
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12810-1
10.1016/j.heliyon.2024.e36779
e36779
Research Article
Comparative analysis of pediatric pulmonary and extrapulmonary tuberculosis: A single-center retrospective cohort study in Syria
Hamdar Hussein Hussein_hamdar14@hotmail.com
a⁎
Nahle Ali Alakbar Ali.AlAkbar.Nahle2001@gmail.com
a
Ataya Jamal dr.jamalataya@gmail.com
b
Jawad Ali dr.alijwd@gmail.com
a
Salame Hadi hadisalame9@gmail.com
a
Jaber Rida ridajbr303@gmail.com
a
Kassir Mohammad mkassir29122001@gmail.com
a
Wannous Hala hala.wannous@damascusuniversity.edu.sy
c
a Faculty of Medicine, Damascus University, Damascus, Syria
b Faculty of Medicine, University of Aleppo, Syria
c Pediatric Nephrology, Head of the Department of Pediatric Nephrology, Hemodialysis and Kidney Transplantation in Children's University Hospital, Faculty of Medicine, Damascus University, Damascus, Syria
⁎ Corresponding author. Faculty of medicine, Damascus University, Damascus, Syria. Hussein_hamdar14@hotmail.com
23 8 2024
15 9 2024
23 8 2024
10 17 e3677919 9 2023
21 8 2024
22 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Background

Tuberculosis (TB) is a global public health challenge, contributing significantly to morbidity and mortality worldwide. This research aims to investigate the epidemiology, clinical characteristics, diagnostic methods, and early mortality rate among pediatric patients with pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) who were admitted to a hospital in Syria.

Methods

This retrospective cohort study was conducted at the University Children's Hospital in Syria, involving pediatric patients diagnosed with TB between January 2013 and January 2023. Data were collected from medical records and encompassed socio-demographic characteristics, diagnostic methods, clinical presentation, chest radiography findings, and patient outcomes. Statistical analysis was performed using SPSS version 25.

Results

A total of 129 patients were included in the study, with 26.4 % diagnosed with PTB and 73.6 % with EPTB. The most common types of EPTB were lymphatic (25.6 %) and gastrointestinal (17.1 %). Patients with PTB and EPTB did not differ significantly in terms of age, weight, or gender. Significant cough was more common in PTB cases (67.6 %), while lymphadenopathy was more prevalent in EPTB cases (48.4 %). Chest X-ray abnormalities were found in 58.1 % of patients, with PTB patients more likely to have abnormal findings (97.1 %). Microbiological confirmation was higher in PTB cases (76.5 %) compared to EPTB cases (25.3 %). The overall mortality rate was 14 %, with higher mortality observed in patients with EPTB (16.8 %), particularly in cases of TB meningitis.

Conclusion

Our study highlights the epidemiological challenges of TB among hospitalized children, with a focus on the complexities of diagnosing and managing EPTB. We emphasize the urgent need for enhanced diagnostic and management strategies, particularly in conflict zones like Syria, where TB control efforts face significant obstacles. Prompt solutions are imperative to improve outcomes, given the high occurrence of EPTB and its associated mortality rates. Clinical recommendations stress the need for comprehensive contact histories and awareness of varied clinical presentations in pediatric TB diagnosis.

Keywords

Pulmonary tuberculosis
Extrapulmonary tuberculosis
Pediatric patients
==== Body
pmc1 Introduction

Tuberculosis (TB) continues to pose a significant worldwide public health challenge, impacting millions of individuals each year. It ranks as the second most prevalent infectious cause of mortality globally, trailing only COVID-19 (above the human immunodeficiency virus (HIV)) [1]. An estimated 2.7 million (2.5–3.0) people died globally from TB in 2020 and 2021 combined, compared to 15.9 million (14.7–17.2) deaths that were due to COVID-19 [2,3]. According to estimates, approximately quarter of the global population is believed to be infected with Mycobacterium tuberculosis [1]. As per the World Health Organization's (WHO) evaluation, around one million children were affected by tuberculosis in 2015 [4]. Among these children, those who are younger than 5 years, HIV-infected, recently exposed to TB, and immunocompromised are at the highest risk of mortality [5,6]. There are estimates of 239 000 (194 000–298 000) deaths in children younger than 15 years infected with tuberculosis during 2015, of which 80 % (191 000, 132 000–257 000) were younger than 5 years [7]. In contrast, COVID-19 accounted for 5.21 million (4.50–6.01) deaths in children younger than 5 years in 2019 [3]. Though COVID-19 has garnered significant attention due to its rapid spread and profound societal impact. Tuberculosis continues to be a significant public health challenge, particularly pediatric cases in developing countries, where roughly 10 % of all tuberculosis incidences occur in children under the age of 15 [8]. That being said, children under the age of 15 account for roughly 20 % of tuberculosis notifications in developing nations [9,10]. The transmission of tuberculosis to young children often occurs due to exposure to an infected adult within their household. Nevertheless, in regions where tuberculosis infection is prevalent, transmission beyond the household is significant. Hence, the incidence of pediatric tuberculosis is an essential indicator of the efficacy of tuberculosis control programs [10,11].

