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A total of 11,155 patients with pulmonary TB were reported from January 1 to December 31, 2020, of which 1,869 were culture-positive. Of the 1,869 patients, 201 were excluded because of infection with non-tuberculosis mycobacteria (NTM), contaminated strains, or ineligible whole-genome sequences, leaving 1,668 patients (Figure 1). For the 1,630 patients with demographic and clinical information (such information was lacking for the remaining 38 patients), the median age was 62 years (interquartile range, 42–71 years). Half of the patients (50.0%, 815/1,630) were male and the majority (81.7%, 1,331/1,630) were farmers (Table 1).
Figure 1. Patient enrollment and study flowchart. NTM, non-tuberculosis mycobacteria; PTB, pulmonary TB.
Variables Total New cases Previously treated cases χ2 P value Demographic factors Sex 0.535 0.464 Female 815 (50.0) 651 (50.5) 164 (48.2) Male 815 (50.0) 639 (49.5) 176 (51.8) Age (years) 40.268 < 0.001 0– 332 (20.4) 291 (22.6) 41 (12.0) 36– 175 (10.7) 152 (11.8) 23 (6.8) 51– 431 (26.4) 346 (26.8) 85 (25.0) ≥ 66 692 (42.5) 501 (38.8) 191 (56.2) Ethnic group 1.237 0.266 Uighur 1,593 (97.7) 1,258 (97.5) 335 (98.5) Others 37 (2.3) 32 (2.5) 5 (1.5) Occupation 6.463 0.091 Farmers or pastoralists 1,331 (81.7) 1,040 (80.6) 291 (85.6) Housekeeping or unemployed 184 (11.3) 151 (11.7) 33 (9.7) Students 54 (3.3) 49 (3.8) 5 (1.5) Others 61 (3.7) 50 (3.9) 11 (3.2) Clinical factors Smear 0.321 0.571 Negative 1,128 (69.2) 897 (69.5) 231 (67.9) Positive 502 (30.8) 393 (30.5) 109 (32.1) HIV 0.177 0.674 Negative 1,560 (95.7) 1,236 (95.8) 324 (95.3) Unknown 70 (4.3) 54 (4.2) 16 (4.7) Patient source 2.948 0.229 Health check or proactive screening 1,008 (61.8) 796 (61.7) 212 (62.4) Referrals 392 (24.0) 303 (23.5) 89 (26.2) Direct consultation 230 (14.1) 191 (14.8) 39 (11.5) Treatment outcome 12.266 < 0.001 Unfavorable outcomes 94 (5.8) 61 (4.7) 33 (9.7) Others 1,536 (94.2) 1,229 (95.3) 307 (90.3) Total delay (weeks) 13.865 0.003 < 4 672 (41.2) 533 (41.3) 139 (40.9) 4– 439 (26.9) 362 (28.1) 77 (22.6) 8– 337 (20.7) 269 (20.9) 68 (20.0) ≥ 12 182 (11.2) 126 (9.8) 56 (16.5) Note. For demographic and clinical factors, N = 1,630. Table 1. Demographic and clinical information of patients included in the study (n, %)
The proportion of previously treated cases in Kashgar was 20.9% (340/1,630). Compared with new cases, previously treated cases tended to be older than 65 years (38.8% of new cases vs. 56.2% of previously treated cases, P < 0.001). In addition, they were associated with a total delay (period from symptom onset to treatment initiation) of > 12 weeks (9.8% vs. 16.5%, P = 0.003) and unfavorable treatment outcomes (4.7% vs. 9.7%, P < 0.001) (Table 1).
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The whole genomes of 1,668 Mycobacterium tuberculosis (MTB) strains isolated from patients were sequenced with an average depth of 215.6 × (23.5× – 476×) and a coverage of 98.6% (97.8%–99.2%). Based on the phylogenetic analysis, these isolates were grouped into three lineages: 46.0% (768/1,668) belonged to lineage 2 (All were Beijing strains), 27.5% (458/1,668) belonged to lineage 3, and 26.5% (442/1,668) belonged to lineage 4 (Figure 2).
Figure 2. The phylogenetic tree of 1,668 MTB strains isolated in Kashgar. The different colors on the branches indicate different lineages. The inner circle (marked with 1) indicates genomic clustered strains. The outside circle (marked with 2) indicates the drug resistance pattern.
