: 16.5–60.7).

Conclusion:

The first Bulgarian retrospective study of COVID-19 hospitalized patients was presented. Older age, male sex, comorbidity, and signs of dyspnea and nausea were estimated as higher risk factors for severe form. Abnormality in inflammatory markers was associated with poor progression of the illness.

Introduction

On December 31, 2019, the World Health Organization (WHO) was informed about cases of pneumonia of unknown etiology detected in Wuhan, Hubei province, China (WHO 2020). Subsequent virological studies indicate that a new coronavirus has been discovered—2019-nCoV (Lu et al. 2020, Zhou et al. 2020, Zhu et al. 2020). Later, on February 11, 2020, the WHO renamed the virus to SARS-CoV-2, and the disease was called COVID-19. Zhu et al. (2020) performed a phylogenetic analysis in three patients with severe pneumonia from Wuhan, China and revealed that the detected CoV had 86.9% identity with bat-SL-CoVZC45 (GenBank accession number: MG772933.1). Lu et al. (2020) reported that the detected SARS-CoV-2 has 87.99% identity with bat-SL-CoVZC45; 87.23% with bat-SL-CoVZXC21; around 79% identity with SARS-CoV; and about 50% identity with MERS-CoV. Zhou et al. (2020) noted that SARS-CoV-2 has 96.2% identity with Bat SARr-CoV RaTG13, and with SARS-CoV is 79.5–79.6% (SARS-CoV GZ02; SARS-CoV BJ01; SARS-CoV Tor2; SARS-CoV SZ3; SARS-CoV PC4-227), and like SARS-CoV, SARS-CoV-2 uses the same host-cell receptor for cell entry—ACE2. The phylogenetic analyses show that SARS-CoV-2 belongs to genus Beta-CoV, subgenus Sarbecovirus (Lu et al. 2020, Zhou et al. 2020, Zhu et al. 2020).

By mid-February 2020, the confirmed cases of SARS-CoV-2 were mainly from China and other Southeastern Asian countries (Guan et al. 2020, Kim et al. 2020, Wu and McGoogan 2020, Young et al. 2020). Since then the virus spread widely in Europe and later to the rest of the world (Docherty et al. 2020, Grasselli et al. 2020, Gudbjartsson et al. 2020, Lechien et al. 2020). WHO declared COVID-19 a pandemic on March 12, 2020, because of the growing number of confirmed cases and deaths.

The first confirmed case of COVID-19 in Bulgaria was reported on March 8, 2020, and the first death from the new coronavirus was reported on March 11, 2020 (ISJ 2020). Since the beginning and mid-March 2020, SARS-CoV-2 infection has spread to all countries from Southeastern Europe.

The aim of the present study was to present the clinical manifestations of COVID-19 patients admitted to the Military Medical Academy, Sofia, Bulgaria. The main reason of the study was the growing number of patients from this new infection in our country.

Materials and Methods

Participants

All participants were laboratory confirmed cases of SARS-CoV-2 infection. Nasopharyngeal and oropharyngeal swabs were collected, and following the protocol, RT-PCR diagnostic test were performed. The analysis was done for a period of 3 months (from early March 2020 to early June 2020). For that period 364 cases were COVID-19 outpatients and were daily monitored by a physician and psychologist. Additional 138 patients with SARS-CoV-2 infection were hospitalized at the Department of Infectious Diseases at the Military Medical Academy, Sofia, Bulgaria.

Data collection

Demographic characteristics, clinical manifestations, laboratory results, imaging procedures, therapy, and clinical outcomes of these patients were obtained from electronic medical records. Clinical signs, laboratory results, and imaging procedures of the patients were acquired on the day of admission. The clinical outcomes of the patients were followed up to June 11, 2020.

Case definition

The hospitalized patients were dived in two groups on admission. First group “Nonsevere,” were cases with mild and moderate clinical forms. Second group “Severe,” those were the patients with severe and critical clinical forms. Definition for nonsevere—patients with clinical signs of pneumonia (fever, cough, dyspnea etc.), but no signs of severe pneumonia, including SpO₂ ≥ 90% on room air. Definition for severe—patients with clinical signs of pneumonia (fever, cough, dyspnea etc.) plus one of the following—respiratory rate >30 breaths/min, severe respiratory distress, or SpO₂ < 90% on room air.

