A Retrospective Look at Early COVID-19 Treatment and Outcomes in Two Tertiary Centers in Türkiye and Bosnia & Herzegovina

Abstract

During the early months of the COVID-19 pandemic, treatment protocols varied substantially among countries and even between hospitals. This study compared the clinical characteristics, management strategies, and outcomes of hospitalized COVID-19 patients treated in tertiary centers in Türkiye and Bosnia and Herzegovina. We retrospectively analyzed 1338 adults hospitalized with laboratory-confirmed SARS-CoV-2 infection: 657 patients in Tuzla (Bosnia and Herzegovina, June–December 2020) and 681 in İstanbul (Turkiye, April–May 2020). Demographic, clinical, and laboratory data, treatment details (including favipiravir use), need for invasive or non-invasive mechanical ventilation, and in-hospital mortality were extracted from medical records. Patients in Bosnia and Herzegovina were older (61.6 ± 14.4 vs. 56.9 ± 15.8 years; p < 0.001) and had longer hospital stays (9.0 ± 5.5 vs. 7.7 ± 6.1 days; p < 0.001). In the Bosnian cohort, leukocyte, neutrophil, platelet, ferritin, CRP, troponin, creatinine, AST, and ALT levels were significantly higher, whereas hemoglobin and D-dimer levels were lower. The need for ventilatory support was greater in Bosnia and Herzegovina (15.1% vs. 12.2%, p < 0.001), and overall mortality was higher (25.7% vs. 9.3%, p < 0.001). No mortality difference was observed between patients treated and not treated with favipiravir. Despite similar inclusion criteria, patients in Bosnia and Herzegovina exhibited more severe disease, greater organ involvement, and higher mortality than those in Turkiye. Favipiravir use did not influence survival. Inter-country comparisons highlight how differing patient profiles and treatment protocols may impact COVID-19 outcomes; however, interpretation should consider that the two centers contributed data from different phases of the 2020 pandemic, and that country-level differences in circulating variants, healthcare capacity, hospital strain, and evolving clinical guidelines may also have influenced the observed patterns.

1. Introduction

The COVID-19 pandemic created an unprecedented global health crisis, challenging healthcare systems, disrupting economies, and prompting rapid adaptation of medical practice worldwide. During the early months of 2020, healthcare providers faced a novel pathogen with limited scientific understanding, no proven antiviral therapy, and rapidly evolving guidelines [1]. Management strategies were largely empirical and varied widely among countries and institutions as clinicians relied on combinations of repurposed agents and supportive measures to manage severe respiratory failure and systemic inflammation [2,3].

Antimalarial and broad-spectrum antiviral drugs such as chloroquine, hydroxychloroquine, lopinavir/ritonavir, interferon-α, ribavirin, and remdesivir were widely tested under emergency use authorizations; however, subsequent evidence demonstrated limited or no mortality benefit for most of these agents [4,5]. The early therapeutic uncertainty reflected the scientific community’s urgent attempt to control a rapidly spreading disease before vaccines or specific antivirals became available. One of the drugs of interest was favipiravir (T-705), an orally available nucleoside analog that inhibits the viral RNA-dependent RNA polymerase, originally developed for influenza and later repurposed for emerging RNA viruses including SARS-CoV-2 [6]. It requires intracellular activation to its ribofuranosyl-triphosphate form, but its nonlinear pharmacokinetics and rapid metabolism via aldehyde oxidase often lead to declining plasma levels during therapy. These pharmacologic characteristics, combined with inconsistent antiviral efficacy, have made its therapeutic role in COVID-19 uncertain.

Beyond pharmacologic management, the pandemic exposed significant disparities in healthcare capacity, public health coordination, and population demographics across countries. Comparative epidemiologic analyses provide valuable insight into how these contextual differences influence disease severity, treatment approaches, and outcomes [7,8]. Collaboration between institutions from regions with differing healthcare resources, such as Turkiye and Bosnia and Herzegovina, offers an opportunity to evaluate how system-level and population factors shaped the course of COVID-19 and to draw lessons relevant for future global health emergencies.