Diagnosing tuberculosis in children presents considerable challenges due to several factors. The low bacterial load of TB in children contributes to poor sensitivity of microbiological tests. Obtaining respiratory samples from children under the age of 5, who cannot expectorate, poses a challenge. Symptoms are non-specific, particularly in children co-infected with HIV or with severe acute malnutrition. Additionally, complex features on chest radiography further complicate the diagnosis [6,12,13].

The incidence of TB in Syria was reported to the WHO at 23 per 100 000 in 2012 and 19 per 100 000 in 2017 [14]. Compared to the relatively stable incidence rates in neighboring countries such as Jordan (7.7 per 100 000 since 2011) and Lebanon (12 per 100 000 in 2016), TB incidence in Syria is significantly higher [14].

Following primary infection, TB can reactivate at any time and at any site within the body. Recent research indicates that the locations of extra-pulmonary tuberculosis (EPTB) may vary depending on geographic location and population studied [[15], [16], [17], [18]]. Our understanding of the host-related factors responsible for the development of extra-pulmonary tuberculosis (EPTB) is limited. Several studies suggest an increase in EPTB cases, possibly due to the HIV epidemic and improvements in diagnostic capabilities [[19], [20], [21]]. A study found that among children admitted to the hospital, EPTB was more prevalent than PTB, with the lymph nodes being the most commonly affected site. Most patients were school-aged children from rural areas [22].

The protracted conflict in Syria has engendered a multifaceted milieu conducive to the proliferation of tuberculosis (TB), characterized by mass displacement, overcrowding, and substantial degradation of healthcare infrastructure [23]. These conditions have led to a surge in both drug-sensitive and drug-resistant strains of TB within Syria, which further accentuates the exacerbating effects of the Syrian humanitarian crisis on TB control efforts, particularly emphasizing the heightened vulnerability of displaced populations [14]. Moreover, Nkereuwem et al. underscored the need to prioritize the detection of childhood TB cases within Syria, a focal point resonant with the thematic orientation of our investigation of pediatric TB patients [24]. Furthermore, there is insufficient information available on the epidemiological and clinical features of pediatric TB in various regions of Syria. Therefore, our study reviewed a 10-year experience in managing pediatric patients with active TB admitted to our hospital in Syria. Our objective was to compare the epidemiology, clinical profile, diagnosis, and early mortality rate of (EPTB) and (PTB) in hospitalized children.

2 Methods and materials

2.1 Study design, settings, and variables

Our research is a retrospective cohort study conducted at University Children Hospital, involving hospitalized patients diagnosed with TB from January 2013 to January 2023. The University Children Hospital is the largest pediatric hospital in Syria and the only government hospital in Damascus. Before data collection, the researchers underwent training sessions covering pediatric TB, the distinctions between PTB and EPTB patients, and the specific information to be gathered. Data extraction from paper-based medical records stored in archives occurred in March 2023 and subsequently entered into an Excel spreadsheet. Due to the extended ten-year duration of our study, parents were contacted via telephone to validate data and provide any additional missing details, including socio-demographic characteristics.

Data collection included socio-demographic characteristics, weight, diagnostic methods employed, tuberculosis (TB) type, clinical presentation, chest radiography findings, and the patients' outcomes during their hospital stay. The study included both microbiologically and non-microbiologically diagnosed cases. Microbiologically proven cases had positive TB PCR (Xpert MTB/RIF assay) and/or TB culture results, while non-microbiologically proven cases had negative TB culture or PCR results but positive tuberculin skin test (TST) or TB smear in conjunction with clinical manifestations of TB or suggestive chest X-ray findings. Patients were categorized into two groups, as per a previous study [25], PTB and EPTB patients. EPTB encompassed active TB cases affecting organs other than the lungs and pleura, including instances of multiorgan TB, defined as TB affecting two or more organs. Additionally, CNS TB, a subtype of EPTB, was defined as TB meningoencephalitis or TB meningitis.

