Analysis of Factors Influencing Multidrug-Resistant Tuberculosis and Validation of Whole-Genome Sequencing in Children with Drug-Resistant Tuberculosis

Abstract

Objective Pediatric tuberculosis (TB) is one of the top ten causes of death in children. Our study was to analyze influencing factors of multidrug-resistant tuberculosis (MDR-TB) and validation of whole-genome sequencing (WGS) used in children with drug-resistant TB (DR-TB). Methods All Mycobacterium tuberculosis (Mtb) strains were isolated from patients aged below 18 years old of Children’s Hospital of Chongqing Medical University, China. A total of 208 Mtb isolates were tested for eight anti-TB drugs with phenotypic drug susceptibility test (DST) and for genetic prediction of the susceptible profile with WGS. The patients corresponding to each strain were grouped according to drug resistance and genotype. Influencing factors of MDR-TB and DR-TB were analyzed. Results According to the phenotypic DST and WGS, 82.2% of Mtb strains were susceptible to all eight drugs, and 6.3% were MDR-TB. Using the phenotypic DSTs as the gold standard, the kappa value of WGS to predict isoniazid, rifampin, ethambutol, rifapentine, prothionamide, levofloxacin, moxifloxacin and amikacin was 0.84, 0.89, 0.59, 0.86, 0.89, 0.82, 0.88 and 1.00, respectively. There was significant difference in the distribution of severe TB, diagnosis, treatment and outcome between MDR and drug-susceptible group (P<0.05). The distribution of severe TB and treatment between DR and drug-susceptible group was statistically different (P<0.05). The results of binary logistic regression showed that Calmette–Guérin bacillus (BCG) vaccine is the protective factor for MDR-TB (OR=0.19), and MDR-TB is the risk factor for PTB and EPTB (OR=17.98). Conclusion The BCG vaccine is a protective factor for MDR-TB, and MDR-TB might not be confined to pulmonary infection, spreading to extrapulmonary organs in children. MDR-TB had more severe cases and a lower recovery rate than drug-susceptible TB. WGS could provide an accurate prediction of drug susceptibility test results for anti-TB drugs, which are needed for the diagnosis and precise treatment of TB in children.

Trends and risk factors for drug-resistant tuberculosis among children in Sichuan, China: A 10-year retrospective analysis, 2013–2022

“…Reasons for consideration: First, although young children are immunocompromised and more susceptible to tuberculosis infection, they have a narrower contact surface and are more susceptible to direct transmission from adult patients, whereas older children have a wider contact surface but relatively higher immunity and relatively less risk of TB infection. [19][20][21] Second, the treatment methods for children of different age groups are basically the same, and under effective treatment and active preventive measures, so the age difference has little effect on the risk of DR-TB. Third, contact duration in the household and with individuals with tuberculosis are risk factors for tuberculosis, most cases of tuberculosis in children are caused by household contacts.…”

Phylogenetic lineages of tuberculosis isolates and their association with patient demographics in Tanzania

“…Although previous treatment for TB is the strongest risk factor for development of DR-TB [32][33][34][35], treatment-naïve patients may also acquire drug resistance due to either transmission of resistant strains or spontaneous mutations. In our study we report strains resistant to some SLDs which are not being used to treat TB in Tanzania.…”

“…Other studies (not including national anti-TB surveys) [7,32] have found that WGS testing of anti-TB drugs has the potential to provide comprehensive resistance detection much faster, with improved turnaround times, allowing for prompt appropriate treatment and associated patient and health-care benefits. [33].…”

Trends and challenges of multi-drug resistance in childhood tuberculosis

“…WGS can thoroughly detect all genes related to drug resistance, which can provide valuable information for clinical treatment, particularly for MDR-TB (Votintseva et al, 2017;Doyle et al, 2018). WGS has also been studied for the identification of MDR-TB in children (Zhang et al, 2021). Compared with the conventional phenotypic drug susceptibility test (DST), it provides accurate results for both first-line and second-line anti-TB drugs.…”