Inclusion and exclusion criteria

The inclusion criteria for present study: (1) people older than 18 years, (2) laboratory confirmed infection with SARS-CoV-2, and (3) patients with clinical presentation of COVID-19. The exclusion criteria were: (1) people younger than 18 years, (2) cases without laboratory confirmed SARS-CoV-2 infection, and (3) patients without clinical signs of COVID-19.

RT-PCR assay

Physicians who collected nasopharyngeal and oropharyngeal samples were under third-level protection. All patients were sampled with nasopharyngeal/oropharyngeal swabs, and then these samples were conducted by RT-PCR at the Department of Virology, Military Medical Academy, Sofia, Bulgaria.

Ethics statement

The study was performed in accordance with the principles of the Declaration of Helsinki. The medical procedures of this study were approved by the Local Ethics Committee of Military Medical Academy, Sofia, Bulgaria.

Statistical analysis

Clinical data and laboratory parameters of SARS-CoV-2 positive cases were compared by t-test, Chi-square test or Fisher's exact test. The COVID-19 patients were separated in two clinical forms (nonsevere and severe). Binary logistic regression was used to evaluate the risk of positive results according to clinical forms. Statistical analysis was performed by Excel 2007 (Microsoft, Redmond, WA) and SPSS Statistics 19.0 (IBM Corp., Armonk, NY). A p value <0.05 was considered statistically significant.

Results

Demographic characteristics

For the analyzed period, 138 patients with laboratory confirmed SARS-CoV-2 infection were hospitalized. The mean age of that patients was 52.9 years (95% confidence interval [CI]: 50.2–55.6), and 83.3% (115/138; mean ± standard deviation: 47.8 ± 12.7 years; 95% CI: 45.5–50.2) of all patients belonged to age range 18–69 years (Table 1). The male sex dominated among analyzed COVID-19 patients (sex ratio: male/female = 1/0.6; p < 0.001). The mean length of hospital stay was 12.3 ± 7.0 days (95% CI: 11.1–13.5), among nonsevere cases—10.6 ± 5.4 days (95% CI: 9.5–11.7), and for severe cases—16.0 ± 8.6 days (95% CI: 13.3–18.7). The exposure history noted domination of familiar/cluster cases.

Table 1.

Demographics and Baseline Characteristics of Bulgarian Patients with COVID-19

Characteristics	All patients (n = 138)	Nonsevere (n = 95)	Severe (n = 43)	p Value
Age, years, mean ± SD	52.9 ± 16.4	48.3 ± 15.7	63.0 ± 12.8	<0.001
Age groups, n (%)
18–49	58 (42.0)	53 (55.8)	5 (11.6)	<0.001
50–69	57 (41.3)	31 (32.7)	26 (60.4)
≥70	23 (16.7)	11 (11.5)	12 (28.0)
Sex, n (%)
Female	51 (37.0)	41 (43.1)	10 (23.2)	0.027
Male	87 (63.0)	54 (56.9)	33 (76.8)
Exposure history, n (%)
Travel abroad	13 (9.4)	9 (9.4)	4 (9.3)	1.000
Familiar/cluster cases	37 (26.8)	25 (26.3)	12 (27.9)	1.000
Medical staff	11 (7.9)	8 (8.4)	3 (6.9)	0.845
Comorbidity, n (%)
Hypertension	69 (50.0)	37 (38.9)	32 (74.4)	0.001
Cardiovascular diseases	22 (15.9)	10 (10.5)	12 (27.9)	0.004
Diabetes mellitus	12 (8.6)	7 (7.3)	5 (11.6)	0.515
Malignant diseases	10 (7.2)	2 (2.1)	8 (18.6)	0.010
Chronic kidney diseases	7 (5.0)	2 (2.1)	5 (11.6)	0.030
COPD	4 (2.8)	1 (1.0)	3 (6.9)	0.089
Cerebrovascular diseases	3 (2.1)	1 (1.0)	2 (4.6)	0.229
Asthma	2 (1.4)	1 (1.0)	1 (2.3)	1.000
Immunodeficiency disorder	2 (1.4)	0 (0.0)	2 (4.6)	0.096

COPD, chronic obstructive pulmonary disease; SD, standard deviation.