This study aimed to compare demographic features, laboratory profiles, clinical presentation, treatment approaches, and outcomes of hospitalized COVID-19 patients treated in two tertiary centers, one in Turkiye and one in Bosnia and Herzegovina. Additionally, we examined the impact of favipiravir therapy on clinical course and mortality.

2. Materials and Methods

2.1. Study Design and Settings

This retrospective, dual-center observational study included adult patients hospitalized with confirmed SARS-CoV-2 infection in two tertiary institutions: the University Clinical Centre Tuzla (Bosnia and Herzegovina) and Gaziosmanpaşa Research and Training Hospital, İstanbul (Turkiye).

All laboratory measurements were performed in accredited hospital laboratories at each center using automated analyzers calibrated according to national internal and external quality assurance programs. In Turkey, measurements were obtained using the Roche Cobas 6000 c501 (Roche Diagnostics, Mannheim, Germany). In Bosnia and Herzegovina, hematology parameters were analyzed on the Sysmex XN-1000 (Sysmex, Kobe, Japan); routine biochemistry on the Alinity c-series (Abbott Laboratories, North Chicago, IL, USA); ferritin on the Advia Centaur XPT (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA); troponin on the Alinity i-series (Abbott Laboratories, Illinois, USA); and D-dimer on the Siemens BCS XP (Siemens Healthcare Diagnostics, Marburg, Germany). Although different platforms were used between sites, both laboratories adhered to standardized operating procedures for sample handling, processing, and reporting, minimizing the likelihood that inter-site analytical variation accounted for observed differences. Routine parameters (CBC, CRP, ferritin, D-dimer, troponin, creatinine, AST, ALT, LDH) were measured according to established institutional protocols and validated reference ranges.

2.2. Participants

In Tuzla, 657 patients were hospitalized between June and December 2020; in İstanbul, 681 patients were treated between April and May 2020. Inclusion criteria were: (1) age 18–80 years, (2) RT-PCR–confirmed SARS-CoV-2 infection, and (3) hospitalization during the study period. Exclusion criteria included pregnancy, lactation, documented contraindication to favipiravir, and incomplete medical records preventing reliable extraction of key clinical variables. Missing data were handled conservatively: patients lacking essential outcome information (mortality, ventilatory support status, or major laboratory parameters) were excluded, while minor missing laboratory values were analyzed on an available-case basis without imputation. This approach ensured standardized diagnostic definitions and minimized bias across centers.

This study used a retrospective convenience sampling approach, including all eligible adult patients hospitalized during each center’s major COVID-19 admission period. No predetermined sample size was set, as the objective was to capture the full real-world hospitalized population during each site’s initial epidemic surge.

All patients included presented to the hospital with symptomatic SARS-CoV-2 infection and were admitted specifically for COVID-19 management. Patients who acquired COVID-19 during hospitalization (nosocomial infections) were excluded. Only community-acquired, RT-PCR–confirmed cases were eligible. Comorbidities and baseline conditions (e.g., hypertension, diabetes, heart failure, COPD) were recorded and incorporated into descriptive and regression analyses; however, broader assessments of pre-existing health status or functional capacity were not used as inclusion criteria due to limitations inherent to retrospective data collection.

2.3. Treatment Protocols

Standard supportive care followed national COVID-19 guidelines in each country. When administered, favipiravir was given at a loading dose of 1600 mg twice on day 1, followed by 600 mg twice daily for 9 days, alongside standard therapy. Concomitant therapies, including systemic corticosteroids, hydroxychloroquine (Plaquenil), and tocilizumab, were recorded for all patients. Treatment decisions were made at the discretion of attending physicians based on national protocols at the time.

2.4. Data Collection

Data were extracted from electronic medical records using a standardized template shared between centers. Collected variables included demographics (age, sex, BMI), vital signs at admission, presenting symptoms, comorbidities, and laboratory parameters including complete blood count, CRP, ferritin, D-dimer, troponin, creatinine, AST, ALT, and LDH. Outcomes included need for non-invasive or invasive mechanical ventilation (NIMV/IMV), length of stay, and in-hospital mortality.

