Complicated community-acquired pneumonia in children—a retrospective cohort study from a tertiary care center in Southeastern Serbia

Introduction

Background

Community-acquired pneumonia (CAP) is one of the most common infectious diseases in children and a leading cause of hospitalization worldwide (1,2). While many cases of CAP resolve with appropriate treatment, some children develop complications that require more intensive medical care.

Complicated community-acquired pneumonia (CCAP) refers to cases involving severe local complications, such as parapneumonic effusion, necrotizing pneumonia, empyema, and lung abscess, often accompanied by a systemic response (3). These complications can prolong illness, increase hospital stays, and necessitate advanced interventions such as drainage procedures, prolonged antibiotic therapy, or even surgical management, occasionally leading to permanent lung damage.

The causes of CCAP most commonly involve bacterial species from the genera Streptococcus and Staphylococcus, as well as atypical pathogens, primarily Mycoplasma pneumoniae. In recent years, the emergence of antibiotic-resistant strains has further complicated treatment strategies. Additionally, viral pathogens have been identified in some cases (4), suggesting that viral infections may play part in the disease pathogenesis or predispose children to secondary bacterial infections.

Radiological imaging has a crucial role in diagnosing CCAP and assessing disease progression. Chest X-ray remains the standard initial imaging modality. However, concerns about radiation exposure have led to increased use of ultrasound as a viable alternative, especially for evaluating parapneumonic effusions and pleural involvement. Computed tomography (CT) is reserved for complex cases, primarily aimed at assessing potential complications.

Most existing studies on CCAP originate from high-income countries (3), while data from Southeastern Europe and other regions with comparable healthcare contexts remain scarce. Yet particularly in such settings, CCAP often presents additional challenges, including limited access to imaging and microbiological diagnostics, alongside heterogeneous and constrained treatment approaches. Studies from middle-income regions, such as report from Ecuador (5) describe a CCAP prevalence approaching 30% among hospitalized children and mortality rates of around 8%, underscoring the substantial burden in resource-restricted environments. These findings highlight the need for region-specific analyses to better characterize the patterns and distribution of the disease, patient characteristics, and outcomes of CCAP. Early recognition and prompt management are essential to improving outcomes and preventing long-term complications, reinforcing its relevance as a pediatric emergency. Broader availability of advanced imaging modalities and microbiological diagnostics, together with evolving treatment guidelines, has the potential to meaningfully enhance early diagnosis and management worldwide.

Objective

This study aims to explore the epidemiology, clinical presentation, diagnostic approaches, and treatment options for CCAP in pediatric patients, providing insights into best practices for optimal patient care. We present this article in accordance with the STROBE reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-25-86/rc).

Methods

This retrospective observational cohort study was conducted at Clinic of Pediatrics, University Clinical Center Niš, Serbia, which has an annual inpatient volume of approximately 4,000–5,000 admissions and a catchment population of roughly 260,000–270,000 children. The study period covered patients admitted between January 2016 and December 2024 with a diagnosis suggestive of CCAP. Children aged between 1 month and 18 years with clinically and radiologically suspected CCAP were screened. Patients were excluded if their final diagnosis did not correspond to CCAP. Specifically, four patients were omitted, three due to malignant pleural effusion, and one due to a primary surgical thoracic condition.

Medical records were reviewed to collect demographic data, clinical characteristics, vaccination status, and relevant laboratory and radiological findings. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the University Clinical Center Niš, Serbia (under request number 33871, with approval number 37365/16). As this was a retrospective study using fully anonymized data, informed consent was waived. Weight was recorded and nutritional status was assessed using Centers for Disease Control and Prevention and World Health Organization growth charts (6,7), classifying patients as undernourished (<5th percentile), overweight/obese (>95th percentile), or normal weight (5th–95th percentile). Microbiological data included blood, pleural fluid, and aspirate/nasopharyngeal swab cultures, serology for atypical pathogens (Mycoplasma pneumoniae, Chlamydia pneumoniae), and viral polymerase chain reaction (PCR) testing when available. The number of samples and positive findings were recorded. Data on imaging procedures and therapy prior to and during hospitalization were collected as well.