Analysis of the genome sequences for drug resistance-conferring mutations showed that 13.4% (223/1,668) of the strains were resistant to at least one of the 13 drugs (Table 2). Thirty resistance profiles were identified, with the highest proportion of cases being resistant to only one drug (8.2%, 136/1,668). (Supplementary Table S1, available in www.besjournal.com). The drug with the highest single-drug resistance rate was isoniazid (7.4%, 124/1,668). Streptomycin ranked second (6.0%, 100/1,668). The third was rifampicin (3.3%, 55/1,668). The rate of rifampicin resistance was 1.8% (23/1,290) in the new cases and 9.4% (32/340) in the previously treated cases. The multidrug resistance rate was 0.8% (10/1,290) in newly diagnosed cases and 6.2% (21/340) in previously treated cases.
Drug resistance mutation types Total New case Previously treated cases Unknown χ2 P value First-line drugs Isoniazid 124 (7.4) 78 (6.0) 42 (12.4) 4 (10.5) 15.692 < 0.001 Rifampin 55 (3.3) 23 (1.8) 32 (9.4) 0 (0.0) 48.032 < 0.001 Ethambutol 15 (0.9) 7 (0.5) 8 (2.4) 0 (0.0) 7.788 0.005 Pyrazinamide 7 (0.4) 6 (0.5) 0 (0.0) 1 (2.6) 1.587 0.208 Streptomycin 100 (6.0) 71 (5.5) 28 (8.2) 1 (2.6) 3.519 0.061 Second-line drugs Fluoroquinolones 12 (0.7) 8 (0.6) 4 (1.2) 0 (0.0) 0.505 0.477 Ethionamide 25 (1.5) 18 (1.4) 6 (1.8) 1 (2.6) 0.253 0.615 Kanamycin 4 (0.2) 2 (0.2) 2 (0.6) 0 (0.0) Fisher 0.194 Amikacin 4 (0.2) 2 (0.2) 2 (0.6) 0 (0.0) 1.662 0.197 Capreomycin 4 (0.2) 2 (0.2) 2 (0.6) 0 (0.0) Fisher 0.194 Para-aminosalisylic acid 3 (0.2) 1 (0.1) 2 (0.6) 0 (0.0) Fisher 0.112 New and repurposed drugs Bedaquiline 1 (0.1) 1 (0.1) 0 (0.0) 0 (0.0) Fisher 1.000 Clofazimine 1 (0.1) 1 (0.1) 0 (0.0) 0 (0.0) Fisher 1.000 Linezolid 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) NA NA Multi-drug resistant 31 (1.9) 10 (0.8) 21 (6.2) 0 (0.0) 31.3731 < 0.001 Pan-susceptible 1,445 (86.6) 1,137 (88.1) 275 (80.9) 33 (86.8) 12.232 < 0.001 Note. Chi-square values and P values are the results of statistical tests of drug resistance rates between new and previously treated cases. Table 2. Drug resistance rates predicted using whole-genome sequencing (n, %)
DR mutations were more frequently detected in lineage 2 (18.6%, 143/768) than in lineages 3 (8.7%, 40/458) and 4 (9.0%, 40/442; χ2 = 33.899, P < 0.001). Resistance rates were not statistically different between lineages 3 and 4 (Supplementary Table S2, available in www.besjournal.com).
