Cerebrospinal Fluid Bacillary Load by Xpert MTB/RIF Ultra Polymerase Chain Reaction Cycle Threshold Value Predicts 2-Week Mortality in Human Immunodeficiency Virus–Associated Tuberculous Meningitis

Martyn, Emily; Bangdiwala, Ananta S; Kagimu, Enock; Rutakingirwa, Morris K; Kasibante, John; Okirwoth, Michael; Stead, Gavin; Wadda, Vincent; Pullen, Matthew F; Bold, Tyler D.; Meya, David B.; Boulware, David R.; Bahr, Nathan C; Cresswell, Fiona V

doi:10.1093/cid/ciaa1444

Cited by 10 publications

(7 citation statements)

References 21 publications

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“…Prevotella in bronchoalveolar lavage fluid also positively correlates with SCFA concentrations and independently predicts incident TB in people without co-prevalent TB 31 . Compared to the other dTBL lymphotypes, “ Mycobacterium” was associated with severe disease and most frequently occurred in PLHIV, agreeing with diagnostics studies that show stronger baseline mycobacterial PCR test readouts predict long term clinical outcomes in pulmonary 32 and extrapulmonary TB 33 . Together, these data show distinct lymphotypes are associated with different clinical characteristics and suggests that patients with the most severe Mycobacterium-dominated lymphotype may initially progress through different site-of-disease microbial states characterised by Corynebacterium-, Streptococcus- and/or Prevotella -domination.…”

Section: Discussionsupporting

confidence: 84%

More than Mycobacterium tuberculosis: specific site-of-disease microbial communities, functional capacities, and their distinct clinical profiles in tuberculous lymphadenitis

Nyawo

Naidoo

et al. 2022

Preprint

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Background: Lymphadenitis is the most common extrapulmonary tuberculosis (EPTB) manifestation and a major cause of death. The microbiome is important to human health but uninvestigated in EPTB. We profiled the site-of-disease lymph node microbiome in tuberculosis lymphadenitis (TBL). Methods: Fine needle aspiration biopsies (FNABs) were collected from 159 pre-treatment presumptive TBL patients in Cape Town, South Africa. 16S Illumina MiSeq rRNA gene sequencing was done. Results: We analysed 89 definite TBLs (dTBLs) and 61 non-TBLs (nTBLs), which had similar α- but different β-diversities (p=0.001). Clustering identified five lymphotypes prior to TB status stratification: Mycobacterium-, Prevotella- and Streptococcus-dominant lymphotypes were more frequent in dTBLs whereas a Corynebacterium-dominant lymphotype and a fifth lymphotype (no dominant taxon) were more frequent in nTBLs. When restricted to dTBLs, clustering identified a Mycobacterium-dominant lymphotype with low α-diversity and other non-Mycobacterium-dominated lymphotypes (termed Prevotella-Corynebacterium and Prevotella-Streptococcus). The Mycobacterium dTBL lymphotype was associated with HIV-positivity and clinical features characteristic of severe lymphadenitis (e.g., node size). dTBL microbial communities were enriched with potentially proinflammatory microbial short chain fatty acid metabolic pathways (propanoate, butanoate) vs. those in nTBLs. 11% (7/61) of nTBLs had Mycobacterium reads. Conclusions: TBL at the site-of-disease is not microbially homogenous and distinct microbial community clusters exist that are associated with different immunomodulatory potentials and clinical characteristics. Non-Mycobacterium-dominated dTBL lymphotypes, which contain taxa potentially targeted by TB treatment, represent less severe potentially earlier stage disease. These investigations lay foundations for studying the microbiome's role in lymphatic TB and the long-term clinical significance of lymphotypes requires prospective evaluation.

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Section: Discussionsupporting

confidence: 84%

More than Mycobacterium tuberculosis: specific site-of-disease microbial communities, functional capacities, and their distinct clinical profiles in tuberculous lymphadenitis

Nyawo

Naidoo

et al. 2022

Preprint

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“…While FujiLAM was falsely negative for some patients with positive Xpert Ultra tests, these data suggest that FujiLAM tends to be positive in the highest risk groups of TBM patients. Sensitivity is highest in those with the greatest Xpert Ultra-determined bacillary load, a group previously shown to have increased mortality [25]. FujiLAM-positive patients are more likely to be profoundly immunosuppressed, and tend to have higher mortality, than those who are negative.…”

Section: Discussionmentioning

confidence: 91%

Fujifilm SILVAMP TB LAM Assay on Cerebrospinal Fluid for the Detection of Tuberculous Meningitis in Adults With Human Immunodeficiency Virus