We also developed a disease severity classification that considered not only the duration of hospitalization but also the potential transfer of patients to higher-level healthcare facilities. Furthermore, the need for oxygen therapy and pleural drainage as an invasive procedure were also taken into account. Hospitalization lasting 14 or more days, oxygen therapy, and pleural drainage were each assigned 1 point, while patient transfer was assigned 2 points. A score of 0 indicated mildly severe CCAP, scores of 1 and 2 indicated moderately severe CCAP, and scores of 3 or 4 indicated very severe CCAP. Such categorization enabled statistical analysis of disease severity and its association with various clinical parameters. It was not designed as a prognostic or diagnostic scoring system, but rather as a pragmatic grouping tool to enable more structured comparison of clinical and laboratory data. The classification was based on objective indicators of disease course that reflect treatment intensity rather than serve as predictive criteria.

Given the retrospective design of the study, some degree of misclassification or missing data can never be excluded. Weight was unavailable for two patients, vaccination records were missing for one patient, and both C-reactive protein (CRP) and leukocyte results were missing for one patient. Observer bias was reduced by having investigators extract the data using consistent criteria based on clinical and radiological characteristics. No imputation was performed for missing values.

Statistical analysis

Data are presented as mean ± standard deviation (SD) or median with interquartile range (25th–75th percentile) for continuous variables, and as frequencies and percentages for categorical variables. Comparisons of continuous variables between two groups were conducted using the Mann-Whitney U test (U statistic). For comparisons among three groups, the Kruskal-Wallis test was applied (H statistic, df = degrees of freedom), followed by post-hoc pairwise comparisons using Dunn’s test (z statistic) with Bonferroni correction where appropriate. Associations between categorical variables were evaluated using the Chi-squared test (χ²) and post-hoc analysis involved examination of standardized residuals (SR) to identify which specific groups contributed to the association. Correlations between examined variables and disease severity were assessed using Spearman’s rank correlation coefficient (ρ), with corresponding 95% confidence intervals (CIs) and P values reported. Statistical significance was set at P<0.05 (two-tailed). All analyses were performed using R software, version 3.0.3.

Results

A total of 52 patients were included in the study (Figure 1), comprising 27 females and 25 males. The average annual incidence was estimated at 2.2 cases per 100,000 children per year. Total incidence accumulated over the entire study period was 19.8 per 100,000 minors within the catchment population. Annual case numbers varied (Figure 2), with the peak observed in 2018 (13 cases) and the lowest in 2016 and 2020 (2 cases each). Seasonal analysis showed a predominance of cases during colder months, particularly in December followed by November, and with an unexpected peak also noted in June (Figure 3).

Figure 1 Flowchart of participant selection. CCAP, complicated community-acquired pneumonia.

Figure 2 Annual distribution of complicated community-acquired pneumonia cases in children from 2016 to 2024.

Figure 3 Monthly distribution of complicated community-acquired pneumonia cases in children from 2016 to 2024.

The median age of affected patients was 77 months (interquartile range: 33.5–130.5 months), while the mean age was slightly higher at 87.7 months (SD ±65.2 months), reflecting a skewed distribution with several older patients. Age distribution showed that 21 patients were aged 3 years or younger, 18 patients were between 4 and 10 years old, and 13 patients belonged to the pubertal age group (11 years and older).

The average hospital stay was 14 days (minimum 1 days, maximum 49 days). There was no statistically significant difference in hospital stay duration based on gender (U=366.5, P=0.60) or age group (H=0.838, df =2, P=0.66). However, it should be noted that some patients were transferred to higher-level centers. To address this situation, we utilized the previously described disease severity categorization. Even with such approach, statistical analysis did not reveal a significant association between gender (χ²=1.881, P=0.39) or age group (χ²=1.693, P=0.79) and the severity of pneumonia. Similarly, weight does not appear to significantly affect disease severity (χ²=2.367, P=0.67). In terms of nutritional status, the majority of patients were of normal weight (n=36, 69.2%), 5 (9.6%) were undernourished, and 9 (17.3%) were classified as obese. For two patients weight data were not found. Vaccine status against Streptococcus pneumoniae was not significantly associated with disease severity (U=146.6, P=0.07). Regrettably, only 21.5% of patients were vaccinated, likely reflecting the relatively recent introduction of mandatory pneumococcal vaccination in Serbia in 2018. Patient baseline characteristics are summarized in Table 1.