Drug resistance type lineage3 lineage4 lineage2 χ2 P value Any drug resistance 40 (8.7)a 40 (9.0)b 143 (18.6)ab 33.899 < 0.001 First line drugs Isoniazid 29 (6.3)a 21 (4.8)b 74 (9.6)ab 10.840 0.004 Rifampin 6 (1.3)a 12 (2.7)b 37 (4.8)ab 11.710 0.003 Ethambutol 3 (0.7) 1 (0.2) 11 (1.4) Fisher 0.092 Pyrazinamide 1 (0.2) 1 (0.2) 5 (0.7) Fisher 0.495 Streptomycin 6 (1.3)a 10 (2.3)b 84 (10.9)ab 62.053 < 0.001 Second line drugs Fluoroquinolones 2 (0.4) 4 (0.9) 6 (0.8) Fisher 0.708 Ethionamide 5 (1.1) 8 (1.8) 12 (1.6) 0.825 0.683 Note. aMeans statistically significant between lineage3 and lineage; bMeans statistically significant between lineage4 and lineage2. No statistical difference in the resistance rates of lineage3 and lineage4. Amikacin, kanamycin, capreomycin, bedaquiline, clofazimine, and linezolid were excluded because the number of drug-resistant strains is too low. Table S2. Drug resistance rates between three lineages (n, %)
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The clustering rate is used in epidemiological studies on TB to indicate recent transmission levels. All the strains formed 164 genomic clusters (each cluster contains 2 to 13 strains). The clustering rate was 25.9% (432/1,668). To screen for factors associated with clustered cases, differences in demographic, clinical, and bacteriological factors were compared between the clustered and non-clustered cases (Table 3). The proportion of previously treated cases among the clustered cases was not significantly different from that among the non-clustered cases, suggesting that previously treated cases were not at an increased risk of TB transmission. The clustering rate of lineage 2 (33.4%, 257/768) was significantly higher than those of lineages 3 (16.4%, 75/458) and 4 (22.6%, 100/442; χ2 = 47.013, P < 0.001). No statistical differences were observed in the clustering rates between lineages 3 and 4. Notably, the clustering rate of the DR mutant strains was significantly higher (32.7%, 73/223) than that of the susceptible strains (24.8%, 346/1,412; χ2 = 6.268, P = 0.012).
Variables Total Non-clustered Clustered χ2 P value Demographic factors Sex 28.429 < 0.001 Female 815 (50.0) 653 (53.9) 162 (38.8) Male 815 (50.0) 559 (46.1) 256 (61.2) Age (years) 102.420 < 0.001 0– 70 (4.3) 37 (3.1) 33 (7.9) 21– 262 (16.1) 148 (12.2) 114 (27.3) 36– 175 (10.7) 111 (9.2) 64 (15.3) ≥ 51 1,123 (68.9) 916 (75.6) 207 (49.5) Occupation 22.578 < 0.001 Farmers 1,331 (81.7) 1,011 (83.4) 320 (76.6) Housekeeping or unemployed 184 (11.3) 130 (10.7) 54 (12.9) Students 54 (3.3) 26 (2.1) 28 (6.7) Others 61 (3.7) 45 (3.7) 16 (3.8) Clinical factors TB history 0.093 0.760 New cases 1,290 (79.1) 957 (79.0) 333 (79.7) Previously treated cases 340 (20.9) 255 (21.0) 85 (20.3) Smear 6.200 0.013 Negative 1,128 (69.2) 859 (70.9) 269 (64.4) Positive 502 (30.8) 353 (29.1) 149 (35.6) Patient source 8.663 0.013 Health check or proactive screening 1,008 (61.8) 769 (63.4) 239 (57.2) Referrals 392 (24.0) 289 (23.8) 103 (24.6) Direct consultation 230 (14.1) 154 (12.7) 76 (18.2) HIV 1.283 0.257 Negative 1,560 (95.7) 1,164 (96.0) 396 (94.7) Positve 70 (4.3) 48 (4.0) 22 (5.3) Total delay (weeks) 0.189 0.979 < 4 672 (41.2) 500 (41.3) 172 (41.1) 4– 439 (26.9) 327 (27.0) 112 (26.8) 8– 337 (20.7) 248 (20.5) 89 (21.3) ≥ 12 182 (11.2) 137 (11.3) 45 (10.8) Bacteriological factors Genotype 47.013 < 0.001 Lineage3 458 (27.5) 383 (31.0) 75 (17.4) Lineage4 442 (26.5) 342 (27.7) 100 (23.1) Lineage2 (Beijing genotype) 768 (46.0) 511 (41.3) 257 (59.5) Drug resistance pattern 6.268 0.012 Susceptible 1,445 (86.6) 1,086 (87.9) 359 (83.1) Drug resistant 223 (13.4) 150 (12.1) 73 (16.9) Note. Bacteriological factors, N = 1,668. The demographic and clinical factors were as follows: N = 1,630. Table 3. Demographic, clinical, and bacteriological characteristics of genomic-clustered ornon-clustered cases
The screened factors were then substituted into the logistic models. Multivariate logistic regression analysis determined the following risk factors for recent transmission (Table 4): the risk of clustering was 1.760 times higher in men than in women [95% confidence interval (CI): 1.370–2.260]. It was more common for patients younger than 35 years to be in clusters than for those older than 36 years [adjusted odds ratio (aOR) = 2.230; 95% CI: 1.677–2.966]. Among the various occupations, the risk of clustering was higher for those engaged in housekeeping or the unemployed (aOR = 1.565, 95% CI: 1.076–2.275) and was highest for students (aOR = 1.887, 95% CI: 1.025–3.474). Beijing strains had a 1.681 (95% CI: 1.323–2.136) increase in the risk of forming genomic clusters compared to the other lineages. Drug resistant strains had a higher risk of forming genomic clusters than susceptible strains (aOR = 1.414, 95% CI: 1.023–1.954).
