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. 2024 Jun 25;9(2):25-42.
doi: 10.20411/pai.v9i2.705. eCollection 2024.

A Transcriptomic Biomarker Predicting Linezolid-Associated Neuropathy During Treatment of Drug-Resistant Tuberculosis

Nika Zielinski  1   2   3 , Dragos Baiceanu  4   5 , Antonela Dragomir  4   5   6 , Jan Heyckendorf  7 , Elmira Ibraim  4   5 , Niklas Köhler  1   2   3 , Christoph Leschczyk  2   8 , Cristina Popa  4   5 , Andrea Rachow  9   10   11 , Jens Sachsenweger  12 , Patricia Sanchez Carballo  1   2   3 , Dagmar Schaub  1   2   3 , Hajo Zeeb  13   14 , Begna Tulu  1   2   3 , Andrew R DiNardo  15   16 , Christoph Lange  1   2   3   15 , Maja Reimann  1   2   3
Affiliations

A Transcriptomic Biomarker Predicting Linezolid-Associated Neuropathy During Treatment of Drug-Resistant Tuberculosis

Nika Zielinski et al. Pathog Immun. .

Abstract

Background: Neuropathic adverse events occur frequently in linezolid-containing regimens, some of which remain irreversible after drug discontinuation.

Objective: We aimed to identify and validate a host RNA-based biomarker that can predict linezolid-associated neuropathy before multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment initiation and to identify genes and pathways that are associated with linezolid-associated neuropathy.

Methods: Adult patients initiating MDR/RR-TB treatment including linezolid were prospectively enrolled in 3 independent cohorts in Germany. Clinical data and whole blood RNA for transcriptomic analysis were collected. The primary outcome was linezolid-associated optic and/or peripheral neuropathy. A random forest algorithm was used for biomarker identification. The biomarker was validated in an additional fourth cohort of patients with MDR/RR-TB from Romania.

Results: A total of 52 patients from the 3 identification cohorts received linezolid treatment. Of those, 24 (46.2%) developed peripheral and/or optic neuropathies during linezolid treatment. The majority (59.3%) of the episodes were of moderate (grade 2) severity. In total, the expression of 1,479 genes differed significantly at baseline of treatment. Suprabasin (SBSN) was identified as a potential biomarker to predict linezolid-associated neuropathy. In the validation cohort, 10 of 42 (23.8%) patients developed grade ≥3 neuropathies. The area under the curve for the biomarker algorithm prediction of grade ≥3 neuropathies was 0.63 (poor; 95% confidence interval: 0.42 - 0.84).

Conclusions: We identified and preliminarily validated a potential clinical biomarker to predict linezolid-associated neuropathies before the initiation of MDR/RR-TB therapy. Larger studies of the SBSN biomarker in more diverse populations are warranted.

Keywords: SBSN; adverse events; linezolid; multidrug resistance; neurotoxicity; precision medicine; tuberculosis.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Figure 1.
Figure 1.
Flow chart for study inclusion and reason for exclusion in identification and validation cohort. GIC = German Identification Cohort; GVC = German Validation Cohort, SCVC = Second German Validation Cohort; EESSC = Eastern European Study Side Cohort; MDR/RR-TB = Multidrug-resistant/rifampicin-resistant tuberculosis; XDR-TB = Extensive drug-resistant tuberculosis
Figure 2.
Figure 2.
Kaplan-Meier curve with 95% confidence interval for the cumulative probability of linezolid-associated neuropathies during the course of linezolid treatment. The entire identification cohort (n=52) from 0 – 600 days is considered. Censored patients are shown with a cross in the curve.
Figure 3.
Figure 3.
Heat map of 1,479 statistically significant differentially expressed genes prior to treatment initiation. The heat map shows the genes on patient-level and z score normalized. The in rows and columns are hierarchically clustered. Upregulated genes are colored red and downregulated genes are colored blue. The annotation highlights patients with (orange; AE = linezolid-associated neuropathy) and patients without linezolid-associated neuropathy (green; NOAE = no linezolid-associated neuropathy) across the top of the heat map.
Figure 4.
Figure 4.
Selected statistically significant differentially expressed pathways and genes in the group of patients with linezolid-associated neuropathy (AE) or without linezolid-associated neuropathy (NOAE). Figure 4A. Over-representation analysis using the molecular signature of database for Hallmark, Reactome, KEGG, and Wikipathways. Figure 4B. Violin plots of z score standardized gene expression levels grouped by biological function. Figure 4C. Violin plot of the SBSN z score standardized gene expression levels.
Figure 5.
Figure 5.
Receiver-Operator Characteristic (ROC) for evaluation of the prediction power of the biomarker algorithm in the validation population. Shown is the ROC curve with the area under the curve (AUC) for predicting linezolid-associated neuropathies with grade 3 or higher in the validation cohort (AUC = 0.628 [95%CI: 0.415 – 0.841]).
See this image and copyright information in PMC

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