Among the laboratory parameters analyzed, both leukocyte count and CRP levels were available for 51 patients. The mean leukocyte count was 15.6×10⁹/L (SD ±7.6×10⁹/L). The mean CRP concentration measured 141.6 mg/L (SD ±126.7 mg/L), spanning from 2.4 to 438.8 mg/L. Spearman’s rank correlation was performed to evaluate the monotonic relationship between severity rank and leukocyte count. The correlation coefficient was ρ=0.198 (95% CI: −0.082 to 0.449, P=0.16), suggesting that a positive correlation exists between specific groups, although the overall monotonic trend across all severity levels did not reach statistical significance. In contrast, CRP levels showed a significant positive correlation with increasing disease severity (Spearman’s ρ=0.451, 95% CI: 0.200–0.646, P<0.001). The Kruskal-Wallis test revealed statistically significant differences in both CRP levels (H=10.283, df =2, P=0.006) and leukocyte counts (H=7.322, df =2, P=0.02) across the three pneumonia severity groups (mildly severe, moderately severe, and very severe CCAP). Post-hoc analysis using Dunn’s test for CRP levels showed that children with mildly severe pneumonia had significantly lower CRP values compared to those with very severe complicated pneumonia (z=−3.177, P=0.001). However, no significant differences were found between mildly and moderately severe pneumonia (z=−1.863, P=0.06), nor between moderately severe and very severe complicated pneumonia (z=−1.795, P=0.07). Regarding leukocyte counts, Dunn’s post-hoc analysis indicated that children with mildly severe pneumonia had significantly lower leukocyte values than those with moderately severe pneumonia (z=−2.660, P=0.008; Bonferroni-corrected P=0.02). No significant differences were observed between the mildly and very severe groups (z=−0.797, P=0.42), nor between the moderately severe and very severe groups (z=1.396, P=0.16).

The average duration of symptoms before hospitalization was 8 days, with the longest recorded period being 40 days. One patient was diagnosed during a routine medical check-up without prior symptoms, based solely on laboratory and radiological findings. A total of 71.5% of patients had been started on antibiotic therapy prior to admission.

All patients underwent chest X-ray. Additionally, ultrasound was performed in 35 patients (67.3%), while CT scans were conducted in 17 patients (32.7%). A Chi-squared test of independence was conducted to examine the relationship between disease severity and the utilization of CT scans. The results indicated a significant association between disease severity and CT scan usage (χ²=12.601, P=0.002). Post-hoc SRs indicated that patients with severe disease were more likely to undergo CT imaging (SR =2.798), whereas those with mild disease were less likely to receive it (SR =–3.035). No significant difference was found for patients with moderate disease compared to the others. Complementary Spearman’s rank correlation, treating disease severity as ordinal and CT scan usage as binary, confirmed a positive relationship (ρ=0.407, 95% CI: 0.180–0.603, P<0.001), indicating that higher disease severity was correlated with increased likelihood of CT imaging. Between-group comparisons demonstrating significant differences across disease severity categories are presented in Table 2, while correlation analyses with corresponding 95% CIs and P values are shown in Table 3.

Considering all microbiological investigations, positive findings were obtained in 23 patients, among whom 7 had mixed infections with more than one isolated pathogens. The most frequently isolated pathogens were Mycoplasma pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae. Detailed results of all microbiological tests and pathogens isolated are presented in Table 4.

Antibiotic therapy prior to hospitalization was administered in 37 patients. When hospitalized, all 52 patients received intravenous antibiotics for an average of 12 days, followed by an additional 7–10 days of oral therapy in most cases. The use of corticosteroids was recorded in 38 patients, accounting for approximately 73% of the cases. Oxygen therapy was required in 17 patients, all of whom received low-flow oxygen for an average duration of 5 days. Pleural drainage was performed in 18 patients, and intrapleural fibrinolysis was applied in 9 of these cases. Additionally, in total, 6 patients were referred to a higher-level surgical center for further management.

