Submitted:
25 May 2026
Posted:
26 May 2026
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Abstract
Tuberculosis remains the world’s top fatal infectious disease, causing more than 1.5 million deaths globally annually, especially in low and/or middle-income countries. Greece, although still considered to be a low prevalence country according to the National and Global Report data, has experienced an epidemiological rise in the post covid era. A major limitation in the identification of the true epidemiological burden is the underreporting, especially of probable cases. The aim of this 4-year retrospective, epidemiological study was to record all newly diagnosed patients with active tuberculosis in a large, tertiary hospital of Northern Greece with their epidemiological and clinical characteristics. The temporal trend of newly diagnosed cases was identified and compared with the reports of the corresponding National Surveillance data. A total of 45 patients were identified with active tuberculosis in the years 2022-2025 with a mean symptom duration of 45 days prior to diagnosis. The patients were mostly adults (≥18 years, 74%), male (66%), of 39 years median age, and 67% natives, of Greek origin. In 38% of the patients the manifestations were exclusively extrapulmonary, more frequently so in the native population. Three strains (6,6%) were rifampicin resistant. This real-world epidemiological study provides a direct reflection of the presentation and prevalence of tuberculosis in the community, describes the clinical spectrum and the available diagnostic approaches, and identifies potential weaknesses of the Health Surveillance system.
Keywords:
tuberculosis
; epidemiology
; Greece
; pulmonary
; extrapulmonary
Introduction
Tuberculosis (TB) remains the leading cause of death from a single infectious agent worldwide, with the greatest burden occurring in low and/or middle-income countries [1]. Despite sustained global efforts to reduce TB incidence, the global burden of disease remains substantial, predominantly affecting socially and medically vulnerable populations such as immigrants, prison inmates and people living with HIV [1,2].
According to the latest WHO Global Tuberculosis Report, an estimated 10.7 million people developed TB in 2024, equaling to 131 incident cases per 100,000 population globally [1]. Most TB cases were accumulated in South-East Asia, the Western Pacific and Africa, with Europe contributing less to the total cases worldwide [1]. Nevertheless, TB continues to represent a significant public health challenge in the European region, with an estimated incidence in 2024 of 22 cases per 100,000 population [1]. As reported by the latest ECDC TB report [2], although most countries in the European Union/European Economic Area (EU/EEA) are classified as low-incidence settings, with notification rates below 10 per 100,000 population, TB remains a persistent concern in the region.
Data from 2021 ranked TB among the 10 leading causes of death worldwide [3]. Although the estimated number of TB deaths declined by 3% compared with 2023 and by 13.8% compared with 2021, in 2024 the mortality rate worldwide remains high [3]. Specifically, the number of TB-related deaths was 1.08 million among HIV-negative individuals, and 150,000 among people living with HIV, resulting in a total of 1.23 million deaths worldwide [3]. The European region accounted for 1.4% of these deaths [3].
Drug-resistant TB remains an additional and significant challenge for public health systems. Whereas the number of people infected by rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB) does not seem to have risen from 2020-2023 [4], TB resistance continues to be considered a global threat. Notably, nine countries within the WHO European Region are included among the 30 countries with the highest burden of RR/MDR-TB globally [2].
Greece remains classified as a low-incidence country according to both national and international surveillance data [5]. However, an epidemiological increase has been observed in the post-COVID era. In 2024, the estimated TB incidence rate in Greece was 3.82 cases per 100,000 population, with nearly half of cases occurring among immigrants [5]. A major limitation in the identification of the true epidemiological burden is the underreporting, especially of probable cases.
Tuberculosis presents with a broad clinical spectrum, ranging from pulmonary disease to extrapulmonary involvement of lymph nodes, central nervous system, bones and other organs. This heterogeneity may contribute to delayed recognition, particularly in low-incidence settings where clinical suspicion may be lower and extrapulmonary disease is often paucibacillary and diagnostically challenging [6]. Rapid molecular assays, including Xpert MTB/RIF-based platforms, have substantially improved the early diagnosis of Mycobacterium tuberculosis infection and the prompt detection of rifampicin resistance [7].
In this context, local hospital-based epidemiological studies may provide valuable complementary data to national surveillance systems. The present 4-year retrospective study aimed to record all newly diagnosed cases of active tuberculosis in a large tertiary hospital in Northern Greece, to describe their epidemiological and clinical characteristics, to assess temporal trends in newly identified cases, and to compare local findings with the corresponding national surveillance data.