Variables Univariate analysis Multivariate analysis cOR (95% CI) P value aOR (95% CI) P value Sex Male 1.846 (1.471–2.316) < 0.001 1.760 (1.370–2.260) < 0.001 Female Reference Age, years 0–35 3.011 (2.334–3.884) < 0.001 2.230 (1.677–2.966) < 0.001 ≥ 36 Reference Occupation Students 3.385 (1.957–5 .853) < 0.001 1.887 (1.025–3.474) 0.041 Housekeeping or employed 1.305 (0.929–1.835) 0.125 1.565 (1.076–2.275) 0.019 Others Reference Smear Positive 1.348 (1.065–1.706) 0.013 1.166 (0.908 –1.497) 0.230 Negative Reference Patient source Direct consultation 1.480 (1.110–1.974) 0.008 1.218 (0.895–1.659) 0.210 Others Reference Genotype Beijing genotype 2.112 (1.684–2.649) < 0.001 1.681 (1.323–2.136) < 0.001 Non-Beijing genotype Reference Drug resistance pattern Drug resistant 1.519 (1.117–2.066) 0.008 1.414 (1.023–1.954) 0.036 Pan-susceptible Reference Note. cOR, crude odds ratio. aOR, adjusted odds ratio. CI, confidence interval. Table 4. Univariate and multivariate logistic analysis of factors associated with genomic-clustered cases
Kernel density maps were plotted to understand the spatial aggregation of the clustered cases. There were nine spatially concentrated areas (hotspots) of clustered patients, seven of which were also hotspots for nonclustered patients. The remaining two hotspots for clustered patients, one in Bachu County and one at the border between Payzawat and Shule counties, were not hotspots for non-clustered patients.
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Resistant strains have a higher risk of clustering; therefore, they may have primarily been caused by transmission. To test this hypothesis, we quantified transmitted resistance based on the recent transmission of resistance mutations and the treatment history of the patients. Of the 73 clustered resistant strains, 66 had at least one resistance mutation from recent transmission. Mutations in the remaining seven strains were acquired independently. These seven strains, as well as 150 non-clustered strains, were uniformly judged based on the patient’s treatment history. We identified 105 strains isolated from new cases, 47 strains isolated from previously treated cases, and 5 strains isolated from cases with missing information on treatment history (these five strains were excluded from the calculation of proportions, thus the denominator was 218). Resistant strains from previously treated cases may have acquired resistance during the course of treatment, whereas resistant strains from new cases usually indicate direct transmission. Therefore, we inferred that the total proportion of transmitted resistance was 78.4% (171/218) (Figure 3). The percentage of resistance transmitted to all anti-TB drugs was higher than 50% (Table 5).
Figure 3. Flowchart for calculating transmitted resistance. Unknown cases mean the cases with missing information on treatment history.
DRM type No. (%) of transmitted resistance No. of DRMs caused by recent transmission No. of DRMs not confirmed by recent transmission DRMs in New cases DRMs in Previously
treated casesDRMs in unknown cases Any drug resistance (N = 223) 171 (78.4) 66 105 47 5 Isoniazid (N = 124) 86 (71.7) 29 57 34 4 Rifampicin (N = 55) 32 (58.2) 13 19 23 0 Streptomycin (N = 100) 78 (78.8) 36 42 21 1 Ethambutol (N = 15) 9 (60.0) 3 6 6 0 Pyrazinamide (N = 7) 6 (100) 0 6 0 1 Fluoroquinolones (N = 12) 10 (83.3) 6 4 2 0 Ethionamide (N = 25) 19 (76.0) 8 11 5 1 Note. DRM, drug-resistant mutations. Kanamycin (N = 4), capreomycin (N = 4), amikacin (N = 4), para-aminosalicylic acid (N = 3), bedaquiline (N = 1), and clofazimine (N = 1) were excluded because of the low number of drug-resistant mutant strains. Table 5. Interpreted proportion of transmitted drug resistance
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To the best of our knowledge, this is the first systematic population-based study conducted in Kashgar. We found that the proportion of previously treated cases in Kashgar (20.9%; 340/1,630) was almost twice as high as that reported in the latest national TB epidemiological survey (11.8%)[29]. The rates of rifampicin resistance in new and previously treated cases were 1.8% and 9.4%, respectively, and the rates of multidrug resistance were 0.8% and 6.2% in the two categories, respectively. The clustering rate was 25.9%, indicating that the prefecture should be aware of the recent transmission of TB. Bacteriological factors (drug-resistant and Beijing strains) and demographic factors (sex, age, and occupation) were associated with recent transmission. The spatial analysis identified seven areas as hotspots shared by both clustered and non-clustered patients, suggesting a denser population distribution in these areas; two areas were hotspots for clustered patients only, thereby suggesting that these areas may be at a high risk for recent transmission. Transmitted drug resistance was 78.4%, suggesting that transmitted resistance is a more significant cause of drug resistance than acquired resistance in Kashgar.
