|Year : 2020 | Volume
| Issue : 4 | Page : 422-428
Role of cerebrospinal fluid C-reactive protein in tuberculous meningitis
Jasper Ratinam1, Ajay Kumar Mishra2, Alice Joan Muthuram1, Angel Miraclin1, Gina Maryann Chandy1, Harshad Arvind Vanjare3, Vijay Prakash Turaka1, John Jude4, Samuel George Hansdak5, Ramya Iyadurai6
1 Department of Internal Medicine, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Internal Medicine, St Vincent Hospital, Worcester, MA, USA
3 Department of Radiology, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
5 Department of Internal Medicine, Unit IV, Christian Medical College, Vellore, Tamil Nadu, India
6 Department of Internal Medicine, Unit V, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||22-Sep-2020|
|Date of Decision||19-Oct-2020|
|Date of Acceptance||22-Oct-2020|
|Date of Web Publication||15-Dec-2020|
Ajay Kumar Mishra
Department of Internal Medicine, St Vincent Hospital, 123 Summer Street, Worcester, MA 01545
Source of Support: None, Conflict of Interest: None
Background: Tuberculosis (TB) is still a significant health problem worldwide. Central nervous system TB amounts to 10% of all cases of TB. Despite advances in the pharmacological management of TB, the overall outcomes remain poor with significant mortality and morbidity. There are no predictors for neurological outcomes in tuberculosis meningitis (TBM). In this study, we aimed to evaluate the role of cerebrospinal fluid (CSF) C-reactive protein (CRP) in predicting mortality and neurological outcome in TBM. Method: In this observational study, all patients with TBM were recruited prospectively over a 12-month duration. Baseline demographic data, laboratory parameters, and Imaging findings were collected. CSF CRP was obtained on the CSF sample collected at the time of diagnosis. Patients were followed up at 3 months to assess neurological status and mortality. Results: Seventy-one patients with TBM were recruited in this study. The overall mortality in this study was 22.5% of patients. The primary composite outcome of mortality and adverse neurological outcome occurred in 40.8%. The CSF CRP levels ranged between 0.1 and 4.8 mg/dl, and the mean CSF CRP level was 1.11 mg/dl. The Relative risk for a patient with high CSF CRP to develop adverse outcome was 1.84 (P = 0.038). CSF CRP was a good predictor of mortality with a relative risk of 2.92 (P = 0.027). Stroke in TBM had a high incidence of 47.9% and a relative risk of 3.42 for an adverse neurological outcome. CSF CRP did not predict the occurrence of stroke. Hydrocephalus and elevated intracranial pressure were good predictors of stroke. Conclusion: TBM is a disease with significant mortality and morbidity. CRP level in the CSF can be measured, but a highly sensitive scale may be needed as the mean values were much lower compared to the serum values. CSF CRP Levels showed significant associations with adverse outcomes and mortality.
Keywords: Infarcts, meningitis, outcome, tuberculosis
|How to cite this article:|
Ratinam J, Mishra AK, Muthuram AJ, Miraclin A, Chandy GM, Vanjare HA, Turaka VP, Jude J, Hansdak SG, Iyadurai R. Role of cerebrospinal fluid C-reactive protein in tuberculous meningitis. Int J Mycobacteriol 2020;9:422-8
|How to cite this URL:|
Ratinam J, Mishra AK, Muthuram AJ, Miraclin A, Chandy GM, Vanjare HA, Turaka VP, Jude J, Hansdak SG, Iyadurai R. Role of cerebrospinal fluid C-reactive protein in tuberculous meningitis. Int J Mycobacteriol [serial online] 2020 [cited 2021 Jan 22];9:422-8. Available from: https://www.ijmyco.org/text.asp?2020/9/4/422/303449
| Introduction|| |
Tuberculosis (TB) continues to be a massive health burden, especially in developing countries. The new cases of TB detected in 2018 were 10 Million globally, and 44% of those cases were in South-East Asia. In 2014, the total death toll due to TB was 1.5 million, of which 0.4 million were HIV positive. As of 2018, there has been a 12% reduction in TB mortality. India continues to be leading in multidrug-resistant TB and contributes to 27% of total cases. Despite the advances in multidrug therapy, testing modalities, extensive national programs, TB continues to be a persistent health burden, having significant morbidity and financial burden to the community.
