Epidemiology of Tuberculosis and the Diagnostic Performance of Lipoarabinomannan Assay for Tuberculosis Testing Among Patients With Chronic Kidney Disease and Diabetes Mellitus in Ethiopia
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Date
2025-11-01
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Addis Ababa University
Abstract
Background: Individuals With Chronic Kidney Disease (CKD) And Diabetes Mellitus (DM) Have A High Risk of Tuberculosis (TB). The Prevalence of CKD And DM Is Alarmingly Rising in Low and Middle-Income Countries, Including Ethiopia, Where TB Is a Significant Public Health Problem, Potentially Complicating TB Prevention and Control Efforts. However, The Epidemiology of TB Among CKD And DM Patients Is Less Explored in Ethiopia. This Study Generated Data on the Epidemiology of TB And the Diagnostic Value of the Determinetm Alere Lateral Flow Lipoarabinomannan (Alere LF-LAM) Assay for TB Testing Among These Patient Groups.
Objective: To Study the Prevalence, Associated Factors, Genomic Diversity, And Drug-Sensitivity Patterns of Mycobacterium Tuberculosis Complex (MTBC), And the Diagnostic Performance of the Alere LF-LAM Assay for TB Testing Among Patients with CKD And DM Who Attended Selected Public Health Facilities in Ethiopia. It Also Investigated the Diversity of Non-Tuberculous Mycobacteria (NTM) And Probe Amplifications in the Genexpert Assays.
Methods: A Health-Facility-Based Cross-Sectional Study Was Employed Among Patients with CKD And DM Who Attended the Selected 11 Health Facilities from January to December 2023. Socio Demographic, Behavioral, Clinical, And Environmental Data Were Collected from Patients with Signs and Symptoms Suggestive of TB Using a Pre-Tested Questionnaire. Morning Sputum and Midstream Urine Specimens Were Collected and Transported to the Ethiopian Public Health Institute for Smear Microscopy, Culture, And Xpert MTB/RIF Ultra Assay Examinations. The Urine Specimen Was Also Tested Using the Alere LF-LAM Assay. The MTBC Isolates Were Examined Using Phenotypic Drug Susceptibility Testing (DST), Line Probe Assays, Genexpert Assays, And Whole-Genome Sequencing (WGS). The NTM Isolates Were Characterized Using the Genotype Common Mycobacterium (CM) And Additional Species (AS) Assays, And Assessed for Probe Amplification Using the Genexpert Assays. Data Were Entered into Epiinfo Version 7.2 And Analyzed Using SPSS Version 27. Descriptive Statistics Were Employed to Characterize Study Variables. Association Between Variables Was Assessed Using the Chi-Squared Test, And A Logistic Regression Model Was Computed to Identify Independently Associated Variables. Amplified Probes' Cycle Threshold (CT) Values Were Compared Across Categories Using the Mann-Whitney U And Kruskal-Wallis Tests. A 95% CI Of the Estimates Was Computed, And Those Variables with a P-Value < 0.05 Were Considered to Have a Statistically Significant Association. The Diagnostic Performance Measurements, Such As Agreement, Sensitivity, And Specificity of the Alere LF-LAM Assay, Were Determined. The Illumina Nextseq Ii 550 Instrument Was Used to Generate Genomic Data, And A Bioinformatics Pipeline, Tbprofiler V6.4.0, Was Used for the Downstream Analysis of Genomic Data.