Based on the information on the included cases, we found a high proportion of previously treated cases, which is a major public health concern. A survey of the treatment outcomes of new smear-positive cases in Kashgar between 2016 and 2018 showed a cure rate of 77%[30], which is below the WHO target of at least an 85% cure rate set in 2005[31]. This low cure rate may explain the high proportion of previously treated patients. Patients with TB in the prefecture are mainly located in rural areas and have low awareness of TB control information and hazards. Therefore, they are prone to discontinue treatment on their own after the initial symptoms have subsided[30]. This finding suggests that Kashgar should strengthen the management of patient treatment processes to improve outcomes.
According to the WGS-based drug susceptibility results, we found that the rates of rifampicin resistance in Kashgar (1.8% in new cases and 9.4% in previously treated cases) were lower than those reported in China and globally. The results of the 2018 National Drug Resistance Surveillance published in November 2022 showed that the rates of rifampicin resistance were 5.08% in new cases and 23.31% in previously treated cases, which were more than twice as high as in Kashgar[32]. WHO published the global estimates of rifampicin-resistant TB as 3%–4% in new cases and 18%–21% in previously treated cases, which were also higher than those in Kashgar[1]. In addition, the resistance rates of the strains in Kashgar to isoniazid, ethambutol, streptomycin, and fluoroquinolones were all lower than those reported in the 2018 National Drug Resistance Surveillance. This suggests that the Kashgar Prefecture in China has low rates of drug resistance.
Based on the genetic distance between the strains, we found that the clustering rate obtained from a one-year sample was 25.9%. As the majority of patients with recent transmission develop active TB within two years of infection[33,34], two years is an ideal time to collect samples. The short sample collection time in this study missed some clustered patients; therefore, the actual clustering rate in Kashgar was > 25.9%. To understand the relative levels of recent transmission in Kashgar, we selected recently published population-based WGS studies for comparison. The clustering rate in Kashgar may be higher than that in low-burden countries; for example, 15.9% from a six-year study in Oxfordshire, UK[35], and lower than that in some high-burden countries in Africa; for example, 66% in Karonga District, Malawi, calculated using strains from three consecutive years[36]. The clustering rate in Kashgar was relatively high when compared to that in Han-dominated sites within China. For example, a one-year study in Guizhou (southwest China) calculated a clustering rate of 13.1%[37], which is lower than that in Kashgar. A 10-year study in Shanghai (eastern China) obtained a clustering rate of 27.25%, which was only 1.35% higher than that reported by Kashgar[38]. A three-year sample from Shenzhen (southern China) yielded a clustering rate of 12.2%[39]. Therefore, we consider that Kashgar is among the regions with a more severe recent transmission within China and that recent transmission should be a local public concern. One possible reason for this is that Kashgar is predominantly Uyghur, whereas studies in North America have found that ethnic minorities are at a higher risk of recent transmission than the dominant ethnic group[40,41]. Another possible reason is that the lack of transportation in Kashgar leads to a longer total delay (time interval between the onset of symptoms and the start of treatment) in patients, which exacerbates the transmission of TB; for example, the proportion of patients with a total delay of more than 8 weeks was 10.8% in Shenzhen when compared to 31.9% in Kashgar[24]. In addition, since 2013, the prefecture has intensified its efforts to alleviate poverty and develop labor-intensive production workshops in rural areas to increase farmers’ incomes, providing more opportunities for people to congregate, thus facilitating the transmission of TB.