Close contact was defined as residing or frequently interacting with a smear-positive TB patient. Immunodeficiency categories included primary immune disorders, immunosuppression caused by concurrent illnesses, or immunosuppressive medications use. Symptoms were determined based on the guidelines established by the South African Guidelines [10].• A significant fever was identified as a temperature equal to or higher than 38 °C persisting for at least 14 days.

• A significant cough was characterized by a persistent cough lasting for 14 or more days.

• Fatigue was described as reported lethargy or decreased playfulness by either the parents or the patients.

• Significant weight loss was not included in our study, due to the limited availability of paper-based information.

Microbiological examinations were conducted for all our patients. Despite resource limitations preventing the use of the interferon gamma release assay (IGRA), a previous study suggests that a tuberculin skin test (TST) can be used as an alternative when IGRA is not available [25], as in our study. Furthermore, fluid specimens were analyzed for the presence of acid-fast bacilli through smear tests and cultured using Lowenstein-Jensen slants and the automated MGIT960 system for solid growth [26,27].

All patients underwent chest X-ray examinations, interpreted by an in-house radiologist. Additionally, all patients received a treatment regimen comprising rifampicin, isoniazid, pyrazinamide, and/or ethambutol for 6 months in the case of (PTB) and 9–12 months for (EPTB). However, due to the challenges posed by the ongoing war and its repercussions in Syria, patient monitoring was limited to the initial 30-day period during their hospital stay. Hence, any patient deaths occurring within this timeframe were classified as early mortality. Patients exhibiting resistance to both isoniazid and rifampicin were classified as having multidrug-resistant tuberculosis (MDR-TB).

2.2 Study size and participants

The eligibility criteria for patient enrollment in our research study included the following conditions: (1) a confirmed diagnosis of (PTB) or (EPTB), confirmed either through microbiological or non-microbiological means; (2) active TB treatment received during hospitalization between January 2013 and January 2023; (3) individuals aged between 0 and 13 years old within this specified time period. Initially, a total of 150 patients were included in the study. However, 10 patients were excluded due to the inability to establish communication with their parents via phone calls or incomplete medical records. Additionally, 11 patients were excluded as they were found to have latent TB. Consequently, the final analysis included 129 patients. Our research adhered to the ethical standards outlined in the Declaration of Helsinki and was carried out on human subjects. This study was reviewed and approved by Ethical Committee at Damascus University's Faculty of Medicine, with the approval number: MD130623-109 in February 2023. All patients' legal guardians provided informed consent for participation in the study and for the publication of the patients' data.

2.3 Statistical analysis

The data analysis was conducted using SPSS version 25. Categorical variables describing demographic characteristics were presented using frequency and percentage. Meanwhile, continuous variables describing the characteristics were presented using mean and standard deviation.

To compare categorical variables, the Chi-square test was employed, while the independent t-test was used to compare means of continuous variables. Statistical significance was determined at a P-value of less than 0.05, with a confidence level of 95 %.

3 Results

A total number of 129 patients were included in the study from January 2013 to January 2023, with 59.7 % (n = 77) being males and 40.3 % (n = 52) females. The mean age of the patients was 5.1 years (SD = 4), whereas the mean weight was 15.64 Kg (SD = 9.753). The oldest patient was 13 years old and the youngest one was 1 year old.

Of the total patients, 26.4 % (n = 34) had PTB, while 73.6 % (n = 95) had EPTB. The distribution of EPTB types was as follows: lymphatic (25.6 %, n = 33), gastrointestinal (GI) (17.1 %, n = 22), multiorgan (14 %, n = 18), (CNS) (11.6 %, n = 15), and bone TB (5.4 %, n = 7). All patients with CNS TB had TB meningitis. Among patients with multiorgan TB, eleven had CNS and pulmonary involvement, two had GI and pulmonary involvement, two had muscoskeletal and pulmonary involvement, one had lymphatics and pulmonary involvement, one had GI and lymphatic involvement, and one had GI, lymphatics and muscoskeletal involvement.