The epidemiology of central nervous system (CNS) TB and tuberculosis meningitis (TBM) varies widely among nations based on the geographical location, the prevalence of Human immune deficiency virus infection, and the age structure of the population. In a large population-based surveillance study done in Germany, the proportion of patients with TBM was 0.9% (422 of 46,349) among all TB patients. Of this, 2/3rd had TBM as the primary site, and 1/3rd had another primary site with coexistent TBM. It was also noted that children below 5 had a higher risk of developing TBM (odds ratio: 4.99). Another report from Brazil, which is a highly endemic country for TB, showed that 6% of the patients with Extrapulmonary TB had TBM as the primary site of involvement (among 57,217 patients with extrapulmonary TB).
CNS TB accounts for 10% of all the cases of newly detected TB. Among the extrapulmonary forms of TB, TBM is the most severe. The incidence of CNS TB in India could be estimated to be 16.7/100,000 population. A long-term follow-up study done in the last decade showed that the overall outcomes of TBM remained poor. Only 26% of the patients had a good outcome, and 16% had an intermediate disability. Among these, 7% had a severe disability, and 51% of patients had died. This shows that there exists a massive burden of the disease and its lethality among patients with TBM. In another large study done in Canada, mortality despite optimal therapy was 23.3%.
Mycobacterial replication is a mandate for the progression of the disease in the cerebrospinal fluid (CSF). However, it is always challenging to demonstrate TB bacilli in the CSF. Even though detected, the bacillary load is often negligible. The predominant site of replication of the tubercle bacilli is the microglial cells. All the other clinical symptoms that develop in TBM happens because of the extensive inflammation that occurs at various levels– in the meninges, arachnoid villi, ventricular systems, brain parenchyma, and blood vessels. Pituitary involvement can be associated with basal exudates, and a significant proportion of them have some form of cortisol insufficiency.,,
The inflammatory mediators involved in the process of tissue damage and cellular dysfunction have been studied extensively. Studies have also shown that the levels of inflammatory cytokines like interleukin (IL)-8, IL-6, IL-1 β, IL-10, Tumor necrosis factor (TNF) – alpha, Vascular Endothelial Growth factor are elevated in the CSF in patients with TBM.,,, However, levels of these inflammatory mediators have not been shown to contribute to predicting disease severity or outcome. C-reactive protein (CRP) has been used in multiple studies to assess its diagnostic role in differentiating pyogenic meningitis from nonpyogenic meningitis. No studies have looked at the prognostic implication of CSF CRP in TBM. We postulated that comparing the levels of CSF CRP between TB patients may show a relationship to the extent of the inflammation and thereby facilitate the prediction of adverse outcomes.
| Method|| |
This prospective, single-center study was conducted in the department of medicine of a tertiary care center in South India. In this study, we recruited all patients with TBM during a period of 12 months from May 2017 to May 2018. To be included, patients had to fulfil the following criteria.
- All patients above 18 years of age
- Fulfilling the Lancet consensus TBM diagnosis criteria as either
- Definite TBM
- Probable TBM
- Possible TBM.
- Newly diagnosed TBM at presentation
- Diagnosed TBM presenting within 1 month of diagnosis
- Providing informed consent.
Patients were excluded if they were (i) age <18, (ii) had past h/o CNS TB, (iii) Already diagnosed with TB and have been on antituberculosis treatment (ATT) and steroids, (iv) patients with a history of cerebrovascular disease, hydrocephalus, (v) evidence of coinfection, (vi) and patients unwilling to provide consent.
Following the inclusion of patients, multiple details were obtained by a trained physician. Demographic details, including age, gender, height, and weight, were obtained. Clinical parameters like fever, seizures, focal deficits, loss of appetite were collected. Laboratory data like cell counts, metabolic parameters were also obtained. Details of CSF analysis and CNS imaging were included. CNS imaging was reported by trained Neuroradiologist, blinded to the patient outcome. At the time of recruitment, neurological status was measured by the Modified Rankin Scale.
Cerebrospinal fluid C-reactive protein measurement
At admission, CSF CRP was obtained on the first diagnostic CSF sample. The CSF CRP samples were collected as an additional sample at the end of the first diagnostic lumbar puncture. CRP was measured using a standard ELISA Technique, which could measure values as low as 0.15 and up to 200 mg/dl. A pilot run of five patients with meningitis was run, and acceptable results were obtained in these patients before implementing the same into the study. Serum CRP levels were also measured in a subset of those patients for a comparison with the CSF CRP.
Patients were also followed up at 3 months in person or by a phone call, and mortality and morbidity data were collected.
The primary outcome was mortality at 3 months. We also studied adverse neurological effects with the help of the Modified Rankin Scale. The classification of outcome was “good” (a score of 0), “intermediate disability” (scores of 1 or 2), or “adverse neurological outcome” (scores of 3, 4, or 5). Along with adverse neurological outcomes, the development of hydrocephalus, stroke was studied as secondary outcomes.