Based on the analysis of risk factors for clustering, we found that the DR strains were more likely to be transmitted than the susceptible strains in Kashgar. Since the transmission of strains is influenced not only by bacteriological factors, but also by host and social environmental factors, there is no uniform conclusion as to whether the risk of transmission of DR strains is higher than that of the susceptible strains. If only bacteriological factors are considered, DR mutations can result in fitness costs in the form of slower growth rates[42]. Thus, the prevailing view was that DR strains were less transmissible; however, this could not explain why DR strains are widely prevalent. Later studies found that the contacts of patients with DR have a higher risk of infection[43], which may have been caused by the higher number of MTB cells in the aerosol produced when patients with DR cough[44,45]. Animal models show significantly higher bacterial loads in the airways after infection with MDR strains, suggesting that DR strains may have a transmission advantage over susceptible strains[46]. These results suggest that bacterial-host interactions also influence the transmission of strains. In addition, the level of healthcare and capacity of the public health system are also drivers of strain transmission[47]. Therefore, the role of socio-environmental factors cannot be disregarded. Perhaps, because of this, DR strains were less likely to spread than susceptible strains in areas where TB is effectively controlled[48,49]. In high-burden countries such as China, DR strains were found to be at a higher risk of transmission than susceptible strains[23,50]. Recent studies have suggested that among the various influencing factors, bacteriological factors play a relatively minor role in transmission, whereas socio-environmental factors play a greater role[20]. Our results provide information for an in-depth analysis of the transmission patterns of DR strains and suggest that the social environment in Kashgar should be improved to suppress the spread of DR strains.
Although it has been suggested that smear-positive patients are more likely to transmit TB, a positive smear result was not a high-risk factor for recent transmission in our study. This may be due to the low sensitivity of smears, resulting in the high proportion of “false” smear-negative patients and thus masking the transmission advantage of smear-positive patients[50]. The smear-positive rate for culture-positive patients in Kashgar was only 30.8%, when compared to 76% in a similar study in Malawi[36].
Consistent with a previous study in China, Beijing strains favored transmission[50]. A study in South Africa observed an expansion of Beijing strains from almost none to 33% in 40 years[51]. These results indicate that the Beijing strains have a transmission advantage. Previous studies have shown that Beijing strains are more virulent[52,53] and are better adapted to the host immune system, such as by evading BCG-induced immune protection[54] or favoring a secondary Th1 response that is less protective of the host[55]. These features may accelerate the progression from infection to disease[50], allowing the strain to exhibit a transmission advantage. Although the proportion of lineage 3 in this region is relatively high in China, the transmission advantage of lineage 3 is not evident. The same conclusion was obtained in another area, with a ratio of lineage 3 close to that of Kashgar[56]. We speculate that the high proportion of lineage 3 in Kashgar may be due to the presence of the ancient Silk Road[19]. Moreover, the prefecture is adjacent to Pakistan and North India, where the frequency of lineage 3 strains is high[57].
We found that students accounted for only 3.3% of all patients, but had a higher risk of cluster formation than other occupations. A previous study suggested that this was due to diagnostic delays[24]. Students worry about interrupting their studies because of illness or a sense of shame. Another possible reason is that this population receives extra attention from the disease prevention and control departments. Following the diagnosis of TB in a student, their classmates are also screened[23], leading to a more timely detection of students who develop TB via recent transmission.
This study has several limitations. First, the short duration of the study meant that some genomic clusters may have been missed, resulting in an underestimation of recent transmission levels, and the proportion of transmitted drug resistance. The novel coronavirus pandemic has added a heavier burden to local primary care institutions and created a major obstacle to our continuous collection of strains; therefore, we have only been able to collect a one-year sample. Secondly, the culture positivity rate in this region needs to be improved. The high laboratory equipment and technical requirements for MTB culture have led to its implementation being less than optimal in developing regions with a high TB burden like Kashgar[58]. We cannot deny that culture-negative patients are also a part of the transmission chain. Finally, the lack of epidemiological survey data in this study, such as household contact tracing, makes it difficult to analyze the populations and sites at high risk of transmission in detail.
In conclusion, control of TB transmission should be strengthened in the prefecture to reduce the prevalence of drug resistance. Continuation of WGS-based TB surveillance and epidemiological surveys in the region will help provide greater insight into the causes of the high TB burden in Kashgar.