Patients with PTB had a mean age of 5.53 years (SD = 4.83) and mean weight of 15.94 Kg (SD = 10.7), while those with EPTB had a mean age of 5.01 years (SD = 3.7) and mean weight of 15.53 Kg (SD = 9.44). There was no statistical significance between the two groups regarding the age and weight (t (127) = 0.419, P = 0.676 and t (127) = 0.209, P = 0.835 Respectively).

Patients who were immunodeficient had no statistical significance between PTB and EPTB (8,8 % vs 8.4 %, X2 (1, N = 129) = 0.05 p = 0.943). Moreover, 58.8 % (n = 20) of PTB were males and 41.2 % (n = 14) were females, and 60 % (n = 57) of EPTB were males and 40 % (n = 38) were females. There was no statistical significance between the two groups regarding gender (X2 (1, N = 129) = 0.14 P = 0.904).

The clinical presentation of both groups showed a significant cough in 26.4 % (n = 34) significant fever in 51.2 % (n = 66), presence of fatigue in 48.1 % (n = 62), and lymphadenopathy in 42.6 % (n = 55). Additionally, 53.5 % (n = 69) had ≥2 significant symptoms. Patients with PTB were more likely to present with significant cough (67.6 % vs 11.6 %, X2 (1, N = 129) = 40.53 P = 0), while those with EPTB were more likely to present with lymphadenopathy (48.4 % vs 26.5 %, X2 (1, N = 129) = 4.93 P = 0.026). Additionally, 19.4 % (n = 25) had positive TB contact and 12.4 % (n = 16) had ≥2significant symptoms and a positive contact history.

Chest X-ray (CXR) abnormalities were found in 58.1 % (n = 75) of patients with the following changes pulmonary infiltrates (n = 45, 34.9 %), hilar adenopathy (n = 1, 0.8 %), lobar collapse (n = 2, 1.6 %), pleural changes (n = 4, 3.1 %), cavitation (n = 1, 0.8 %), widened mediastinum (n = 3, 2.3 %), and a combination of the previous changes (n = 19, 14.7 %). PTB patients were more likely to present with abnormal CXR than those with EPTB (97.1 % vs 44.3 %, X2 (1, N = 129) = 28.73 P = 0).

Microbiological confirmation was higher in PTB patients compared to EPTB patients (76.5 % vs 25.3 %, X2 (1, N = 129) = 27.6 P = 0). In our study five patients were MDR-TB, with four having EPTB and one having PTB. Sample details and characteristics of PTB and EPTB patients were shown in Table 1. No statistical significance was noted regarding the multidrug resistance as shown in Table 1.Table 1 Showing the characteristics and details of PTB and EPTB patients.

Table 1	Pulmonary n = 34 (%)	Extrapulmonary n = 95 (%)	P value	
Age (In years)	5.53 (SD = 4.83)	5.01 (SD = 3.7)	0.676	
Weight (In kg)	15.94 (SD = 10.7)	15.53 (SD = 9.44)	0.835	
Gender	
Male	20 (58.8)	57 (60 %)	0.904	
Female	14 (41.2)	38 (40 %)	
Place of Residency	
Damascus	12 (35.3)	20 (21.1)	0.099	
Non-D	22 (64.7)	75 (78.9)	
Contact History	
Positive	10 (29.4)	15 (15.8)	0.085	
Negative	24 (70.6)	80 (84.2)	
Symptoms	
S. Fever	21 (61.8)	45 (47.7)	0.15	
S. Cough	23 (67.6)	11 (11.6)	.000a	
Fatigue	14 (41.2)	48 (50.5)	0.349	
Lymphadenopathy	9 (26.5)	46 (48.4)	.026a	
≥2symptoms	21 (61)	48 (50.5)	0.26	
Microbiologically Proven	
Yes	26 (76.5)	24 (25.3)	.000a	
No	8 (23.5)	71 (74.7)	
TST Positive	
Yes	20 (58.8)	70 (73.7)	0.1	
No	14 (41.2)	25 (26.3)	
CXR	
Normal	1 (2.9)	53 (55.8)	.000a	
Abnormal	33 (97.1)	42 (44.2)	
Early Mortality	
Dead	2 (5.9)	16 (16.8)	0.113	
Alive	32 (94.1)	79 (83.2)	
a Bolded P values indicate a statistically significant difference between PTB and EPTB groups.

