|Year : 2022 | Volume
| Issue : 3 | Page : 229-235
Role of IL 6 as a biomarker in the diagnosis of tuberculous meningitis – A systematic review
Department of Microbiology, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Tamil Nadu, India
|Date of Submission||07-Jun-2022|
|Date of Decision||12-Jul-2022|
|Date of Acceptance||10-Aug-2022|
|Date of Web Publication||12-Sep-2022|
Department of Microbiology, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Kelambakkam, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Tuberculous meningitis (TBM) is the most common and serious form of central nervous system tuberculosis (TB) with high morbidity and mortality. Following the encounter of tubercle bacilli by microglial cells, inflammatory process sets in and series of cytokines are secreted such as tumor necrosis factor, interleukin-6 (IL6), and interferon γ. The following study was undertaken with the aim of systemically reviewing the diagnostic and prognostic evidence of IL6 in TBM. Methods: After a thorough search of databases for the articles with IL6 association in TBM published from 2001 onwards to September 2021. Articles were identified and assessed according to the inclusion and exclusion criteria. Excel spreadsheets were used for the extraction of data and analysis. Results: A total of 10 studies were included for review which focused on IL6 in the role of TBM diagnosis. All the age group persons of both sexes were included in the study. The experiment was conducted mostly in the developing countries. The range of measured IL6 values was very wide and difficult to interpret. Conclusion: TBM patients' IL 6 was higher than healthy controls in all the studies mentioned, but the results of cerebrospinal fluid IL6 and serum IL6 were less consistent. Due to a small number of prospective studies, it was not possible to analyze the IL6 cut-off value to diagnose TB. Further studies are required to provide information on IL6 as biomarker in the diagnosis of TBM.
Keywords: Central nervous system, cytokines, interleukin 6, Mycobacterium tuberculosis, tuberculous meningitis
|How to cite this article:|
Kruthika P. Role of IL 6 as a biomarker in the diagnosis of tuberculous meningitis – A systematic review. Int J Mycobacteriol 2022;11:229-35
|How to cite this URL:|
Kruthika P. Role of IL 6 as a biomarker in the diagnosis of tuberculous meningitis – A systematic review. Int J Mycobacteriol [serial online] 2022 [cited 2022 Oct 6];11:229-35. Available from: https://www.ijmyco.org/text.asp?2022/11/3/229/355915
| Introduction|| |
Tuberculosis (TB) is one of the oldest and dreadful diseases known to humankind and caused by bacteria Mycobacterium tuberculosis (M. tb) complex. Among the infectious diseases, TB is the second most leading cause of death worldwide following COVID-19. This bacilli has managed to succeed in infecting one-quarter of world's population, despite available with universal vaccination and effective drug regimens. In the year 2020, there were 10 million new cases of TB, among them 1.1 million were children. A total of 1.5 million people died of TB in the same year. The prevalence of HIV/AIDS has increased both the incidence and mortality among TB patients.
TB is primarily a lung disease, but can also affect other organs in our body. The pathogen gains entry to lungs by inhalation of infectious aerosols and invades lung barrier cells and infects the alveolar phagocytic cells, polymorphonuclear cells, and antigen-presenting cells of the lung. After a brief inflammatory process, the infection will either be completely resolved or controlled by inflammatory cells in the immunocompetent population. Several secretory proteins will be released at the site of inflammation such as interleukin (IL) 1, IL6, tumor necrosis factor (TNF)γ, and other proinflammatory cytokines. In a fewer susceptible population like people of extremes of age and immunocompromising can progress to active disease and also disseminate the infection to distant organs. It is estimated that 10% of all TB cases have central nervous system (CNS) involvement. CNS TB can manifest with a variety of neurological presentations, tuberculous meningitis (TBM) is the most common and serious form of CNS TB followed by tuberculoma, TB brain abscess, and Pott's spine.
The tubercle bacilli gets transported to CNS by various routes, hematogenous and lymphatic route being the prime., TBM occurs when the pial or ependymal foci breaks down and release the bacilli. Inflammatory response sets in as various cytokines are secreted at the site of infection by astroglia, endothelial cells, and microglia cells., TNF is considered as the pivotal cytokine secreted during the pathogenesis. IL6 and interferon γ are the other two major cytokines secreted by microglial cells following encounter with tubercle bacilli along with minor cytokines such as IL-1α, IL-10, IL12p40, G-cerebrospinal fluid (CSF), and GM-CSF.,, Astrocytes produce CXCL10.