Clinical signs

The leading clinical signs on hospital admission were fatigue, cough, and fever (Table 2). Gastrointestinal disorders were rarely mentioned by patients. On hospital admission 79.0% (109/138) of patients had body temperature above 37.5°C, and three patients had lymphadenomegaly. On admission oxygen saturation below 93% was found in 39.9% (55/138) of patients using pulse oximeter.

Table 2.

Signs and Symptoms of Bulgarian Patients with SARS-CoV-2 Infection

Characteristics	All patients (n = 138)	Nonsevere (n = 95)	Severe (n = 43)	p Value
Fever, n (%)
<37.5	29 (21.0)	23 (24.2)	6 (14.0)	0.201
37.5–38.0	51 (37.0)	37 (39.0)	14 (32.5)
38.1–39.0	55 (39.9)	34 (35.8)	21 (48.9)
>39.0	3 (2.1)	1 (1.0)	2 (4.6)
Fatigue, n (%)	124 (89.8)	83 (87.3)	41 (95.3)	0.225
Cough, n (%)	95 (68.8)	64 (67.3)	31 (72.0)	0.721
Headache, n (%)	95 (68.8)	62 (65.3)	33 (76.7)	0.250
Myalgia/arthralgia, n (%)	67 (48.5)	42 (44.2)	25 (58.1)	0.129
Sore throat, n (%)	46 (33.3)	38 (40.0)	8 (18.6)	0.014
Chest tightness/dyspnea, n (%)	39 (28.2)	15 (15.7)	24 (55.8)	<0.001
Nausea, n (%)	18 (13.0)	8 (8.4)	10 (23.2)	0.017
Conjunctivitis, n (%)	12 (8.6)	10 (10.5)	2 (4.6)	0.340
Diarrhea, n (%)	7 (5.0)	3 (3.1)	4 (9.3)	0.204

Laboratory results

The laboratory results of hospital admission are presented in Tables 3 and 4. Elevation of acute phase reactants was observed (C-reactive protein [CRP], ferritin and fibrinogen). Leukopenia was found in 7.2% (10/138) and leukocytosis in 5.1% (7/138) of all patients. Elevation of values of aspartate aminotransferase (AST), and alanine aminotransferase was noted in 25.4% (35/138) and 22.5% (31/138) of patients, respectively. On comparative analysis of both groups (nonsevere and severe) was measured significant elevation of white blood cells (WBC; odds ratio [OR] = 1.238; p value = 0.006), CRP (OR = 1.021; p < 0.001), creatinine (OR = 1.037; p < 0.001), AST (OR = 1.014; p = 0.040), lactate dehydrogenase (LDH; OR = 1.004; p < 0.001), ferritin (OR = 1.002; p < 0.001), fibrinogen (OR = 2.028; p < 0.001), and d-dimer (OR = 2.162; p = 0.002) in severe group than in nonsevere group (Table 4). Interleukin 6 was tested in 17.4% (24/138) of patients and high value was found—38.6 pg/mL (95% CI: 16.5–60.7).

Table 3.