The overall mortality rate is 14, with PTB and EPTB mortality rates at 5.9 % and 16.8 %, respectively. Multiorgan TB and CNS TB had higher mortality rate compared to other types of EPTB (37.5 % and 31.3 % respectively, X2 (4, N = 95) = 10.23 P = 0.037). Among the sixteen deaths in patients with EPTB, TB meningitis was present in 62.5 % (n = 10) of them existing solely or as multiorgan TB. Additionally, among six patients with multiorgan meningitis and pulmonary TB, 83.3 % (n = 5) have died. Around 8.52 % (n = 11) were immunodeficient, were they showed to have higher mortality rate in contrast to immunocompetent patients (33.3 % vs 4.5 %, X2 (1, N = 129) = 16.5 P = 0). Table 2 shows the types of immunodeficiencies between PTB and EPTB patients.Table 2 Types of immunodefiencies in pulmonary and extrapulmonary TB.

Table 2Types of immunodeficiencies	Pulmonary n = 34 (%)	Extrapulmonary n = 95 (%)	
Primary Immune deficiency	1 (2.9)a	5 (5.2)b	
HIV	2 (5.9)	1 (1)	
Malignancy	0 (0)	1 (1)c	
Others	0 (0)	1 (1)d	
a Severe Combined Immunodeficiency.

b One Common Variable Immunodeficiency and four Severe Combined Immunodeficiency.

c neuroblastoma on chemotherapy.

d Ulcerative Colitis on immunosuppressant.

4 Discussion

Tuberculosis (TB) is a disease that has the potential to affect any organ in the body, which poses a significant challenge to the diagnosis of EPTB. The diagnosis of EPTB is often complicated by non-specific symptoms that vary depending on the affected organ, resulting in delayed diagnosis [28]. Our research aimed to compare the epidemiology, clinical profile, diagnosis and early mortality rate of EPTB and PTB in hospitalized children. Additionally, it underscores the intricate hurdles associated with diagnosing and managing TB within conflict zones such as Syria. The notably high occurrence of EPTB, particularly TB meningitis, coupled with its elevated mortality rates underscores the critical necessity for enhanced diagnostic and management strategies [24]. These challenges are significantly compounded by ongoing conflict dynamics, including widespread displacement, overcrowding, and extensive degradation of healthcare infrastructure [23]. Moreover, the disproportionately high incidence of TB among children emphasizes the urgent need to prioritize childhood TB case detection, as advocated by Nkereuwem et al. (2021) [24]. Our study contributes to the expanding body of scholarly work elucidating the ramifications of conflict in TB control efforts, underscoring the imperative for a multifaceted, customized, and practical approach to TB management within conflict settings [14,23].

Our study revealed that the majority of patients included (73.6 %) were diagnosed with EPTB. This finding may be attributed to the relatively small sample size of the study and the inclusion of only hospitalized patients. The mean ages of patients diagnosed with EPTB and PTB were similar and did not exhibit any statistical significance. However, this finding contrasts previous studies on pediatric TB, where children with EPTB tended to be younger [25,29]. Age may play a critical role in the development and progression of TB with younger children at a higher risk of severe and extrapulmonary forms of TB. This risk is particularly elevated in children under the age of five [30]. A recent study conducted in Italy reported a higher incidence of TB in children under five years old [31]. Nevertheless, our study identified cases both older and younger than five years old, with a mean age of 5.1 years, suggesting that the age distribution may vary across different countries. It is important to recognize the significant impact that malnutrition and vitamin D deficiency can have on the epidemiology and outcomes of tuberculosis. These conditions have been associated with weakened immune function, potentially heightening susceptibility to TB and worsening disease severity. Moreover, malnutrition can hinder the timely diagnosis of TB in children, resulting in delays in treatment and poorer prognoses. Low levels of vitamin D have also been correlated with a higher probability of latent, active, or past tuberculosis infection [32,33]. Understanding these associations can inform targeted interventions to improve TB control efforts and mitigate the impact of malnutrition on disease outcomes. This is particularly crucial in conflict zones like the one mentioned, where widespread displacement, overcrowding, and extensive degradation of healthcare infrastructure exacerbate the challenges. In Catalonia, Spain, a study involving 134 children under 2 years old with tuberculosis found that only one patient, representing 0.7 %, passed away [34]. In Greece, out of 43 children with TB meningitis, two patients, accounting for 5 %, did not survive [35]. In Ethiopia, a study of 400 TB patients reported that 23 individuals, making up 5.75 %, succumbed to the disease [36]. Contrastingly, the overall mortality rate in this study discussed in our article was higher at 14 %, emphasizing the idea that malnutrition, the conflict in Syria, and inadequate healthcare infrastructure might have contributed to this higher mortality rate.