Discussion

Pneumonia, although often perceived as a highly alarming diagnosis by parents, remains one of the most common reasons for hospitalization in pediatrics. For pediatricians, its high prevalence makes it a daily encounter, and in the majority of cases, it presents as a straightforward, almost tediously ordinary condition. Yet, CAP remains the leading cause of pediatric mortality outside the neonatal period worldwide, particularly in children aged 1 to 59 months, and continues to rank among the most common causes of serious illness and death in older children (8,9). This becomes especially evident in the setting of CCAP, where the disease deviates from its usual course. With that in mind, it is concerning that reports increasingly point to a sustained, or even rising incidence of CCAP, despite significant advancements in diagnostic methods, treatment strategies, and preventive measures (10-13). In our cohort, the average annual incidence was 2.2 per 100,000, whereas the total incidence accumulated over the entire study period was 19.8 per 100,000, figures that, despite appearing low, represent a meaningful clinical burden given the severity and treatment demands of these cases.

The number of cases fluctuated over the study period, with the highest incidence coinciding with the year Serbia introduced mandatory pneumococcal vaccination. Similar patterns of fluctuation have been reported in related studies from Poland and Romania (10,14). The coronavirus disease 2019 (COVID-19) pandemic undoubtedly played an important role in the frequency of CCAP (4), which is especially evident in year 2020, its first year, when strict lockdown and isolation measures were in place. It was followed by a rise in case numbers, that, in our center, has remained elevated since.

As expected, the majority of admissions occurred during the colder months, a seasonal distribution pattern consistent with findings reported by other authors (14-16). Conversely, the summer months are typically associated with a lower patient load. The unusually high number of cases recorded in June in our cohort may potentially be explained by methicillin-resistant Staphylococcus aureus (MRSA)-related infections (17). Still, broader studies with larger sample sizes are needed to confirm these seasonal trends and pathogen-specific associations. Continued surveillance and large-scale multicenter studies will be essential for a better understanding of the epidemiology.

CCAP is typically observed in younger children, with the average age of affected patients around 4 years (18,19). The mean and median age of our patients was slightly higher, though accompanied by considerable variation reflected in a high SD. This may be linked to the frequent isolation of Mycoplasma pneumoniae, a pathogen more commonly affecting older children (20). However, when cases were stratified by age groups, it became clear that the most vulnerable population, namely infants and toddlers, remained the most frequently affected.

Length of hospitalization is an important indicator of both disease severity and the burden placed on patients, families and the healthcare system. In neighboring Romania, the reported average hospital stay for CCAP is 16.7 days (14), while a 2022 study from Turkey reported 19.7 days (21). Even in higher-income countries like Israel (11), durations similar to ours were observed, while couple of days shorter stays are reported in Canada (22). In our cohort, the length of hospitalization did not significantly differ by sex or age group. This suggests that while younger children are generally more susceptible to severe disease, once complications arise, the impact on the clinical course is comparable across the all groups. In addition, neither length of hospitalization nor patient sex or age showed a significant correlation with disease severity, as assessed by our severity ranking. Nutritional status also did not emerge as a potential risk factor influencing disease severity in our cohort. This contrasts with findings from Iran and a recent study from Egypt, where malnourished children accounted for between one fourth and one fifth of all hospitalized cases (15,18). Notably, Ecuador have reported that more than 50% of patients were undernourished (5). A study from Afghanistan even identified malnutrition as a significant risk factor for fatal outcome in children with pneumonia (23). The relatively favorable socioeconomic conditions in our country and smaller territory which enables easier and more consistent access to healthcare services likely serve as protective factors, mitigating the impact of malnutrition on disease severity. Notably, in our study, although the majority of patients were well-nourished, among those with nutritional imbalances, obesity was twice as common as undernutrition. Given the global shift toward increasing rates of childhood obesity, special attention should be directed toward this population in the future. It may even be justified to consider including CCAP among the long and growing list of potential complications associated with pediatric obesity.