Laboratory Results of 138 Patients with COVID-19 at Admission

Parameter	Reference range	Min	Max	Mean	SD
WBC ( × 10⁹/L)	3.5–10.5	1.9	17.8	6.4	2.5
Lymphocyte percentage	19.3–53.1	3.2	50.3	22.5	11.4
Monocyte percentage	4.7–12.5	0.9	191.0	12.1	17.2
Hemoglobin ( × 10¹²/L)	120–180	60.0	188.0	138.2	16.2
Thrombocytes ( × 10⁹/L)	140–440	70.0	506.0	227.4	88.0
CRP (mg/L)	0.0–5.0	0.5	272.0	57.8	69.8
CPK (U/L)	15–180	10.0	891.0	148.3	140.8
Creatinine (μmol/L)	74–130	53.0	448.0	98.5	45.1
AST (U/L)	5–40	10.7	345.3	42.4	37.9
ALT (U/L)	5–40	8.3	247.7	41.7	41.1
LDH (U/L)	208–378	197.0	1793.0	553.2	305.1
Ferritin (μg/L)	10–300	10.0	1578.0	451.2	395.7
Fibrinogen (g/L)	2.0–4.5	2.4	9.5	5.0	1.7
INR	0.8–1.1	0.7	2.4	1.1	0.2
D-dimer (mg/L)	0.0–0.5	0.3	4.3	0.9	0.9
Potassium (mmol/L)	3.5–5.5	2.4	6.9	4.1	0.6
Natrium (mmol/L)	136–150	124.0	151.0	141.1	4.7

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; CRP, C-reactive protein; LDH, lactate dehydrogenase; WBC, white blood cells.

Table 4.

Binary Logistic Regression Showing the Relationship Between the Severity of SARS-CoV-2 Infection and Laboratory Indicators

Parameter	Group	Min	Max	Mean	SD	OR	95% CI	PE	SE	p Value
WBC	Nonsevere	1.9	11.4	5.9	2.1	1.000
WBC	Severe	3.2	17.8	7.4	3.1	1.238	1.062–1.443	0.213	0.078	0.006
Lymphocyte percentage	Nonsevere	3.2	50.3	26.1	11.1	1.000
Lymphocyte percentage	Severe	3.4	32.6	14.5	6.9	0.872	0.825–0.921	–0.137	0.028	<0.001
Monocyte percentage	Nonsevere	0.9	31.3	10.4	4.9	1.000
Monocyte percentage	Severe	2.5	191.0	15.8	29.2	1.004	0.984–1.026	0.004	0.011	0.687
Hemoglobin	Nonsevere	109.0	171.0	140.7	19.0	1.000
Hemoglobin	Severe	60.0	188.0	132.1	21.3	0.967	0.943–0.991	–0.034	0.013	0.009
Thrombocytes	Nonsevere	104.0	506.0	233.4	82.9	1.000
Thrombocytes	Severe	70.0	473.0	217.2	97.2	0.998	0.993–1.002	–0.002	0.002	0.292
CRP	Nonsevere	0.5	219.9	31.1	45.1	1.000
CRP	Severe	8.8	272.0	117.1	77.1	1.021	1.014–1.029	0.021	0.004	<0.001
CPK	Nonsevere	10.0	891.0	134.7	122.2	1.000
CPK	Severe	35.0	836.0	195.4	170.9	1.003	1.000–1.005	0.003	0.001	0.078
Creatinine	Nonsevere	53.0	134.0	86.4	16.8	1.000
Creatinine	Severe	69.0	448.0	126.0	73.1	1.037	1.017–1.058	0.037	0.010	<0.001
AST	Nonsevere	11.0	216.0	36.6	28.3	1.000
AST	Severe	10.7	345.3	52.4	51.3	1.014	1.001–1.027	0.014	0.007	0.040
ALT	Nonsevere	8.3	238.7	40.4	38.8	1.000
ALT	Severe	13.3	247.7	48.4	45.3	1.003	0.995–1.012	0.003	0.004	0.436
LDH	Nonsevere	197.0	1341.0	453.2	201.2	1.000
LDH	Severe	298.0	1793.0	774.0	371.6	1.004	1.002–1.006	0.004	0.001	<0.001
Ferritin	Nonsevere	10.0	1578.0	348.8	324.9	1.000
Ferritin	Severe	11.1	1572.0	691.5	440.6	1.002	1.001–1.003	0.002	0.001	<0.001
Fibrinogen	Nonsevere	2.4	9.2	4.5	1.5	1.000
Fibrinogen	Severe	2.8	9.5	6.2	1.4	2.028	1.493–2.756	0.707	0.156	<0.001
INR	Nonsevere	0.7	2.0	1.1	0.2	1.000
INR	Severe	0.9	2.4	1.1	0.2	0.971	0.850–1.109	–0.029	0.068	0.665
D-dimer	Nonsevere	0.3	4.3	0.7	0.8	1.000
D-dimer	Severe	0.3	3.5	1.3		2.162	1.317–3.547	0.771	0.253	0.002
Potassium	Nonsevere	2.4	6.6	4.2	0.5	1.000
Potassium	Severe	2.7	6.9	4.1	0.7	0.868	0.444–1.695	–0.142	0.342	0.678
Natrium	Nonsevere	126.0	151.0	141.1	4.7	1.000
Natrium	Severe	124.0	148.0	140.9	4.8	0.997	0.921–1.080	–0.003	0.040	0.945

