Tuberculous Meningitis: Pathogenesis, Immune Responses, Diagnostic Challenges, and the Potential of Biomarker-Based Approaches

Manyelo, Charles M.; Solomons, Regan; Walzl, Gerhard; Chegou, Novel N.

doi:10.1128/jcm.01771-20

Cited by 43 publications

(53 citation statements)

References 113 publications

(171 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Considering the suboptimal sensitivities of existing immunological and microbiological TB tests in children, the combined use of immune-based tests with culture and nucleic acid amplification tests provides substantially higher positive diagnostic yields; therefore, it should be standard clinical practice in high-resource settings [ 26 ]. Additionally, TB diagnostic tests have been developed and largely validated in adults with pulmonary TB [ 27 ]. Research focusing on the development and validation of biomarkers or tools in children should be encouraged, particularly concerning tests that may be useful in the diagnosis of EPTB.…”

Section: Discussionmentioning

confidence: 99%

Epidemiology of extrapulmonary tuberculosis among pediatric inpatients in mainland China: a descriptive, multicenter study

Chu,

Chang,

Zhang

et al. 2022

Emerging Microbes & Infections

View full text Add to dashboard Cite

Pediatric tuberculosis (TB) is a serious infectious disease that affects many children worldwide and is more likely to be extrapulmonary than adult TB. However, the clinical and epidemiological profile, and cost burden of pediatric extrapulmonary TB (EPTB) in China remain unknown. Here, we conducted a descriptive, multicenter study of pediatric TB patients from 22 hospitals across all six regions in China from October 2015 to December 2018. Of 4,654 patients, 54.23% (2,524) had pulmonary TB (PTB), 17.76% (827) had EPTB, and 28.00% (1,303) had concurrent extrapulmonary and pulmonary TB (combined TB). Compared with PTB, EPTB and combined TB were associated with lower hospitalization frequency (2.43 and 2.21 vs. 3.16 times), longer length of stay (10.61 and 11.27 vs. 8.56 days), and higher rate of discharge against medical advice (8.46% and 9.44% vs. 5.67%). EPTB was associated with higher mortality (0.97% vs. 0.24% and 0.31%), higher rate of low birth weight (17.69% vs. 6.79% and 6.22%), worse diagnosis at the first visit (21.16% vs. 34.67% and 44.47%), and worse hospitalization plan situation (4.35% vs. 7.81% and 7.44%), compared with PTB and combined TB. EPTB and combined TB had higher financial burdens (17.67% and 16.94% vs. 13.30%) and higher rates of catastrophic expenditure (8.22% and 9.59% vs. 5.03%), compared with PTB. Meningitis TB (34.18%) was the most frequent form of total extrapulmonary infection and had the highest cost burden and rate of catastrophic expenditure. In conclusion, improved screening approaches for pediatric EPTB are needed to reduce diagnostic challenges and financial burden.

show abstract

Section: Discussionmentioning

confidence: 99%

Epidemiology of extrapulmonary tuberculosis among pediatric inpatients in mainland China: a descriptive, multicenter study

Chu,

Chang,

Zhang

et al. 2022

Emerging Microbes & Infections

View full text Add to dashboard Cite

show abstract

“…The infected immune cells from the alveoli migrate to the lymphoid tissue, activating type 1 T-helper cells, producing pro-inflammatory cytokines such as interleukins (IL) and tumor necrosis factor alpha (TNF-α). These initial immune reactions lead to inflammatory changes in the lungs ( 30 , 34 – 36 ). The Ghon focus, the primary site of infection in the lungs, enlarges as the disease progresses or the foci heal, leading to dense scars that may calcify ( 37 ).…”

Section: Brief Overview Of Tbmentioning

confidence: 99%

“…Macrophage infection triggers a localized pro-inflammatory response, resulting in the recruitment of activated innate immune components, including the neutrophils and dendritic cells. This then leads to the secretion of antimicrobial peptides (e.g., cathelicidin), cytokines (including IL-1α, IL-1β, TNF-α, IL-6 and IL-12), chemokines and additional macrophages that convene into a TB granuloma – a multicellular structure that cloisters the infecting Mtb from the surrounding tissue ( 36 , 50 , 72 , 73 ). The formation of the TB granuloma is controlled by chemokines and cytokines, produced by local tissue cells and infiltrating leukocytes ( 74 , 75 ).…”