2.5. Statistical Analysis

Statistical analyses were performed using IBM SPSS Statistics version 23. Continuous variables are reported as mean ± standard deviation (SD) or median [interquartile range, IQR], and categorical variables as counts (percentages). Between-group comparisons used Student’s t-test or Mann–Whitney U test for continuous variables and χ² or Fisher’s exact test for categorical variables. Binary logistic regression was used to identify independent predictors of mortality. A two-sided p-value < 0.05 was considered statistically significant.

3. Results

3.1. Demographic and Clinical Characteristics

A total of 1338 patients were analyzed: 657 from Bosnia and Herzegovina and 681 from Turkiye. Patients in Bosnia and Herzegovina were significantly older and had higher baseline blood pressure (

Table 1. Comparison of age and hemodynamic parameters of two groups.

Variable	Bosnia and Herzegovina (n = 657)	Türkiye (n = 681)	p Value	OR, 95% CI
Age (years)	61.6 (14.4)	56.9 (15.8)	<0.001	—
Male sex, n (%)	344 (52.3)	338 (49.7)	0.42	—
Systolic BP (mmHg)	123.6 (22.9)	116.6 (19.1)	0.005	—
Diastolic BP (mmHg)	78.8 (11.3)	72.0 (14.0)	<0.001	—
Length of stay (days)	9.0 (5.5)	7.7 (6.1)	<0.001	—
Mortality	169 (25.7%)	63 (9.3%)	<0.001	3.40 (2.48–4.64)

Data are presented as mean (standard deviation) or total (%).

).

3.2. Laboratory Findings

Patients from Bosnia and Herzegovina showed significantly higher leukocyte, neutrophil, platelet, ferritin, CRP, troponin, creatinine, AST, and ALT levels, while hemoglobin and D-dimer were lower (

Table 2. Selected laboratory parameters at admission.

Parameter	Bosnia & Herzegovina	Türkiye	p Value
Hemoglobin (g/dL)	12.4 (2.3)	13.3 (1.7)	<0.001
WBC (×103/µL)	8.82 (2.0)	6.82 (3.1)	<0.001
Neutrophils (×103/µL)	6.34 (4.7)	4.91 (3.0)	<0.001
Platelets (×103/µL)	243 (113)	210 (76)	<0.001
Ferritin (µg/L)	838 (1301)	308 (782)	<0.001
CRP (mg/L)	81.3 (77.5)	60.8 (68.2)	<0.001
D-dimer (ng/mL)	1666 (1392)	2106 (4812)	0.021
Troponin (ng/L)	470.7 (4309)	19.0 (98)	<0.001
Creatinine (mg/dL)	1.28 (1.7)	0.9 (0.7)	<0.001
AST (U/L)	49.4 (69)	36.4 (38)	<0.001
ALT (U/L)	54.6 (61.6)	30.1 (51.1)	<0.001

Data are presented as mean (standard deviation).

).

3.3. Ventilatory Support and Outcomes

Inter-country comparisons showed that mortality was significantly higher in Bosnia and Herzegovina than in Turkiye (25.7% vs. 9.3%). The odds of in-hospital death were 3.40 times higher in Bosnia (OR 3.40, 95% CI 2.48–4.64). The need for mechanical ventilation was also higher in Bosnia (15.1% vs. 12.2%), although this difference did not reach statistical significance when quantified by effect size (OR 1.28, 95% CI 0.93–1.75).

3.4. Favipiravir Subgroup Analysis

Patients treated with favipiravir were more often male and had a higher prevalence of coronary artery disease or previous CABG/stenting, greater use of tocilizumab and hydroxychloroquine, and more frequent mechanical ventilation (

Table 3. Patient demographics, drug use, mortality and need for mechanical ventilation according to Favipiravir use.