CI, confidence interval; OR, odds ratio; PE, parameter estimate; SE, standard error.

Imaging procedures

On admission, chest x-ray was performed in 92.8% (128/138) of patients. Peribronchial cuffing was shown in 34.4% (44/128) of patients, pneumonia (lobar and bronchopneumonia) was observed in 32.8% (42/128), interstitial pneumonia in 27.3% (35/128), and normal in 5.5% (7/128). During the hospital stay chest computed tomography (CT) was performed in 9.4% (13/138) of patients. Chest CT showed ground-glass opacity in 76.9% (10/13) and bilateral patch shadow in 23.1% (3/13).

Therapy

All patients were treated in hospital isolation. The following antiviral treatment was applied: rimantadine hydrochloride (20.3%; 28/138), aviron rapid (17.4%; 24/138), oseltamivir (3.6%; 5/138), and lopinavir-ritonavir (2.9%; 4/138). Therapy with hydroxychloroquine and chloroquine phosphate was used in 23.2% (32/138) of patients, but prolongation of QT interval was noted in a few cases. Antibacterial therapy (intravenous antibiotics) was applied in 89.9% (124/138) of patients. Systemic glucocorticoids were used in 50.7% (70/138) of patients, anticoagulant therapy—50.0% (69/138), and antifungal medications—17.4% (24/138).

Clinical outcome

Discharged with improvement was 87.7% (121/138) of patients, still hospitalized—8.0% (11/138), and lethal outcome—4.3% (6/138). Nine patients passed through the intensive care unit (eight patients were intubated). One patient was extubated and discharged home after a 49-day hospital stay. All dead patients had underlying diseases (hypertension, cardiovascular diseases, malignant diseases, diabetes mellitus, and/or chronic obstructive pulmonary disease). Discharge from the hospital was performed after two negative RT-PCR tests with an interval of 24 h between them and/or clinical symptoms of improvement and presentation of antibodies IgG against SARS-CoV-2.

Discussion

In current study, the mean age of all 138 patients was 52.9 years and 63% prevalence of male sex. Zheng et al. (2020b) found mean age of 49.4 years, and 51.5% of patients were men in their hospital study. Liu et al. (2020) reported 57 years as a mean age and 55.5% female in their observation. Li et al. (2020) found mean age of 50 years and 53.3% (120/225) of patients were males in their research. Wang et al. (2020b) reported 49.4 ± 13.6 years as a mean age of critical patients and 56.8% (71/125) female of all patients. Tian et al. (2020) found mean age of 61.4 years of severe patients and 51.5% (135/262) of all patients were female in their retrospective study. We supposed that these slight differences are influenced by demographic characteristics and national features. The present study showed significant morbidity with severe form in older age group, male gender, and comorbidity as hypertension, heart diseases, malignancy, and kidney disorders. It is similar to data from other authors (Colaneri et al. 2020, Petrilli et al. 2020, Wang et al. 2020a, Zheng et al. 2020b).