Results: In Total, 1033 Study Participants (CKD; 381, DM; 652) Were Enrolled. Tuberculosis Was Detected Among 12.9% (49) Of CKD Patients And 11.2% (73) Of DM Patients. Among CKD Patients, Those With Previous Or Current Cigarette Smoking History (Aor; 2.82), Decreased Appetite (Aor; 5.97), Night Sweats (Aor; 2.21), DM Comorbidity (Aor; 3.01), Positive Dipstick Albuminuria (Aor; 5.55), < 1 Year Follow-Up In The Renal Unit (Aor; 9.49), BMI < 18.5 Kg/M2 (Aor; 6.69), And On Hemodialysis (Aor; 4.41) Had A Statistically Significant Association With Having TB. The Independently Associated Factors Of TB Among DM Patients Were Being Younger Age Group (15-24 Years; Aor; 10.98, 25-34 Years; Aor; 4.74, 35-44 Years; Aor; 5.70, And 45-54 Years; Aor; 2.68), Cough Lasting ≥ 2 Weeks (Aor; 2.73), Cigarette Smoking (Aor; 7.50), Contact With A Known TB Case (Aor; 9.16), HIV Seropositivity (Aor; 4.40), >10 Years Of DM Follow-Up (Aor; 4.87), Insulin Medication (Aor; 3.00), And Fasting Blood Sugar Level >126 Mg/Dl (Aor; 2.72). Among 47 MTBC Isolates with Valid WGS Results, Four M. Tuberculosis Lineages, Lineage 4 (33, 70.2%), Lineage 3 (12, 25.5%), Lineage 2 (1, 2.1%), And Lineage 1 (1, 2.1%), And M. Bovis Lineage La1 (1, 2.1%) Were Detected. Fifteen Sublineages Were Identified, With L4.2.2.2 (13, 27.7%) And L3 (10, 21.3%) Being the Most Frequent. Based On ≤ 5 Single-Nucleotide Polymorphism Distances, Six Genomic Clusters Comprising 25 Isolates (53.2%) Were Identified. The NTM Was Identified Among 9.39% (93) Of 990 Patients (369 With CKD And 621 With DM) With Valid Culture Results, With 13.01% (48) And 7.25% (45) Positivity Among CKD And DM Patients, respectively. Among The NTM Isolates, 87 Had Valid Genotype CM And AS Assay Results, With M. Fortuitum Group (45, 51.7%), Mycobacterium Species (17, 19.5%), M. Simiae (8, 9.2%), M. Gordonae (7, 8.0%), And M. Avium Complex (6, 6.9%) Being Most Frequently Identified. Any Drug Resistance and Multi-Drug Resistance Were Detected Among 25.0% (19) And 7.9% (6) Of MTBC Isolates, respectively. Resistance To Streptomycin (STR), Isoniazid (INH), Rifampicin (RIF), Ethambutol, Pyrazinamide (PZA), And Fluoroquinolones (FLQ) Was 11.8% (9), 13.2% (10), 10.5% (8), 6.6% (5), 11.8% (9), And 1.3% (1), Respectively. The Common RIF And INH-Resistant Conferring Mutations Were Rpob P. Ser450Leu and Katg P. Ser315Thr, respectively. Resistance To STR Was Detected in the Rpsl and Gid Genes, Whereas Resistance To PZA, EMB, And FLQ Was Detected in the Pnca, Embb, And Gyra Gene, respectively. Any Drug Resistance Was Detected Among Four (33.3%) Lineage 3, And Three (9.1%) Lineage 4 Strains. Previous TB Treatment (Aor; 6.14) And TB Contact History (Aor; 6.14) Were Associated with Any DR-TB. The Overall Test Agreement, Sensitivity, And Specificity of the Alere LF-LAM Assay in Detecting TB Cases Were 74.4% (95%CI; 71.6-77.0%), 46.7% (95%CI; 37.6-56.0%), And 78.1% (95%CI; 75.2-80.7%), Respectively. All The Tested 87 NTM Isolates Had Negative Results in the Genexpert Assays. Of Them, 88.5% (77) And 78.2% (68) Had At Least One Rpob Probe Amplification in the Xpert MTB/RIF Ultra Assay and Xpert MTB/RIF Assay, respectively. The Most Common Amplified Probes in the Xpert MTB/RIF Ultra And Xpert MTBB/RIF Assays Were Rpob2 (77, 88.5%) And Probe C (64, 73.6%), Respectively. The CT Value for Rpob2 (X2=18.857, P=0.016) And Probe C (X2=13.199; P=0.041) Had A Statistically Significant Difference Among the NTM Species.
Conclusions: Tuberculosis, Including Drug-Resistant TB, Is A Substantial Cause of Morbidity Among CKD And DM Patients in Ethiopia. Diverse M. Tuberculosis Lineages (L1-L4), And M. Bovis (La1), Comprising 15 Sub-Lineages, Were Detected, L4.2.2.2 And L3 Being the Most Frequent Sublineages. Genomic Clusters Were Detected. Any Type of Anti-TB Drug Resistance Was Detected Among the Identified Lineages Except L1. The TB Risk Was Higher Among Certain Patient Groups, Necessitating Strengthening Targeted Programmatic Interventions Such as Active and Regular TB Screening and Surveillance. The Ntms Are Also Common Among TB-Presumptive CKD And DM Patients, Necessitating Screening For NTM. The Alere LF-LAM Assay Has a Promising Diagnostic Performance for Rapid Point-Of-Care TB Testing in CKD And DM Patients. The Rpob Probe Amplifications Observed in the Genexpert Negative Specimens May Be Important in Suggesting the Presence of Ntms in the Specimens. The National TB Program Should Work to Strengthen the Integration of TB Prevention and Control Activities into the Routine CKD And DM Care, Including Active TB Screening, Contact Investigation, Implementing Infection Prevention Activities, and Considering NTM in its Program Management.
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Keywords
Chronic kidney disease, Drug-resistance, Diabetes Mellitus, Ethiopia, Lateral-flow lipoarrabinomannan assay, Mycobacterial lineages, Probe amplification, Non-tuberculous mycobacteria, Tuberculosis