Materials – Methods
This retrospective observational study included all patients diagnosed and treated for active tuberculosis at Hippokration General Hospital of Thessaloniki during the period 2022–2025. The ICD-10 discharge coding system was used to identify and record both probable and confirmed tuberculosis cases. A probable case was defined as a patient presenting with clinical symptoms and imaging findings suggestive of tuberculosis, a positive screening test (Purified Protein Derivative – PPD skin test or Interferon Gamma Release Assay – IGRA) and/or close contact with a confirmed case, in the absence of microbiological confirmation. A confirmed case was defined as a patient with laboratory confirmation of infection with Mycobacterium tuberculosis, based on culture or molecular methods. Patients’ data were collected including demographic characteristics (age, sex, nationality, etc), clinical presentation, localization of the disease, image findings and risk factors (e.g. immunosuppression and contact with a confirmed case). Treatment adherence, subsequent clinical course and follow-up were also noted. Resistance to first-line anti-tuberculosis drugs was additionally recorded, which was detected by molecular diagnostic methods and confirmed by standard microbiological techniques). The study period was divided in two intervals (2022-2023 and 2024-2025), to compare temporal trends.
All samples were analyzed in the same accredited laboratory (Molecular Department of the Microbiology Laboratory at Hippokration Hospital of Thessaloniki). Quantitative and qualitative values of the above parameters were manually entered into a Microsoft Excel® Datasheet, while risk perception data were analyzed using signed-rank tests, with a level of p<0.05 being statistically significant. Statistical analysis was performed using the IBM Statistical Package for Social Sciences (SPSS)® statistical software, version 23.0. Comparisons between variables were conducted using the chi square (x2) test and the independent samples – t-test, as appropriate. Correlations were assessed using Pearson’s or Spearman’s correlation coefficients, depending on the distribution and type of the variables. A two-tailed p-value <0.05 was considered statistically significant. The retrospective collection and usage of data were approved by the Ethics Committee of the Hippokration General Hospital of Thessaloniki (decision no:11/07/05/2026).
Results
A total of 45 patients were included (66% male, 26% children) The median age was 39 years (IQR 12.5–65.5). Approximately, one third of the patients (13/45, 28,9%) had been referred from other regional hospitals. The study population consisted of 66% patients of Greek origin, 13% of Asian origin, 11% from Africa and 10% from Eastern Europe. The mean duration of symptoms prior to admission was 45 days [ranging from 1 day to 8 months]. The most common presenting symptoms were fever (37%), cough (28%), and lymphadenopathy (17%). Hemoptysis, low back pain in patients with spondylodiscitis, and neurological symptoms in patients with central nervous system (CNS) infection were also reported.
Overall, 36 patients had confirmed infection either by GeneXpert MTB/RIF or by culture growth of Mycobacterium tuberculosis, while 9 patients had compatible clinical/laboratory findings and/or epidemiological data and received empirical anti-tuberculosis treatment with favorable response. The GeneXpert MTB/RIF method confirmed diagnosis in samples from sputum (n=13), cerebrospinal fluid (CSF) (3), gastric fluid (n=6), pleural fluid (n=2), lymph node biopsies (n=7), and other tissues (n=2). Characteristics of the patients are included in Table I. No significant differences were observed between the patients included in the two different time periods of the study, except for the % of positive sputum samples between the two cohorts.
In total, 62% of patients (28/45) had pulmonary disease, 6 of which also presented with extrapulmonary tuberculosis and 38% had exclusively extrapulmonary disease. Tuberculous lymphadenopathy accounting for 58% of extrapulmonary cases. In particular, 10 patients presented with tuberculous lymphadenopathy, 4 with tuberculous pleural effusion, 4 with spondylitis, 5 with tuberculous meningitis, and 2 with peritonitis. Extrapulmonary tuberculosis was more frequently encountered in local patients (10/18=55,6% vs 5/17=29,4%). Most patients underwent chest CT, with the most common findings being cavities, nodules, pulmonary infiltrates, and pleural effusion. Cavitation on chest CT, which is a radiographical feature associated with more advanced disease and increased transmission potential, was identified in 21% of patients with pulmonary disease.
Eight patients had close contact with a confirmed case, and 3 had a history of prior tuberculosis. Eleven patients (24%) had a history of immunosuppression, mainly due to HIV infection (4 patients) and anti-TNF therapy (3 patients). Resistant strains were identified in 5 cases (11%), including 3 cases of rifampicin-resistant TB (RR-TB), 1 case of isoniazid-resistant TB (R-INH TB), and 1 case of resistance to isoniazid, ethambutol and streptomycin (R-INH/ETH/STREP). These resistance rates slightly diverge from national data from the Hellenic National Public Health Organization (EODY), which report rifampicin resistance (RR-TB) at 0.04%, multidrug resistance (MDR-TB) at 3%, and extensively drug-resistant TB (pre-XDR and XDR) at 0.6%. This may be due to the underreporting and/or the smaller size of the sample. Two patients died, and two were lost to follow-up.
Importantly, there was a noticeable increase in diagnosed cases over the study period, from 9 cases in 2022 to 16 cases in 2025, showing a steady upward trend (Figure Ia). It is also noteworthy that, over time, tuberculosis in the Greek population mainly affects older individuals, whereas in the foreign population it predominantly affects young adults (Figure Ib).