Parameter	No Favipiravir (n = 1134)	Favipiravir (n = 204)	p Value	Odds Ratio (95% CI)
Sex, n (%)	590 (52.0)	124 (60.8)	0.021	1.43 (1.05–1.94)
Fever, n (%)	616 (54.3)	74 (36.3)	<0.001	0.48 (0.35–0.65)
Cough, n (%)	793 (69.9)	137 (67.2)	0.428	0.88 (0.64–1.21)
Dyspnea, n (%)	567 (50.0)	68 (33.3)	<0.001	0.50 (0.37–0.68)
GI symptoms, n (%)	103 (9.1)	10 (4.9)	0.048	0.52 (0.26–1.01)
Chest pain, n (%)	187 (16.5)	2 (1.0)	<0.001	0.05 (0.01–0.20)
Tachypnea, n (%)	191 (18.9)	43 (21.1)	0.466	1.32 (0.91–1.91)
Type 2 diabetes, n (%)	354 (31.2)	65 (31.9)	0.855	1.03 (0.75–1.42)
Hypertension, n (%)	555 (48.9)	90 (44.1)	0.204	0.82 (0.61–1.11)
CAD/CABG/Stent, n (%)	85 (7.5)	24 (11.8)	0.040	1.65 (1.02–2.66)
Heart failure, n (%)	106 (9.3)	7 (3.4)	0.005	0.34 (0.16–0.75)
Renal failure, n (%)	71 (6.3)	12 (5.9)	0.836	0.94 (0.50–1.76)
COPD, n (%)	74 (6.5)	11 (5.4)	0.541	0.82 (0.43–1.57)
Steroid use, n (%)	458 (40.4)	27 (13.2)	<0.001	0.23 (0.15–0.34)
Tocilizumab use, n (%)	7 (0.6)	50 (24.5)	<0.001	52.27 (23.28–117.35)
Hydroxychloroquine use, n (%)	473 (41.7)	195 (95.6)	<0.001	30.28 (15.36–59.68)
Mechanical ventilation, n (%)	83 (7.5)	75 (36.9)	<0.001	7.36 (5.13–10.57)
Mortality, n (%)	199 (21.0)	33 (16.2)	0.120	0.91 (0.61–1.36)

). However, mortality did not differ significantly between those treated and not treated with favipiravir (p = 0.12). Fever, dyspnea, gastrointestinal symptoms, and chest pain were less common in the favipiravir group.

4. Discussion

This bi-national retrospective comparison provides an important opportunity to understand how demographic structures, disease severity at presentation, and health-system preparedness shaped COVID-19 outcomes during the pandemic. Although COVID-19 is no longer a global emergency, such comparative analyses remain relevant because they highlight patterns that are transferable to future outbreaks, especially regarding how healthcare organization, early response, and population characteristics survival during large-scale health crises [9].

Our findings showed that hospitalized patients in Bosnia and Herzegovina were significantly older, had higher inflammatory and cardiac biomarkers, and experienced longer hospitalizations and higher mortality than patients in Turkiye. These differences likely reflect a combination of factors: an older population structure, delayed presentation, differences in access to critical care, and variations in national treatment algorithms. Elevated CRP, ferritin, and troponin levels in the Bosnian cohort indicate more advanced systemic involvement at admission, well-known predictors of poor prognosis in COVID-19 [10].

Mortality in Bosnia and Herzegovina (25.7%) was nearly threefold higher than in Turkiye (9.3%), a pattern consistent with previous studies showing wide variability in COVID-19 fatality rates across Europe and the Middle East [11,12]. This heterogeneity has been linked not only to age and comorbidity burden but also to healthcare system capacity and timing of epidemic peaks. A regional analysis from the Federation of Bosnia and Herzegovina estimated about 12,000 excess deaths between 2020 and 2022, approximately 20% higher than expected mortality, with the highest rates in adults aged 45–74 years and in males [13]. Similarly, surveillance data from Federation of Bosnia reported over 249,000 confirmed cases and 8845 deaths in the same period, reflecting the substantial burden in this population [14]

National-level studies from Turkiye also showed relatively lower in-hospital mortality across diverse clinical settings. For example, a multicenter study of 1500 patients from 26 Turkish centers reported a mortality rate of 4.5%, with independent predictors including male sex, severe pneumonia, multiorgan dysfunction, malignancy, sepsis, and interstitial lung disease [15]. In a much larger registry (CORONATION-TR) of 60,980 hospitalized patients, mortality was 4.0%, and key predictors included older age, elevated CRP, higher neutrophil-lymphocyte ratio, creatinine, low albumin, D-dimer, pneumonia on CT, diabetes, and heart failure [16]