Cytokine IL6 is very important proinflammatory marker which appears in the system following infection. IL6 is secreted from monocytes, macrophages, and neutrophils. They have a wide range of influence on liver cells, bone marrow, bone cells, and other cells. IL6 is an independent inflammatory marker released during inflammation., The role of IL6 is been evaluated in various illnesses.
Even in the present COVID-19 pandemic, IL6 was very extensively evaluated for its role as a biomarker in disease diagnosis and prognosis. However, its role in TBM is less explored.
There is an availability of a wide range of laboratory diagnoses for TBM ranging from microscopy to gold standard culture and much promising molecular diagnosis. However, studies have shown a sensitivity of detecting M. tb by all the available tests are not adequate, as there is a paucibacillary picture in TBM. Several studies have been undertaken to detect and evaluate novel biomarker in the diagnosis of TBM, among them proinflammatory cytokines are the most prominent. There are lacunae in knowledge about the utility of cytokines especially IL6 as biomarker in the diagnosis of TBM. Therefore, the following systemic review was undertaken to evaluate the role of IL6 as biomarker in the diagnosis of TBM. As far as our knowledge and thorough literature search, this is the first systemic review on IL6 in TBM patients.
First to study the role of cytokine IL6 in TBM diagnosis and second to evaluate the prognosis of IL-6 in TBM.
| Methods|| |
Search strategy and study selection
The PubMed, Medline, and Google scholar databases were searched to identify suitable studies published from 2001 onwards to September 2021. The keywords for the literature search in PubMed and Google scholar were as follows: IL-6, TB meningitis, TBM, and TBM. A manual search of the bibliographies listed in the retrieved articles was also conducted.
The inclusion criteria were: (1) studies that evaluated IL6 in the diagnosis of TBM; (2) studies that reported the sample size of TBM and non-TBM patients; (3) only Prospective observational study; (4) only the journals and articles in English are considered; (5) the materials that are published after 2001 are only focused; and (6) the peer-reviewed journals are articles are only taken in account.
The exclusion criteria were: (1) animal studies; (2) non-English publications; (3) conference abstracts; and (4) case report, case series.
Data extraction and quality assessment
Articles were identified and assessed according to the inclusion and exclusion criteria. Titles and abstracts were first screened to identify eligible studies and, if necessary, the full texts were reviewed to assess the eligibility of a study. Excel spreadsheets were used for the extraction of bibliography data, which includes the title of the article, name of the first author, publication year, country were study was conducted, demographic details, diagnostic and management details, prognostic indicators, and outcome. It also included both CSF IL6 cytokines measured and serum/blood IL6 cytokines measured in both case and control groups. The suitable method used for this systematic review is SPICE.
Since the present study is a systemic review. Ethical approval is not applicable.
| Results|| |
The study which measured the proinflammatory marker IL6 among TBM patients from the year 2001 onwards to September 2021 were searched by electronic databases. In a total of 577 studies were identified using specific search terms. From this, 25 articles with duplicate records were removed before screening. From 552 articles at the level of title and abstract screening, 520 articles were excluded. Furthermore, 32 full-text articles were assessed to determine their eligibility to be included in systemic review: 23 articles were excluded as they were not relevant for the study. Finally, only 10 studies were included for review which focused on IL6 in the role of TBM diagnosis. The process of selection and exclusion of the study are mentioned in [Figure 1].
|Figure 1: Schematic illustration of patient selection process. PRISMA flow diagram for the systematic review which included searches of databases|
Click here to view
Description of included studies
A total of 10 articles with prospective observational studies were included in this systemic review. In two of the articles, the study was performed on adults. In three of the articles, the study was performed on both adults and children. Five of the articles had study performed in the pediatric age group. There were a total of 565 TBM cases and 191 healthy controls. The articles included in study were work conducted in India (3), China (3), South Africa (2), Turkey (1), and Indonesia (1).