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Type of resistance No. (%) Total New case Retreated cases cases Unknown Resistance to single drug only 136 (8.15) 110 (8.53) 33 (9.71) 3 (7.89) RIF 21 (1.26) 12 (0.93) 9 (2.65) 0 (0.00) INH 53 (3.18) 37 (2.87) 14 (4.12) 2 (5.26) EMB 1 (0.06) 0 (0.00) 1 (0.29) 0 (0.00) PZA 5 (0.30) 4 (0.31) 0 (0.00) 1 (2.63) SM 46 (2.76) 49 (3.80) 7 (2.06) 0 (0.00) FQs 10 (0.60) 8 (0.62) 2 (0.59) 0 (0.00) Multi-drug resistant (MDR) 31 (1.86) 10 (0.78) 21 (6.18) 0 (0.00) INH+RIF+FQs 1 (0.06) 0 (0.00) 1 (0.29) 0 (0.00) INH+RIF 8 (0.48) 3 (0.23) 5 (1.47) 0 (0.00) INH+RIF+EMB 3 (0.18) 2 (0.16) 1 (0.29) 0 (0.00) INH+RIF+SM 5 (0.30) 0 (0.00) 5 (1.47) 0 (0.00) INH+RIF+ETH 1 (0.06) 1 (0.08) 0 (0.00) 0 (0.00) INH+RIF+SM+FQs 1 (0.06) 0 (0.00) 1 (0.29) 0 (0.00) INH+RIF+PZA+SM 1 (0.06) 1 (0.08) 0 (0.00) 0 (0.00) INH+RIF+EMB+SM 7 (0.42) 2 (0.16) 5 (1.47) 0 (0.00) INH+RIF+SM+PAS 1 (0.06) 0 (0.00) 1 (0.29) 0 (0.00) INH+RIF+SM+ETH 1 (0.06) 0 (0.00) 1 (0.29) 0 (0.00) INH+RIF+EMB+PZA+ETH 1 (0.06) 1 (0.08) 0 (0.00) 0 (0.00) INH+RIF+SM+KAN+AMI+CAP 1 (0.06) 0 (0.00) 1 (0.29) 0 (0.00) Resistance to two drugs (except MDR) 35 (2.10) 25 (1.94) 8 (2.35) 2 (5.26) RIF+SM 2 (0.12) 1 (0.08) 1 (0.29) 0 (0.00) RIF+EMB 1 (0.06) 0 (0.00) 1 (0.29) 0 (0.00) INH+ETH 16 (0.96) 12 (0.93) 3 (0.88) 1 (2.63) INH+SM 13 (0.78) 10 (0.78) 2 (0.59) 1 (2.63) INH+EMB 1 (0.06) 1 (0.08) 0 (0.00) 0 (0.00) SM+PAS 1 (0.06) 0 (0.00) 1 (0.29) 0 (0.00) BDQ+CFZ 1 (0.06) 1 (0.08) 0 (0.00) 0 (0.00) Resistance to three or more drugs 11 (0.66) 8 (0.62) 3 (0.88) 0 (0.00) INH+EMB+SM 1 (0.06) 1 (0.08) 0 (0.00) 0 (0.00) INH+SM+ETH 6 (0.36) 4 (0.31) 2 (0.59) 0 (0.00) INH+SM+PAS 1 (0.06) 1 (0.08) 0 (0.00) 0 (0.00) SM+KAN+AMI+CAP 1 (0.06) 0 (0.00) 1 (0.29) 0 (0.00) INH+SM+KAN+AMI+CAP 2 (0.12) 2 (0.16) 0 (0.00) 0 (0.00) Pan drug susceptible 1,445 (86.6) 1,137 (88.1) 275 (80.9) 33 (86.8) Note. INH, isoniazid; RIF, rifampicin; PZA, pyrazinamide; EMB, ethambutol; SM, streptomycin; FQs, fluoroquinolones; ETH, ethionamide; KAN, kanamycin; AMI, amikacin; CAP, capreomycin; BDQ, bedaquiline; CFZ, clofazimine. Table S1. Drug resistance profiles of 1,668 patients predicted by whole genome sequencing
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Basic Information for Patients with Culture-positive TB
WGS to Delineate Lineages and Predict Drug Resistance of Isolated Strains
Risk Factors and Spatial Hot Spots of Genomic-clustered Cases
Inference of the Major Cause of Drug Resistance
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