Section: Tb Granuloma Function and Importancementioning

confidence: 99%

Tuberculous Granuloma: Emerging Insights From Proteomics and Metabolomics

et al. 2022

View full text Add to dashboard Cite

Mycobacterium tuberculosis infection, which claims hundreds of thousands of lives each year, is typically characterized by the formation of tuberculous granulomas — the histopathological hallmark of tuberculosis (TB). Our knowledge of granulomas, which comprise a biologically diverse body of pro- and anti-inflammatory cells from the host immune responses, is based mainly upon examination of lungs, in both human and animal studies, but little on their counterparts from other organs of the TB patient such as the brain. The biological heterogeneity of TB granulomas has led to their diverse, relatively uncoordinated, categorization, which is summarized here. However, there is a pressing need to elucidate more fully the phenotype of the granulomas from infected patients. Newly emerging studies at the protein (proteomics) and metabolite (metabolomics) levels have the potential to achieve this. In this review we summarize the diverse nature of TB granulomas based upon the literature, and amplify these accounts by reporting on the relatively few, emerging proteomics and metabolomics studies on TB granulomas. Metabolites (for example, trimethylamine-oxide) and proteins (such as the peptide PKAp) associated with TB granulomas, and knowledge of their localizations, help us to understand the resultant phenotype. Nevertheless, more multidisciplinary ‘omics studies, especially in human subjects, are required to contribute toward ushering in a new era of understanding of TB granulomas – both at the site of infection, and on a systemic level.

show abstract

“… 57 This form of TB is typically the most severe, as up to 50% of people die or suffer neurological complications. 57 In PLHIV, in whom 40% of TB is extrapulmonary (compared to the 10% in HIV-negative patients), there is a fivefold increase of the likelihood of CNS involvement. 58 PLHIV who get TB meningitis will commonly present with extrameningeal involvement and are more likely to suffer from altered mental status.…”

Section: Challenges That Drive Tb-related Mortality In Plhivmentioning

confidence: 99%

Addressing TB-related mortality in adults living with HIV: a review of the challenges and potential solutions

Sullivan

Nathavitharana

2022

Therapeutic Advances in Infection

View full text Add to dashboard Cite

Tuberculosis (TB) is the leading cause of death in people living with HIV (PLHIV) globally, causing 208,000 deaths in PLHIV in 2019. PLHIV have an 18-fold higher risk of TB, and HIV/TB mortality is highest in inpatient facilities, compared with primary care and community settings. Here we discuss challenges and potential mitigating solutions to address TB-related mortality in adults with HIV. Key factors that affect healthcare engagement are stigma, knowledge, and socioeconomic constraints, which are compounded in people with HIV/TB co-infection. Innovative approaches to improve healthcare engagement include optimizing HIV/TB care integration and interventions to reduce stigma. While early diagnosis of both HIV and TB can reduce mortality, barriers to early diagnosis of TB in PLHIV include difficulty producing sputum specimens, lower sensitivity of TB diagnostic tests in PLHIV, and higher rates of extra pulmonary TB. There is an urgent need to develop higher sensitivity biomarker-based tests that can be used for point-of-care diagnosis. Nonetheless, the implementation and scale-up of existing tests including molecular World Health Organization (WHO)-recommended diagnostic tests and urine lipoarabinomannan (LAM) should be optimized along with expanded TB screening with tools such as C-reactive protein and digital chest radiography. Decreased survival of PLHIV with TB disease is more likely with late HIV diagnosis and delayed start of antiretroviral (ART) treatment. The WHO now recommends starting ART within 2 weeks of initiating TB treatment in the majority of PLHIV, aside from those with TB meningitis. Dedicated TB treatment trials focused on PLHIV are needed, including interventions to improve TB meningitis outcomes given its high mortality, such as the use of intensified regimens using high-dose rifampin, new and repurposed drugs such as linezolid, and immunomodulatory therapy. Ultimately holistic, high-quality, person-centered care is needed for PLHIV with TB throughout the cascade of care, which should address biomedical, socioeconomic, and psychological barriers.

show abstract

Tuberculous Meningitis: Pathogenesis, Immune Responses, Diagnostic Challenges, and the Potential of Biomarker-Based Approaches

Cited by 43 publications

References 113 publications

Epidemiology of extrapulmonary tuberculosis among pediatric inpatients in mainland China: a descriptive, multicenter study

Epidemiology of extrapulmonary tuberculosis among pediatric inpatients in mainland China: a descriptive, multicenter study

Tuberculous Granuloma: Emerging Insights From Proteomics and Metabolomics

Addressing TB-related mortality in adults living with HIV: a review of the challenges and potential solutions

Contact Info

Product

Resources

About