Discussion
According to the Greek National Health Surveillance reports, the incidence of TB remains low, <5 cases in 100,000 inhabitants, despite a recorded rising trend in the post pandemic era (National Health Surveillance Organization, Epidemiological Report 2024). However, the continuous underreporting of the disease, especially the “probable” cases, as detected through electronic drug prescription, hampers accurate estimation of the true epidemiological burden of the disease, which may be significantly higher [8]. Undernotification may occur even more frequently among migrating populations, where incidence is expected to be even larger.
In the post-pandemic period, (2022-2025), 45 patients were diagnosed in Hippokration Hospital with active tuberculosis, with a gradual increase in case numbers (9, 7, 13 and 16 respectively). In agreement with the National Surveillance data, the cases among immigrant/refugees slightly exceeded those among natives. The immigrants/ refugees were, more often, of Asian origin, followed by Africans and Eastern Europeans [9]. The diagnosed native patients were usually either elderly or children, in contrast to the non-native ones which were most often young adults. Among 45 patients in our cohort, 17 (38%) had only extrapulmonary tuberculosis, compared to 170 of 1213 patients (14%) in National Surveillance data. This corresponded to a significantly higher proportion in our cohort (38% vs 14%, p <0.0001). As it was not possible to determine whether all cases from our cohort were included in the national dataset, the comparison should be interpreted with caution. Nonetheless, the magnitude of difference suggests a substantially higher burden of extrapulmonary disease in our population.
This report, besides confirming the mainstay epidemiological data of tuberculosis in Greece, provides clinical information on the diversity of the disease’s clinical presentation, and shows a rising trend of non-typical forms of the disease in low-incidence settings, similar to other reports [10]. Extrapulmonary tuberculosis is more difficult to diagnose and confirm with microbiological methods [11,12]. It is thus associated with less diligent reporting. Extrapulmonary forms of the disease usually represent reactivation of latent disease and often result from severe immunosuppression. Moreover, extrapulmonary tuberculosis is associated with higher utilization of healthcare systems, prolonged treatment regimens, higher healthcare-associated charges and higher risk of mortality [13]. The relative ratio of immunosuppressed patients was higher than previous reports (24%) reflecting the increased implementation of novel immunomodulating therapies [14]; however, successful treatment rates (91.1%) were comparable to the standards set by the World Health Organization [15]. Overall, this study provides a real-world snapshot of tuberculosis in a tertiary care setting in Greece and underscores the need for improved surveillance systems, particularly regarding extrapulmonary and clinically diagnosed cases.
Funding
The authors received no financial support for the research, authorship, and/or publication of this; Article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
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Table I.
Patient characteristics.
| Patient characteristics | 2022-2023 (n=16) |
2024-2025 (n=29) |
Total (n=45) |
p |
|---|---|---|---|---|
| Age(years; mean) | 40.7 (SD 29.1) | 40.2 (SD 27.9) | 40.6 | 0.955 |
| Male gender(n; %) | 9 (56,3%) | 21 (72,4%) | 30 | 0.31 |
| Native origin (n; %) | 10 (62.5%) | 20 (69%) | 30 | 0.75 |
| Positive GeneXpert (n; %) | 11 (68.8%) | 22 (75.9%) | 33 | 0.73 |
| Positive Culture (n; %) | 1 (6.3%) | 2 (6.9%) | 3 | 1.00 |
| Probable (n; %) | 4 (25%) | 5 (17.2%) | 9 | 0.70 |
|
Tested biological sample (n; %) Sputum Gastric fluid Pleural fluid Lymph node biopsy Other |
12 (75%) 1 (6.3%) 1 (6.3%) 2 (12.5%) 2(12.5%) |
7 (24.1%) 6 (20%) 2 (6.9%) 4 (13.8%) 4 (13.8%) |
19 7 3 6 6 |
0.002 0.36 1.00 1.00 1.00 |
| Pulmonary (n; %) | 11 (68.8%) | 17 (58.6%) | 28 | 0.53 |
| Extrapulmonary (n; %) | 5 (31.3%) | 12 (41.4%) | 17 | 0.53 |
| Disseminated (n; %) | 2 (12.5%) | 5 (17.2%) | 7 | 1.00 |
| Immunosuppression (n; %) | 2 (12.5%) | 9 (31%) | 11 | 0.26 |
| Resistance to any drug (n; %) | 1 (6.3%) | 4 (13.8%) | 5 | 0.64 |
| Outcome (death) (n; %) | 0 | 2 (6.9%) | 2 | 0.53 |
The cohort was sub-divided into patients included during the first and the consecutive two years of the study (2022-2023 and 2024-2025) and their characteristics were compared. (n;number).
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