In the present study, the leading clinical signs on admission were fatigue, cough, and fever. The same symptoms but in other proportion were noted by Chinese patients (Liu et al. 2020, Wang et al. 2020a, Zhang et al. 2020b, Zheng et al. 2020b). Fever, cough, and dyspnea were the most common signs on admission in Italian patients (Colaneri et al. 2020). Zheng et al. (2020a) reported the following clinical signs—fever (75.8%; 122/161), cough (62.7%; 101/161), fatigue (39.8%; 64/161), and dyspnea (14.3%; 23/161). Zhang et al. (2020a) found temperature 38.0–39.0°C in 28.6% of the patients with severe clinical forms and fever >39.0°C in 57.6% of the patients in the same group. In our research, the presentation of dyspnea/chest tightness and nausea were assessed as factors for severe clinical form. Dyspnea was a risk factor for aggravation of illness by Wang et al. (2020a).

In this research, the laboratory parameters showed the significant values of WBC, lymphocyte percentage, hemoglobin, CRP, creatinine, AST, LDH, ferritin, fibrinogen, and d-dimer in case of SARS-CoV-2 infection. These indicators could be obligatory in patient with COVID-19. Significantly, higher levels of CRP, LDH, ferritin, fibrinogen, creatinine, and low lymphocyte percentage were associated with severe clinical form (p < 0.001). These parameters could be predictor markers for developing more severe clinical manifestation. Significant abnormality of values of d-dimer, AST, hemoglobin, and WBC were observed in severe group compared with nonsevere group (p < 0.05). Zhang et al. (2020b) estimated significant meaning of elevated CRP (increased—91.9%, 125/136 of patients; p < 0.001) and d-dimer (increased—43.2%, 35/81 of patients; p < 0.001), lower lymphocyte percentage in severe cases (12.7%) than in nonsevere cases (20.0%). Colaneri et al. (2020) found significant higher odds of severe disease associated with increased level of LDH (OR = 1.090; 95% CI: 1.022–1.163; p = 0.008). Petrilli et al. (2020) estimated association with critical illness and elevation of CRP (>200 mg/L; hazard ratio = 5.07; p < 0.001), d-dimer (>2500 μg/L; hazard ratio = 2.16; p < 0.001), and oxygen saturation below 88% (hazard ratio = 2.00; p < 0.001). All these parameters are important in assessment of patient with COVID-19. Starting value and follow-up levels of these indicators predicted the clinical forms.

Our therapy was based on worldwide recommendations, national protocol, and researchers' experience. No significant data were found on antiviral treatment in current survey. In present study, the estimated mortality rate (4.3%; 6/138) was lower than in national level—5.8% (167/2889) up to date June 11, 2020. Our explanation for this statement is the individual approach to each patient, the conservative ventilation approach with a pulmonary-protective strategy. Wang et al. (2020a) reported the same mortality (4.3%) in their research. This Chinese study was performed among 138 hospitalized patients in Wuhan, China in January 2020 (Wang et al. 2020a). The Italian experience of the first week in European outbreak estimated 4.5% mortality rate among 44 hospitalized patients in a single hospital in Pavia, Italy (Colaneri et al. 2020). This indicator was influenced by many factors, so the values are influenced by various reasons. Therefore, in our opinion, it is appropriate to search for prognostic factors for a severe clinical form to take timely measures.

This study has some limitations that need to be addressed. It was a single-center research; some patients are still hospitalized at the time of writing this article; short follow-up; and small number of participants. Despite these limitations, this is the first study for Bulgarian hospitalized patients with COVID-19, which gives new insights into this infection in our country.

Conclusion

We presented the first Bulgarian retrospective study on COVID-19 hospitalized patients. Our study estimated that older men with underlying hypertension, cardiovascular, malignant, and chronic kidney diseases with signs of dyspnea and nausea are at higher risk for severe clinical form. Significant abnormality in laboratory parameters—AST, creatinine, CRP, ferritin, fibrinogen, hemoglobin, LDH, lymphocyte percentage, and WBC were seen in severe group.

Footnotes

Authors' Contributions

G.T.P., M.B., and V.M.—study design, data collection, data interpretation, article preparation, literature search, and funds collection; V.V.—data collection and literature search; T.K.—statistical analysis. All authors read and approved the final version of the article.

Acknowledgments

We are grateful to all physicians, nurses, laboratory staff, and patients who participated in the study. We thank the staff of the Military Medical Academy, Sofia, Bulgaria for the medical care and treatment of the patients.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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