Data recruitment and analysis
All data were collected by the principal investigator and then entered in Epidata 3.1 software. This was exported for analysis to IBM SPSS Statistics for Windows, Version 17.0. Armonk, NY IBM Corp. All data analysis was performed by the primary investigator with the assistance of a biostatistician. This study was conducted after obtaining permission from the Institutional review board (IRB number dated February 05, 2017 Appendix number 2) prior to the commencement of the study. Descriptive statistics were reported using frequency and percentage for categorical data. Continuous data were reported using mean ± standard deviation (SD). Association between the CSF CRP and primary and secondary outcomes were assessed by using Chi-square/Fisher's exact test as appropriate for categorical variables derived from clinical and radiological parameters. Continuous variables were evaluated using two independent sample t-test after checking for normality. The risk factor analysis was done using Binary logistic regression using the stepwise method. P value significance at 0.05 was considered statistically significant.
| Results|| |
Between April 2017 and July 2018, all patients with a clinical diagnosis of TBM were screened for the study. All patients who were fulfilling inclusion criteria and gave informed consent and had a CSF sample available at diagnosis were included in the study. A total of 132 patients were screened for the study [Figure 1]. Five did not fulfill inclusion criteria or had an alternate diagnosis by the end of the evaluation. Twenty-four patients were excluded as they were already treated with ATT and Steroids. For 32 patients CSF sample could not be obtained at the time of diagnosis and hence excluded. Finally, a total of 71 patients were included in the study. The mean age of the patients was 49.6, and 66.2% (47/71) of the patients were men. Lancet consensus scoring system was used, and the mean Lancet score for the patients included in the study was 12.66 (SD: 2.76). Using the Lancet score, 31%, 42%, 27% of patients were classified into definite, probable, possibly TBM, respectively [Table 1].
The mean duration of the development of TBM after diagnosis of HIV was 5.4 years. The most common clinical symptom was headache, fever, and was seen in 98.6%, 95.8% of patients, respectively. Seizures were seen in 14.1% of patients. Constitutional symptoms and loss of weight were more common and focal deficits, including motor weakness, cranial nerve palsies, and visual disturbances, were rarer. Patients were graded into Medical research council (MRC) Grades 1, 2, 3 at the time of admission based on their sensorium and clinical presentation. MRC Grade 2 was the most common clinical stage of presentation. Twenty-seven patients (38%) presented with MRC Grade – 1, 30 (42.3%) with MRC Grade-2, and 14 (19.7%) patients with MRC Grade-3. Mean CSF cell counts were 137, with the mean lymphocyte percentage of 73%. The mean CSF protein was 251 mg/dl, and glucose was 53 mg/dl. Hyponatremia was a frequent finding and was seen in 60.6% of patients in our study (43/71). The mean sodium value was 129. The mean serum ESR and CRP values were 34.36 and 55.46.
The CSF CRP values ranged from 0.1 to 4.8. The mean CSF CRP was 1.13 (SD: 1.06). The median CSF CRP Was 0.8 mg/dl, and the patients were classified into two groups based on the median, as proposed earlier, into High CSF CRP and low CSF CRP groups. A total of 31% (22/71) of patients had a confirmation of their diagnosis microbiologically based on AFB smear, TB PCR, or Mycobacterial culture. The AFB Smear positivity was only 2.8% (2/71), and Xpert TB PCR was positive in 14.1% (10/71). Mycobacterial culture positivity by LJ Medium or MGIT medium was seen in 26.8% of patients (19/71).
All patients had at least one form of diagnostic imaging at admission. Magnetic resonance imaging (MRI) brain was performed in 90.1% of patients (64/71). The most common MRI feature was a meningeal enhancement, as seen in 64.8% of patients (46/71 patients). Hydrocephalus and Elevated intracranial pressure were the other common findings on imaging. The overall occurrence of stroke was 47.9% (34/71). Admission imaging revealed evidence of infarcts in 36.6% of patients. Eleven patients developed new infarcts during the follow-up period (15.5%).