The predominant form of EPTB observed in our study was TB of the lymph nodes, followed by GI TB. This finding is consistent with a previous study conducted in Turkey that identified lymph node tuberculosis as the most common form of EPTB in children [37]. Among the patients in our study, 26 were diagnosed with (CNS) involvement, with 15 cases exhibiting TB affecting the CNS exclusively, while the remaining 11 patients displayed multiorgan TB with coexisting CNS involvement. The percentage of patients with CNS involvement identified in our study was relatively high, accounting for 20.1 % of all TB cases. This finding is in line with previous reports that have suggested a similarly high proportion of CNS involvement in TB, which can reach as high as 15.8 % [31,38]. A recent study conducted in China also reported a high incidence of TB meningitis, reaching 38.8 % in cases of TB [29]. The high incidence of CNS TB in our patients may be attributed to the low rate of BCG vaccination in our country. A previous retrospective study of pediatric cases showed that EPTB was more prevalent among individuals who had not received BCG vaccination, with a proportion of 59 % compared to 41 % in the vaccinated group, which was statistically significant [29].

Consistent with previous research, fever, cough, and weight loss were commonly observed clinical manifestations in children diagnosed with PTB. Moreover, a more precise symptom-based diagnostic method for PTB in children indicated that cough, weight loss, and fatigue exhibited favorable diagnostic accuracy [39]. In this study, the incidence of cough was significantly higher in the PTB group (67.6 %) compared to the EPTB group (11.6 %). However, patients with EPTB were more likely to present with lymphadenopathy (48.4 %) compared to patients with PTB (26.5 %). A survey conducted in a high TB burden community indicated that children with TB rarely exhibit typical symptoms [40]. Conversely, our study identified that 53.5 % of patients presented with at least two of the five primary symptoms listed by the South African Society for Paediatric Infectious Diseases [10], which is in contrast to the previous survey.

Obtaining a comprehensive history of potential TB exposure is critical in diagnosing TB in children, as most pediatric TB cases are thought to arise from transmission from adult TB cases. The reported incidence of obtaining a contact history ranges from 16 % to 40 % in the literature, indicating some variation across different studies [[41], [42], [43]]. Our study found that 19.4 % of evaluated pediatric TB cases had a positive contact history for TB, emphasizing the importance of obtaining a thorough contact history during the diagnostic evaluation of TB in children.

Abnormal CXR findings were observed in 58.1 % of our patients, which was lower than a study conducted in Singapore [25]. Almost all patients diagnosed with PTB exhibited abnormal CXR findings, with a proportion of 97.1 %. In contrast, only about half of individuals with EPTB displayed abnormal CXR findings, with a percentage of 44.3 %. The significant variation in interpretation of chest X-rays in pediatric patients among radiologists could account for this finding [44]. Furthermore, CXR demonstrated a high level of sensitivity but low specificity for identifying active TB, as many radiographic abnormalities associated with TB can also be present in other types of infections [45].

The gold standard for diagnosing TB is microbiological confirmation, which provides the most accurate and reliable results. Furthermore, this method can also detect drug-resistant TB strains, making it an essential component of TB diagnosis and management [46]. However, obtaining microbiological confirmation for pediatric TB can be challenging due to the paucibacillary nature of this condition, which means that the number of bacteria present in clinical samples is often low. Moreover, it can be challenging to obtain appropriate samples for testing in pediatric patients [39]. Our study demonstrated that microbiological confirmation was achieved in a higher proportion of patients with PTB compared to those with EPTB. Specifically,76.5 % of PTB cases were microbiologically proven, while only 25.3 % of EPTB cases were also proven microbiologically. These results are in agreement with other studies that have reported higher rates of microbiological confirmation in PTB cases compared to EPTB cases [39,47]. This might be due to the fact that EPTB patients exhibit pauci-bacillary nature of the disease and the need of more invasive procedures to be microbiologically proved [48].