Misra et al., in their study, correlated CSF cytokine levels and magnetic resonance imaging (MRI) findings among TBM patients and there was no relationship between cytokine levels and severity of illness, MRI changes, and outcome. IL6 was significantly expressed and decreased after 3 months following treatment. IL 6 can serve as a prognostic marker. Sharma et al., found elevated IL 6 levels both in serum and CSF in comparison to controls, only serum IL6 (0.007) level had a positive association with worsening of MRI findings at follow-up. In a study by Ma et al. demonstrated the activation of autophagy genes, mRNA levels of Beclin1 and LC3-II in CSF were increased which correlated with the IL6 inflammatory markers level in CSF. Van Laarhoven et al. showed in TBM patients there exists a proliferation of myeloid blood cells, CSF lymphoid cells, which could be utilized for diagnosis and patient-directed treatment. Liu et al. observed an elevation in the levels of CSF Th1, Th2, and Th17 cytokines in CNS infections. Also suggests in their study that the combination of CSF IL6 and glucose can serve as new biomarker to differentiate CNS diseases. Manyelo et al., in their study, IL6 levels were significantly secreted in TBM along with other cytokines. Also previously identified biomarkers such as vascular endothelial growth factor, IL13, and cathelicidin LL37 were revalidated. Loxton et al. conducted their experiment for evaluating the utility of inflammatory markers in brain extracellular fluid of TBM patients as a prognostic marker. Shen et al., in this study, the association between IL6 and IL6 single-nucleotide polymorphisms SNPs in TB patients was performed. Allan et al. state in their study that higher levels of CSF IL-6 than serum IL-6 and may be suggestive of TBM, can be used as a diagnostic tool. Bhasin et al. noted CSF IL6 was strongly associated with the occurrence stroke in TBM cases. [Table 1] shows master list of all the articles and their observations in the systemic review.
|Table 1: Master list of all the articles and their observations in the systemic review|
Click here to view
Diagnostic value interleukin 6 in tuberculous meningitis
Among the cases, the range of IL6 detected was between 9.60 and 6683 pg/ml among the patients. In controls, IL6 range was between 0 and 93.2 pg/ml, respectively.
Among the cases, the range of blood IL6 detected in three studies ranged between 49.8 and 578.78 pg/ml. In controls, the range of blood IL6 detected in three studies ranged between 0.77 and 69.5 pg/ml. Whole blood ex vivo cytokine IL6 analysis shows 2281 (700–6104) pg/ml response with M. tb (Van Laarhoven et al.,)
[Table 2] shows the IL6 measurements from the articles in our study.
Prognostic value of interleukin 6 in tuberculous meningitis
Only two of the Indian studies addressed the prognosis aspect of IL6 among TBM patients. In the study by Mishra et al., the IL6 was significantly expressed and decreased after 3 months of treatment. Sharma et al., on analysis, there was a positive association between serum IL 6 (0.007) with worsening of MRI finding at follow-up.
| Discussion|| |
Even with the availability of treatment and vaccine, TB still remains the disease with high mortality and morbidity in India among communicable diseases. There exists an requirement of novel biomarkers which can ease our diagnosis in paucibacillary conditions like TBM. The discovery of new biomarkers can guide us in synthesizing new drugs and designing new vaccines.
IL6 is a pivotal pleiotropic and independent cytokine released during inflammation. IL6 plays a pivotal role in the induction of acute inflammatory cytokines and mediates immediate inflammatory response.
Studies have shown the importance of IL6 playing an important role in disease progression among a wide spectrum of illnesses. However, the role of IL6 in TB pathophysiology and diagnosis is less understood.
The present systemic review is the first of systemic review to our knowledge, to analyze the role of IL6 as a biomarker in the diagnosis and prognosis of TBM. After a thorough search of articles, only 10 nonbiased articles were identified which investigated the diagnostic performance of IL6 in TBM. This less number of studies makes it very evident, that less studies are conducted on TBM.
Most of the studies in our systemic review were from developing countries basically the South Asian countries. The cases in the studies were from all the age groups. TB is the disease which affects the individuals of all age groups. Male sex was the predominant, even the WHO report says the same.