Twelve patients out of the 71 patients were HIV positive. The mean CD 4 count of the patients was 124 cells/cu mm. Among these patients, most were in WHO clinical Stage 4 (75%). Mortality was noted at follow-up in 22.5% of patients. The modified Rankin score of the patients at follow up is shown in [Figure 2].
|Figure 2: MRS score at follow.up. MRS: Modified Rankin scale, ATT: Antituberculosis treatment, CSF: Cerebrospinal fluid|
Click here to view
| Discussion|| |
The inflammatory mediators involved in the process of tissue damage and cellular dysfunction have been studied extensively in various animal and human studies at the molecular level. The benefit of Dexamethasone has been proven beyond doubt, indicating the advantage of anti-inflammatory therapy in TBM. Data has shown that the use of Dexamethasone has reduced the various inflammatory proteins concentration and interferon-γ levels. Elevated levels of IL – 6 has an association with the severity of TBM. There is evidence to suggest that IL 1 beta levels and TNF – alpha levels are elevated in the CSF in patients with TBM., Similarly, Inflammatory cytokines like IL-8, IL-6, IL-1 β, IL-10 are elevated in the CSF and are reported to reduce at follow-up. Another agent that has some association with the adverse outcome indicating the extent of inflammation and injury in TBM is the Vascular Endothelial Growth factor. Studies on TBM and immune reconstitution inflammatory syndrome (IRIS) also showed a positive association between inflammatory protein transcription and the occurrence of IRIS in HIV-infected individuals on the initiation of antiretroviral therapy. The factors that predict the intensity of the immune response have still not been identified. More so, no significant association between the various inflammatory markers with the severity of TBM and in its outcome is studied. There are seven strains (lineages) of Mycobacterium tuberculosis. They are called Modern (lineage – 2, 3, and 4) and Ancient (lineage – 1, 5, 6, and 7) based on their epidemiology. However, there have not been any significant associations between the lineages and the severity of illness in TBM.
It is known that multiple immunological responses are under the genetic control of genetic polymorphisms. Various Genetic polymorphisms involving genes like SPN, toll-like receptor (TLR)– 9, SIGIRR, MRC-1, TIRAP, TLR-2 have been shown to have multiple associations with the phenotypic manifestations of TBM and immunological responses in these patients. Single-nucleotide polymorphisms involving the Leukotriene A4 Hydrolase plays a significant role in modulating the inflammatory responses through the Leukotriene B4 and LipoxinA4 pathways. These were studied in patients with TBM in Vietnam, and some polymorphisms showed an increased risk of death and a varied response with dexamethasone.
CRP is a pentameric molecule that is of hepatocyte origin, and it belongs to the pentraxin group of plasma proteins. These are calcium-dependent ligand binders. It was first described as a distinct plasma protein that was detected in the initial phases of an infection in 1930 by Francis and Tiller and was further defined in 1947 by McCarty. Its name is derived from its ability to precipitate the C-polysaccharide of Streptococcus pneumonia. It is one of the mediators of the body's nonspecific acute phase response to any insult – which could possibly be infective, traumatic, inflammatory, or neoplastic. It was one of the first acute-phase reactants to be extensively studied. Normal serum levels of CRP are usually below 1 mg/L, with the 90th percentile being about 3 mg/L.
The hepatic synthesis of CRP is generally regulated by cytokines released at the site of inflammation, and it attains peak values by 48 h. There is also no variation in the production depending on the health status or nutritional status, and only hepatic failure impairs production. The production also does not change based on diet, race, age, sex, and timing of food intake, and there is also no diurnal variation in the synthesis of CRP.
The production is under IL-6 transcriptional control, and the serum levels also rise rapidly within 5 h after an inciting stimulus. It also remains exceptionally stable and lends itself to be a reliable and accurate measurement with immunoassay tests. The production of CRP is driven only by the inciting event. As soon as the stimulus is removed or falls, the levels of circulating CRP drop immediately. The plasma half-life of CRP is about 19 h, and renal clearance is around 4 h, derived from mouse models. Therefore, the CRP value is generally determined only by the rate of production and the levels of circulating CRP reflect very closely the in vivo status of the inciting event. The baseline levels tend to increase with age, probably reflecting underlying undetected subclinical pathologies. Other inflammatory markers do not exhibit the sensitivity and rapid response to inflammation as CRP. Serum amyloid P protein, another member of the pentraxin family, does exhibit similar rises but does not lend itself to easy estimation IL-6 and other cytokines are not practical to measure routinely.
CRP has been used in multiple studies to assess its diagnostic role in differentiating pyogenic meningitis and nonpyogenic meningitis. They revealed that CRP is significantly high in the pyogenic group.,,,, Among TBM patients, the mean CRP level in CSF has been found to be 1.09 mg/dl. Most studies involving CSF CRP demonstrate a marked increase in pyogenic meningitis and only a modest increase in TB. There are no studies looking at the prognostic implication of CSF CRP and its prognostic implications TBM. But, we postulate that still comparing the levels of CSF CRP between TB patients may show a relationship to the extent of the inflammation and thereby adverse outcome. This prospective observational cohort study evaluated the relationship between CSF CRP levels and long-term neurological outcome and mortality in patients with TBM.