Beyond patient-level characteristics, differences in national health care capacity likely contributed to the mortality gap observed between Bosnia and Herzegovina and Turkiye. Early in 2020, Bosnia and Herzegovina faced major constraints in ICU availability, staffing ratios, and access to high-flow oxygen and advanced respiratory support, which may have result to later presentation and more advanced disease at admission. Reports from the period also describe uneven testing capacity and delays in diagnostic confirmation, further affecting timely escalation of care. In contrast, Turkiye entered the pandemic with a comparatively larger ICU bed capacity per capita, a more centralized procurement and triage systems, and broader access to early testing. These system-level factors, combined with different surge timings, likely influenced the severity profile of hospitalized patients and help contextualize the higher mortality observed in the Bosnian cohort. This interpretation aligns with cross-country analyses showing that health-system indicators [17] together with demographic, socio-economic and political-legal characteristics, explain much of the marked global variation in COVID-19 morbidity and mortality [18].

Despite initial optimism, favipiravir therapy offered no survival benefit in our study. This result aligns with systematic reviews and meta-analyses that found favipiravir improved viral clearance and early clinical symptoms but did not reduce mortality or need for mechanical ventilation [19,20]. The likely explanation is that antiviral efficacy diminishes once patients progress to the hyperinflammatory stage of disease. Nevertheless, including favipiravir data in our analysis provides valuable retrospective context for evaluating early antiviral strategies and highlights the importance of rapid trial construction during emerging pandemics.

Although COVID-19 itself is no longer a dominant clinical concern, the lessons from this analysis are broadly relevant. The striking mortality difference between Bosnia and Herzegovina and Turkiye demonstrates that viral pathogenicity alone does not determine outcomes; contextual factors such as health-system resilience, ICU preparedness, and coordinated national response are equally decisive.

These results align with the observation that the healthcare absorptive capacity and the ability of a system to accommodate surges without collapsing is strongly correlated with survival, especially in ageing societies. Strengthening emergency preparedness, rapid data sharing, and cross-border collaboration are therefore crucial steps for mitigating mortality in future outbreaks [21]. Our experience also reinforces the value of international cooperation where partnerships between countries of different resource levels enabled mutual learning, quicker evaluation of therapeutic strategies, and more adaptive responses.

Strengths and Limitations

While health-system capacity and disease severity at presentation likely contributed to inter-country differences, additional unmeasured factors may also have played a role. Baseline population health, genetic background, patterns of chronic disease, socioeconomic status, occupational exposure risk, and health-seeking behavior differ between Bosnia and Herzegovina and Turkiye and may influence immune response, inflammatory markers, and clinical trajectory [22,23]. Although both laboratories followed accredited protocols, minor inter-assay variability between centers cannot be completely excluded. These factors, together with environmental and demographic differences, underscore the complexity of comparing real-world cohorts across countries and represent inherent limitations of retrospective observational research.

A major strength of this study is the use of a large, real-world dataset from two distinct healthcare environments using standardized outcome definitions. The dual-center design allowed for meaningful cross-national comparison. However, limitations include the retrospective design, differences in study periods corresponding to distinct epidemic phases, and lack of detailed variant information. The broader inclusion window in Tuzla (June–December 2020) and the shorter window in İstanbul (April–May 2020) reflect the different timing and magnitude of pandemic waves in each country rather than intentional sampling differences. İstanbul experienced an early and concentrated surge in spring 2020, resulting in a large number of admissions over a short period, whereas Tuzla’s first substantial wave was more prolonged. Including all eligible patients during each site’s peaks minimized selection bias and preserved the comparability of clinical and outcome data. Treatment protocols evolved rapidly throughout 2020, and our results may not reflect subsequent therapeutic improvements. In addition, unmeasured socioeconomic and policy factors, such as timing of lockdowns and vaccine introduction, may have influenced outcomes.

Because the study draws data from a single tertiary center in each country, the findings may not fully represent national-level patterns, and some interpretations should be viewed as contextual rather than definitive. Future pandemic responses should prioritize harmonized protocols, early triage, and data integration across borders. Comparative analyses such as ours can help policymakers identify structural vulnerabilities and guide preparedness planning.

Beyond COVID-19, these findings contribute to the broader field of pandemic systems epidemiology, demonstrating that successful management depends as much on governance and logistics as on pharmacologic innovation. Applying these lessons can improve resilience against future emerging infections.