All the ten studies had various parameters and other cytokines studied along with IL6. IL 6 levels varied with each study. In four of the studies, the median IL6 was analyzed and in six of the studies mean IL6 was calculated. It was difficult to analyze and correlate results of each of the studies. The values were less consistent. There exists a wide difference in the measured values between case and control in all the studies. Due to this inconsistent data, no statistical analysis could be performed other than descriptive analysis. Consistent data from well-performed studies are required for high-quality evidence. Our review showed very few studies had high-quality data. Most of the studies were not optimally designed or sized.
However, in most of the studies, IL6 levels were many folds higher in cases than in the controls, they are even statistically significant. To assess the clinical significance of increase in the level of IL6, still further studies are required to strongly confirm the role of IL6 as biomarker in TBM. However, these studies give us hope that IL6 can be a potential candidate as biomarker in differentiating TBM from other CNS infections in future. Various inflammatory markers of CSF and blood are studied extensively for their role as biomarker in the diagnosis of TBM by various research workers around the world. These biomarkers appear to be promising as a potential candidates which can be a boon in the diagnosis of TBM.
| Conclusion|| |
The aim was to systemically review the diagnostic and prognostic evidence for an association of IL6 an inflammatory cytokine with TBM. After a thorough search, we included 10 studies in the review. TBM patients' IL 6 was higher than healthy controls' in all the studies mentioned, but the results of CSF IL6 and serum IL6 were less consistent. Due to a small number of prospective studies, it was not possible to analyze the IL6 cut off value to diagnose TB. Further studies are required to provide information of IL6 as biomarker in the diagnosis of TBM.
Limitation of study
The main limitation of our systemic review is very less number of studies identified, suboptimal number of participants per study, the profound variation in the definition and methods used.
Since the present study is a systemic review. Ethical approval is not applicable.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Mohidem NA, Osman M, Muharam FM, Elias SM, Shaharudin R, Hashim Z. Prediction of tuberculosis cases based on sociodemographic and environmental factors in Gombak, Selangor, Malaysia: A comparative assessment of multiple linear regression and artificial neural network models. Int J Mycobacteriol 2021;10:442-56.
] [Full text]
Coronel JE, Del Carpio CC, Dianderas EJ, Florentini EA, Kemper GL, Sheen P, et al.
Evaluation of microbiological variants of sputum processing and concentration of mycobacteria to optimize the microscopic and imaging diagnosis of tuberculosis. Int J Mycobacteriol 2019;8:75-82.
] [Full text]
Desai A, Gupta N, Korishetty L, Saravu K. Treatment outcomes of patients with tuberculosis and diabetes: A prospective cohort study from India. Int J Mycobacteriol 2021;10:111-5. [Full text]
Davis AG, Rohlwink UK, Proust A, Figaji AA, Wilkinson RJ. The pathogenesis of tuberculous meningitis. J Leukoc Biol 2019;105:267-80.
de Martino M, Lodi L, Galli L, Chiappini E. Immune response to Mycobacterium tuberculosis
: A narrative review. Front Pediatr 2019;7:350.
Ratinam J, Mishra AK, Muthuram AJ, Miraclin A, Chandy GM, Vanjare HA, et al.
Role of cerebrospinal fluid C-reactive protein in tuberculous meningitis. Int J Mycobacteriol 2020;9:422-8.
] [Full text]
Ryan ET, Hill DR, Solomon T, Aronson N, Endy TP. Hunter's Tropical Medicine and Emerging Infectious Diseases E-Book. 10th
Edition. Canada: Elsevier Health Sciences; 2020.
Soleiman-Meigooni S. Central nervous system tuberculosis. In: The Microbiology of Central Nervous System Infections. USA: Academic Press; 2018. p. 149-17.
Krishnan N, Robertson BD, Thwaites G. The mechanisms and consequences of the extra-pulmonary dissemination of Mycobacterium tuberculosis
. Tuberculosis (Edinb) 2010;90:361-6.
Jain SK, Paul-Satyaseela M, Lamichhane G, Kim KS, Bishai WR. Mycobacterium tuberculosis
invasion and traversal across an in vitro
human blood-brain barrier as a pathogenic mechanism for central nervous system tuberculosis. J Infect Dis 2006;193:1287-95.
Mastroianni CM, Paoletti F, Lichtner M, D'Agostino C, Vullo V, Delia S. Cerebrospinal fluid cytokines in patients with tuberculous meningitis. Clin Immunol Immunopathol 1997;84:171-6.