Quinn

Kagimu

Okirworth

et al. 2021

Clinical Infectious Diseases

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Background Tuberculous meningitis (TBM) has a high fatality rate with inadequate diagnostic tests being a major contributor. The rollout of Xpert MTB/Rif and Xpert MTB/Rif Ultra (Xpert Ultra) have improved time-to-diagnosis with sensitivities similar to culture, yet test availability and sensitivity are inadequate. The TB lipoarabinomannan lateral flow assay (AlereLAM) offers ease of use, but its low sensitivity in cerebrospinal fluid (CSF) limits clinical utility for TBM. The Fujifilm SILVAMP TB LAM (FujiLAM) assay has excellent sensitivity in urine, but performance on cerebrospinal fluid is uncertain. Methods We conducted a prospective cohort study at Kiruddu National Referral Hospital in Kampala, Uganda enrolling patients suspected to have TB meningitis. CSF was tested using AlereLAM, Xpert Ultra, culture, and FujiLAM. Results were compared to two reference standards: probable and definite TBM, or definite TBM alone by the uniform TBM case definition. Results Of 101 patients enrolled (95/101 HIV-positive), 34 had definite TBM and 24 had probable TBM. FujiLAM sensitivity on CSF was 52% (30/58) for definite or probable TBM, compared to 55% (32/58) for Xpert Ultra. AlereLAM had lower sensitivity than FujiLAM in the subgroup of patients tested with both assays (14%, 4/28 vs. 50%,14/28; p<0.01). FujiLAM specificity was 98% (42/43) for patients without probable or definite TBM. Conclusions FujiLAM showed higher sensitivity than AlereLAM, with sensitivity potentially approaching that of Xpert Ultra. FujiLAM could improve time-to-treatment-initiation, especially in settings where the more technical Xpert Ultra system might not be feasible. Large confirmatory studies are needed.

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“…This may be explained by that the following: (1) due to non-specific symptoms and poor awareness of infant TBM, a significant patient delay may occur and result in a high bacterial burden; (2) due to the immature immunity of infants, a high CSF TB burden may be common. Moreover, it is worth noting that a high CSF TB burden means an increased risk of seriously poor outcomes [ 17 ]. Two emergency measures should be taken: the first is to increase awareness of infant TBM among the general population; the second is to shorten the diagnostic delay of infant TBM.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid findings of infant tuberculous meningitis: a scoping review

Hou

Liu

et al. 2022

Annals of Medicine

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Background Cerebrospinal fluid (CSF) examinations play an important role in the diagnosis of tuberculous meningitis (TBM). However, their yield in the diagnosis of infant TBM remains unclear. This scoping review aims to detail the role of CSF examination for the diagnosis of infant TBM. Methods A comprehensive literature search of PubMed, EBSCO, Embase, Scopus, Web of Science, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials was performed to identify articles published prior to October 14th, 2021. Articles describing the results of CSF exanimations among infant TBM were eligible for inclusion. Data extracted from each study included age, sex, CSF microbiological evidence (such as AFB smear, TB PCR, and TB culture), and routine CSF examinations (such as appearance, red blood cell count, white blood cell count, protein, and glucose). Results A total of 98 cases were included in the final analysis. The yield of microbiological methods was listed as follows: CSF AFB smear, 20.5% (9/44); CSF TB culture 47.5% (29/61); CSF TB PCR, 65.0% (26/40); the combination of them, 57.3% (47/82). According to Marais criteria, the positivities of CSF examinations were calculated as follows: WBC count (ref, 50–500/μL), 65.5% (55/84); lymphocyte predominance (ref, >0.5), 75.4% (49/65); total protein (ref, >100 mg/dL), 67.8% (59/87); glucose (ref, <2.2 mmol/L, or CSF/serum ratio < 0.5), 68.2% (58/85). Conclusions Our data demonstrated that routine microbiological tools for infant TBM diagnosis have a sensitivity ranging from 20.5% to 65.0%, and most CSF features are non-specific and insufficient to predict a diagnosis of infant TBM. Therefore, further effort is required to develop new tools for infant TBM diagnosis. Key messages: Routine microbiological tools (such as acid-fast bacilli smear, PCR, and culture) have an unsatisfactory sensitivity for infant TBM diagnosis, and most CSF features are non-specific and insufficient to predict a diagnosis of infant TBM. Therefore, further effort is required to develop new tools for infant TBM diagnosis.

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Cerebrospinal Fluid Bacillary Load by Xpert MTB/RIF Ultra Polymerase Chain Reaction Cycle Threshold Value Predicts 2-Week Mortality in Human Immunodeficiency Virus–Associated Tuberculous Meningitis

Cited by 10 publications

References 21 publications

More than Mycobacterium tuberculosis: specific site-of-disease microbial communities, functional capacities, and their distinct clinical profiles in tuberculous lymphadenitis

More than Mycobacterium tuberculosis: specific site-of-disease microbial communities, functional capacities, and their distinct clinical profiles in tuberculous lymphadenitis

Fujifilm SILVAMP TB LAM Assay on Cerebrospinal Fluid for the Detection of Tuberculous Meningitis in Adults With Human Immunodeficiency Virus

Cerebrospinal fluid findings of infant tuberculous meningitis: a scoping review

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