This article revealed that individuals diagnosed with EPTB had higher mortality rates compared to those with PTB. TB meningitis was present in 62.5 % of EPTB deceased patients, in which previous research has shown that the highest risk of TB meningitis is observed in young children and individuals living with human immunodeficiency virus (HIV). TB meningitis is considered the most severe form of TB and can lead to significant morbidity and mortality if not promptly diagnosed and treated [[49], [50], [51], [52], [53]]. Given the elevated incidence and mortality rates associated with TB meningitis among children, prevention and treatment of this form of TB should be a top priority in public health efforts. Further research is warranted to improve the diagnosis and management of TB meningitis in pediatric patients.

Our study was constrained by several limitations, primarily related to its retrospective design and small sample size. This study primarily focused on early mortality outcomes due to the war and resulting circumstances in Syria, therefore, it is important to conduct further studies that concentrate on long-term mortality and monitoring for potential disease relapse and complications. This study relied on paper-based medical records, making it impractical to include detailed microbiological results. Therefore, the data was analyzed categorically as either microbiologically proven or non-microbiologically proven. Also, prevalence and mortality rates may be underestimated due to the underdiagnosis of pediatric TB. In a previous global study, it was found that some fatalities attributed to pneumonia, meningitis, and AIDS might actually have resulted from tuberculosis. Conversely, certain tuberculosis-related deaths were likely not accounted for in these worldwide mortality assessments, suggesting that the overall estimates are underestimated [7]. Unfortunately, such study is not available in Syria; consequently, preventing us from estimating precise rates because of the mentioned cause. Furthermore, the study only included patients who received inpatient treatment for TB, which may have led to an underestimation of disease prevalence and potentially missed the less severe group who received outpatient therapy. Additionally, missing data was observed due to incomplete medical records. The study was also conducted at a single center, which may limit the generalizability of our findings.

5 Conclusion

In conclusion, our study sheds light on the epidemiological landscape of TB in hospitalized children, particularly emphasizing the challenges associated with diagnosing and managing EPTB. Our findings underscore the critical necessity for enhanced diagnostic and management strategies, especially in conflict zones like Syria, where TB control efforts are significantly hampered by widespread displacement, overcrowding, and degraded healthcare infrastructure. Prompt solutions must be devised to address these challenges effectively and ensure improved outcomes for patients in such settings. The notably high occurrence of EPTB, coupled with its elevated mortality rates, highlights the urgent need for tailored approaches to TB management within such settings. Furthermore, our study emphasizes the impact of malnutrition and vitamin D deficiency on TB epidemiology and outcomes, indicating the importance of targeted interventions to mitigate these factors. Clinical and diagnostic recommendations derived from our work emphasize the importance of obtaining comprehensive contact histories, recognizing the varied clinical presentations of pediatric TB, and employing microbiological confirmation whenever possible.

Funding

Not Applicable.

Data availability statement

The database used and analyzed in the present study is not publicly available as its information may compromise the participants’ privacy and consent involved in the research, but are available from the corresponding author on reasonable request.

Ethics statement

This study was reviewed and approved by Ethical Committee at Damascus University's Faculty of Medicine, with the approval number: MD130623-109 in February 2023. All patients' legal guardians provided informed consent for participation in the study and for the publication of the patients' data.

CRediT authorship contribution statement

Hussein Hamdar: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Data curation, Conceptualization. Ali Alakbar Nahle: Writing – review & editing, Writing – original draft, Investigation, Data curation, Conceptualization. Jamal Ataya: Writing – review & editing, Writing – original draft. Ali Jawad: Visualization, Resources. Hadi Salame: Visualization, Resources. Rida Jaber: Visualization, Resources. Mohammad Kassir: Visualization, Resources. Hala Wannous: Visualization, Validation, Supervision.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations:

TB Tuberculosis

PTB Pulmonary Tuberculosis

EPTB Extrapulmonary Tuberculosis

MDR-TB Multidrug-resistant tuberculosis

TST Tuberculin Skin Test

IGRA Interferon gamma release assay

Acknowledgments

We would like to express our sincere appreciation to Ziad Kaddour for his dedicated efforts in reviewing and refining the language of this manuscript. His meticulous language editing has greatly contributed to the clarity and professionalism of the content.
==== Refs
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