Rock RB, Hu S, Gekker G, Sheng WS, May B, Kapur V, et al. Mycobacterium tuberculosis
-induced cytokine and chemokine expression by human microglia and astrocytes: Effects of dexamethasone. J Infect Dis 2005;192:2054-8.
Yang CS, Lee HM, Lee JY, Kim JA, Lee SJ, Shin DM, et al.
Reactive oxygen species and p47phox activation are essential for the Mycobacterium tuberculosis
-induced pro-inflammatory response in murine microglia. J Neuroinflammation 2007;4:27.
Uciechowski P, Dempke WC. Interleukin-6: A masterplayer in the cytokine network. Oncology 2020;98:131-7.
Daneshmandi Z, Pourdowlat G, Rekabi M, Honarpisheh P, Mirzendedel M, Sadati E, et al
. Coronavirus disease 2019 and Mycobacterium tuberculosis
reactivation and coinfections: A review of the literature. J Prev Diagn Treat Strategies Med 2022;1:76-81. [Full text]
Misra UK, Kalita J, Srivastava R, Nair PP, Mishra MK, Basu A. A study of cytokines in tuberculous meningitis: clinical and MRI correlation. Neurosci lett 2010;483:6-10.
Sharma S, Goyal MK, Sharma K, Modi M, Sharma M, Khandelwal N, et al
. Cytokines do play a role in pathogenesis of tuberculous meningitis: a prospective study from a tertiary care center in India. J Neurol Sci 2017;379:131-6.
Ma Y, Zhang Y, Zhao Y, Wang X, Lin Y, Ma A, et al
. Expression of autophagy-related genes in cerebrospinal fluid of patients with tuberculous meningitis. Exp Ther Med 2018;15:4671-6.
Van Laarhoven A, Dian S, Van Dorp S, Purnama F, Koeken VA, Diandini E, et al
. Immune cell characteristics and cytokine responses in adult HIV-negative tuberculous meningitis: An observational cohort study. Sci Rep 2019;9:1-1.
Liu Q, Gao Y, Zhang B, Sun F, Yang Q, Liu Y, et al
. Cytokine profiles in cerebrospinal fluid of patients with meningitis at a tertiary general hospital in China. J Microbiol Immunol and Infect 2020;53:216-24.
Manyelo CM, Solomons RS, Snyders CI, Manngo PM, Mutavhatsindi H, Kriel B, et al
. Application of cerebrospinal fluid host protein biosignatures in the diagnosis of tuberculous meningitis in children from a high burden setting. Mediators Inflamm 2019.
Loxton NW, Rohlwink UK, Tshavhungwe M, Dlamini L, Shey M, Enslin N, et al
. A pilot study of inflammatory mediators in brain extracellular fluid in paediatric TBM. PloS One 2021;16:e0246997.
Shen C, Qi H, Sun L, Xiao J, Yin QQ, Jiao WW, et al
. A 3'UTR Polymorphism of IL-6R Is Associated with Chinese Pediatric Tuberculosis. BioMed Res Int;2014.
Alhan E, Yildizdas D, Yilmaz HL, Yilmaz M, Yaman A, Herguner O, et al
. Serum and cerebrospinal fluid interleukin-6 and interleukin-8 levels in children with tuberculous, bacterial and aseptic meningitis. Ann Med 2001;10:123-7.
Bhasin A, Kuthiala N, Sharma S, Subramaniyam V, Srivastava MV. Predictors of Infarction in Tuberculous Meningitis in Indian Patients. Journal of Stroke and Cerebrovascular Diseases 2021;30:106088.
Boni FG, Hamdi I, Koundi LM, Shrestha K, Xie J. Cytokine storm in tuberculosis and IL-6 involvement. Infect Genet Evol 2022;97:105166.
Kamimura D, Hirano T, Murakami M. Interleukin-6. In: The Curated Reference Collection in Neuroscience and Biobehavioral Psychology. London: Elsevier Science Ltd; 2016. p. 430-9.
Manyelo CM, Solomons RS, Walzl G, Chegou NN. Tuberculous meningitis: Pathogenesis, immune responses, diagnostic challenges, and the potential of biomarker-based approaches. J Clin Microbiol 2021;59:e01771-20.
[Table 1], [Table 2]