The overall mortality in this study was 22.5% of patients, which was significantly lower than what has been described in the literature. The mortality in the group treated with ATT and Steroids in the Thwaites et al. trial was 31.8%. The mortality is though similar to what was reported in another trial done in Canada. The overall reduction, in mortality, maybe due to advances in supportive care, as all the patients included in this study were under care in a tertiary care center. The overall mortality and adverse neurological outcome were seen in 40.8% of patients in this study, indicating the significant morbidity that is associated with TBM. This was similar to the patients treated with ATT and steroids in the Thwaites et al. trial (44.2%).
Cerebrospinal fluid – C reactive protein
The key parameter that was measured in the study was CSF CRP. Compared to Serum CRP results, the range of CSF CRP in patients was significantly different. There was only a modest increase in the CSF CRP levels. This could be explained by the fact that CRP is produced mainly in the liver, and a disrupted blood-brain barrier due to inflammation would be needed for the entry of CRP into the CSF. The CSF CRP levels ranged between 0.1 and 4.8 mg/dl compared with the serum CRP that ranged between 3.0 and 701 in the same group of patients. The mean CSF CRP level in our study was 1.1 mg/dl. This was comparable with earlier studies that showed a mean CSF CRP level of 1.09 mg/dl.
Cerebrospinal fluid C reactive protein as a predictor of outcome
CSF CRP was also noted to be a good predictor of mortality with a relative risk of 2.92 with a significant P-value and a bigger difference between the means (0.64). As shown in [Table 2], it had a similar prediction of hydrocephalus. The Relative risk for a patient with high CSF CRP to develop adverse outcome was 1.84 with a significant P-value and the 95% confidence interval being >1 (1.038–2.864). The means difference (0.57) between the groups was also statistically significant. However, the measure of the association and the scale of difference were small. Hence, despite the statistical significance of the result, the routine use of this test may not be practical as a prognostic marker. And to measure small values of CSF CRP, a highly sensitive kit will be needed.
|Table 2: Differences in outcome in patients with low and high cerebrospinal fluid C reactive protein|
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Predictors of outcome in tuberculosis meningitis
Apart from CSF CRP, all other parameters were also compared with the outcome in TBM. It was interesting to note that HIV positive patients in our study did better than the HIV negative group. The relative risk for adverse outcomes in HIV positive patients was only 0.78, but this was not statistically significant. Previous data show that HIV is a risk factor for adverse neurological outcome. This may be because of the poor immune system and decreased inflammation in HIV-positive patients. The other factors that were significantly associated with the adverse outcome were low Glasgow Coma Scale at presentation, higher MRC class at presentation, diabetes, hydrocephalus, and syndrome of inappropriate antidiuretic hormone (SIADH). The other factors that had no association with outcome were hypertension disseminated TB, CSF counts, CSF protein. Evidence of Stroke in patients with TBM was noted to be the strongest predictor of poor outcome (relative risk of 3.42 with statistical significance), probably because of the neurological sequelae and complications associated with it.
Predictors of mortality in tuberculosis meningitis
Apart from CSF CRP, the key parameters that showed a significant association with mortality were SIADH, Diabetes, MRC grading. The presence of hyponatremia had a very significant association with mortality with a relative risk of 9.76, which was statistically also very significant [Table 3]. Diabetes being significant comorbidity, showed a significant risk of mortality with a relative risk of 4.42. MRC grading showed a significant association but no statistical significance in our study. But, previous data have established the prognostic significance of MRC grading at the time of diagnosis beyond doubt. As described earlier, even in mortality, the subgroup that had HIV had a protective effect.,
|Table 3: The different factors contributing to death in patients with tuberculosis meningitis|
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The limitations of this study included (i) small sample size, (ii) shorter duration of follow-up, (iii) exclusion of potential TBM patient's due to unavailability of CSF samples for these patients, (iv) nonavailability of follow-up imaging. We also did not study either impact of drug susceptibility, multidrug regimen, the role of corticosteroid, and other medication interactions in this subgroup of patients. Follow-up was mostly telephonic as most of the patients were from locations that were far away. However, the strength of the study was strict inclusion criteria, multidisciplinary management, availability of robust neuroimaging, and structured follow-up TBM patients.,
| Conclusion|| |
TBM is a disease with significant mortality and morbidity. CRP level in the CSF can be measured, but a highly sensitive scale may be needed as the mean values are much lower compared to the serum values. CSF CRP levels showed significant associations with adverse outcomes and mortality. It has a promising role in predicting neurological outcome.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]