Pneumococcal vaccination status also was not associated with disease severity. Although the P value (0.07) was marginally above the threshold of 0.05, suggesting a trend toward significance, the difference between vaccinated and unvaccinated patients was not statistically significant. Given that mandatory pneumococcal immunization was introduced during the study period, and that vaccination coverage among our patients was low, with only about 20% having received the vaccine, adequate assessment of its impact on disease incidence and severity remains limited. Other studies have demonstrated that pneumococcal vaccination has altered the epidemiological landscape, reducing the frequency of invasive pneumococcal disease (3). However, breakthrough infections continue to be reported, and Streptococcus pneumoniae remains a leading cause of complicated pediatric pneumonia (24). Continued close monitoring will hopefully clarify the precise role of vaccination in shaping the occurrence and clinical course of CCAP.

On the other hand, statistical significance was observed among severity groups regarding CRP levels and leukocyte counts. According to our analysis, these basic laboratory parameters may serve as useful indicators in assessing disease severity and could aid in the early identification of complicated cases. Given their accessibility, low cost, and rapid turnaround time, these tests remain valuable tools in routine clinical decision-making, particularly in resource-limited settings. Our findings are consistent with those reported in other studies, which have similarly emphasized the diagnostic and even prognostic value of elevated inflammatory markers in complicated pneumonia (21,25-27). The observed leukocyte patterns, higher counts in moderately severe compared to mildly severe cases, but lower counts in the very severe group, may reflect the limited sample size but also a physiological leukopenic response in severely ill children, who may be unable to mount a proportional leukocyte response despite greater disease severity, emphasizing the need for cautious interpretation. Additionally, the absence of a significant overall correlation between leukocyte count and disease severity suggests that leukocyte levels alone have limited value as a universal severity marker, reinforcing the need to interpret them in conjunction with other clinical and laboratory indicators.

The average duration of symptoms prior to hospitalization among our patients was 8 days, slightly higher than what has been reported in other studies (10,25). Taking into account that our institution serves as a tertiary care center, such data are unsurprising. However, a substantial portion of these patients (71.5%) had already been started on antibiotics prior to admission, a finding aligning with results reported in another recent studies (18,22). These data highlight an important clinical consideration, that in cases where symptoms persist despite prior antibiotic use, particularly when inflammatory markers such as CRP and leukocyte count are elevated, clinicians should maintain a high index of suspicion for complicated pneumonia. In fact, one of the commonly accepted criteria for defining CCAP is the persistence of symptoms for three or more days without clinical improvement in spite of the therapy (3). Early recognition of this pattern is essential to prevent delays in diagnosis and appropriate management.

Radiological techniques are an indispensable part of a pediatric pulmonologist’s work. Chest X-ray, being convenient, easily accessible, and quick, remains the standard of care in CCAP diagnosis (28). Accordingly, all patients in our cohort underwent radiography. However, given the imperative in pediatrics to minimize radiation exposure, there is a growing emphasis on utilizing imaging modalities that are both safe and effective, most notably, lung ultrasound. With its increasing availability and expanding clinician experience, a growing number of patients are being diagnosed through this modality. On the other hand, the diagnostic superiority of CT over both X-ray and ultrasound is well established. Nevertheless, its high radiation dose remains a significant limitation, and thus CT should be reserved for selected, particularly complicated or diagnostically uncertain cases. Our findings support this principle since disease severity was significantly associated with the likelihood of undergoing CT imaging, suggesting that appropriate triage and clinical judgment were applied.

Aside from radiological imaging, microbiological findings provide valuable guidance to treating physicians. Unfortunately, ideal conditions for obtaining reliable microbiological data are rarely met in everyday clinical practice. As previously noted, the frequent use of antibiotics prior to hospitalization and consequently prior to microbiological sampling likely contributed to the low yield of positive cultures in our study, a limitation also acknowledged in a Lancet review (3). Furthermore, the relatively small number of samples taken, along with the frequent isolation of Staphylococcus epidermidis, a usual contaminant, suggest that the sampling and processing procedures should be better standardized. Finally, low- and middle-income countries face challenges related to limited access to advanced diagnostic methods, especially expensive molecular techniques. Between the identifiable pathogens, Mycoplasma pneumoniae was the most frequently diagnosed, which aligns with its known role in atypical pneumonia, particularly in older children, as reflected in our cohort. A substantial proportion of positive isolates were Staphylococcus aureus, making it, along with Streptococcus pneumoniae, one of the most commonly cultured bacteria among our patients. The role of viruses in the pathogenesis of CCAP remains under investigation, with respiratory syncytial virus and influenza virus most frequently implicated. In our study, rhinovirus was isolated in two patients, supporting literature that suggests its potential role in weakening host immunity and predisposing to bacterial superinfection (29,30).

The therapeutic approach to CCAP remains largely non-standardized on a global scale. Antibiotic therapy represents the cornerstone of treatment, and all patients in our center received appropriate antimicrobial coverage. However, when it comes to treatment duration, there is ongoing debate. Thus, microbiological findings play a crucial role in guiding both the choice and length of therapy. Oxygen supplementation is also frequently required and often correlated with disease severity and prognosis. One of the most controversial aspects of CCAP management is the use of corticosteroids. While some studies in adults with severe pneumonia suggest a beneficial effect, pediatric data are limited. Nonetheless, corticosteroids may shorten the duration of illness in children (3), which could explain why the majority of our patients received this form of therapy. Still, their use is not currently recommended for routine management of all CCAP cases. Another area of clinical uncertainty lies in the role of invasive procedures and adjunctive therapies such as fibrinolysis. Various studies have reported different protocols and outcomes, underscoring the lack of consensus on the optimal timing and indications for such interventions (3,31). According to published data, the reported frequency of invasive procedures with or without fibrinolysis varies significantly and typically tend to be more prevalent in developed countries (22) and markedly less common in economically constrained settings (5). Our data indicate that approximately one-third of patients required drainage, with about half of these receiving intrapleural therapy. This experience is consistent with findings reported by authors from Bulgaria (16). Such variations in treatment modalities reflect the absence of agreement among pediatric pulmonology authorities worldwide and emphasize the ongoing need for CCAP management guidelines.

Optimizing the management of pediatric CCAP requires structured protocols both prior to hospital admission and during hospitalization to ensure timely triage, early recognition of high-risk patients, and prompt in-hospital management. Systematic documentation of initial interventions, appropriate use of microbiological testing and simple laboratory analyses such as CRP and leukocyte counts, and judicious application of radiological techniques can guide clinical decision-making and escalation to advanced therapies when needed. Although formal guidelines for the use of corticosteroids or invasive procedures are lacking, decisions should be informed by current evidence and tailored to individual patients, particularly in complex cases. A multidisciplinary approach and integration of these insights into local protocols can strengthen evidence-based practice, especially in resource-limited or heterogeneous care settings. Lessons learned from local experiences may further inform the development of globally applicable, evidence-based recommendations.

Limitation

One of the main limitations of our work is its retrospective nature, which inherently carries the risk of missing or incomplete data and restricts analysis to only those variables previously recorded in medical documentation. Also, we recognize that our severity categorization has not been formally validated or compared with established scoring systems, thus it should not be interpreted as a verified severity score. Its purpose was purely analytical, to provide a pragmatic framework for within-cohort comparisons and facilitate subgroup analysis within the limitations of a retrospective dataset. The small sample size, particularly in the very severe group, limits statistical power and may have contributed to non-significant findings in some analyses, including post-hoc comparisons of leukocyte counts across the severity groups and vaccination effects. While modest, the study population reflects all pediatric patients with CCAP admitted to our tertiary center during the study period, providing a complete cohort and real-world perspective on this condition.

Conclusions

With all the above considered, we may finally conclude that this first study of its kind conducted in our region, provides an initial insight into the clinical, diagnostic, and therapeutic aspects of CCAP in children. As repeatedly emphasized throughout the discussion, and although it may sound like a common refrain in retrospective studies, there remains a clear and pressing need for broader, multicenter studies, ideally followed by prospective designs, to better understand this complex condition. Although the applied severity categorization provides useful insights into patterns of clinical management, future multicenter studies using validated pediatric pneumonia severity scores would be valuable to confirm these findings. Research efforts within our and multiple other centers aim to provide just that, a more comprehensive and up-to-date understanding of CCAP in pediatric populations.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-25-86/rc

Data Sharing Statement: Available at https://pm.amegroups.com/article/view/10.21037/pm-25-86/dss

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-25-86/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-25-86/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the University Clinical Center Niš, Serbia (under request number 33871, with approval number 37365/16). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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