Abstract
Background
To understand the treatment outcomes and factors influencing unfavorable outcomes in older asymptomatic pulmonary tuberculosis patients (aPTB) in China, compare them with symptomatic patients, so as to provide a reference for further efforts in the prevention and treatment of asymptomatic tuberculosis in older people.
Methods
Data on older patients with asymptomatic pulmonary tuberculosis registered between 2021 and 2024 were obtained from the China Disease Prevention and Control Information System, including demographic characteristics, clinical features, and treatment management information. Descriptive epidemiological methods were employed to analyze the characteristics and treatment outcomes of the patients, and logistic regression models were used to identify factors influencing unfavorable treatment outcomes. Comparisons were also made with symptomatic patients during the same period.
Results
Asymptomatic patients accounted for 11.54% (25,735/223,014). Treatment success rates were comparable between aPTB and symptomatic pulmonary tuberculosis (sPTB) groups (90.83% vs. 90.55%, P = 0.142). However, among patients with unfavorable outcomes, aPTB patients had higher loss to follow-up (18.52% vs. 13.69%) and not evaluated rates, while sPTB patients had higher mortality (76.87% vs. 72.15%) and treatment failure. Independent risk factors for unfavorable outcomes in aPTB included advanced age (≥ 80 years: AOR = 3.30), western residence (AOR = 1.38), pathogen-positivity (AOR = 1.35), comorbidities (AOR = 1.72), retreatment (AOR = 1.27), non-standard regimens (AOR up to 1.81), non-use of fixed-dose combinations (AOR = 1.18), no initial follow-up visit (AOR = 1.80), and adverse drug reactions (AOR = 6.58). Active case finding (AOR = 0.64) and high adherence (AOR = 0.02–0.06) were associated with lower odds of unfavorable outcomes.
Conclusions
Older aPTB patients constitute a notable proportion with treatment success comparable to sPTB patients, but exhibit distinct patterns of unfavorable outcomes. Multiple factors (such as advanced age ≥ 80 years, comorbidities, adverse drug reactions, and non-standard regimens) were associated with unfavorable outcomes within this surveillance cohort, supporting targeted interventions for this overlooked population.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12877-026-07941-6.
Keywords: Treatment outcome, Tuberculosis, Asymptomatic pulmonary tuberculosis, Older people
Introduction
Tuberculosis (TB) remains a major global public health threat. According to the global TB report 2025, the estimated global incidence rate of tuberculosis in 2024 was 131 per 100,000 population, with an estimated 10.7 million people falling ill and 1.23 million dying from the disease. China ranks fourth among the 30 high-burden countries of TB, with an estimated incidence rate of 49 per 100,000 people and an annual new case number of 696,000, with approximately 25,000 deaths [1].
The World Health Organization (WHO), in its “End TB Strategy [2]”, set clear milestone targets: to reduce global TB incidence and deaths by 50% and 75%, respectively, by 2025, compared to 2015 levels. However, data indicate that compared to 2015, the global and Chinese TB incidence rates in 2024 had only decreased by 12% and 24%, respectively, while deaths decreased by 29% and 34%, respectively [1]. These figures remain far from the targets set in the “End TB Strategy.” Among these, the harm of asymptomatic tuberculosis (aTB) cannot be overlooked. Individuals with aTB typically do not exhibit obvious TB-related symptoms and are therefore often missed in traditional case-finding methods that rely primarily on symptom screening. However, the existence of this hidden group has potentially significant implications for TB transmission and control. Studies have shown that aTB patients account for up to 50% of TB cases that are bacteriologically confirmed [3], and approximately 68% of global TB transmission may originate from individuals with asymptomatic infection [4]. A key pillar of implementing the End TB Strategy is treating all TB patients, so monitoring and evaluating the treatment outcomes of such hidden patients holds significant public health importance.
The older population is a key priority for TB prevention and control. Due to factors such as waning immune function, a high prevalence of comorbid conditions, and reduced drug metabolism ability, the risk of tuberculosis in older people is significantly higher than that of the general population [5–7]. Once infected, they often experience greater treatment difficulty and poorer prognosis. For example, comorbidities—especially coinfections—complicate treatment management, particularly in resource-limited settings [8]. With accelerating population aging, the TB burden among older people is becoming increasingly prominent. Research indicates that from 2000 to 2023, the number of TB cases and deaths among individuals aged ≥ 65 years globally rose steadily. In 2023, people aged ≥ 65 years accounted for 21% of global TB cases and 23% of TB deaths [9]. Notably, older aTB patients exhibit the dual characteristics of being both older and asymptomatic, which compounds the challenges for timely detection and effective management.
Currently, most studies have concentrated on the epidemiological features of aTB, while data on treatment outcomes and factors associated with unfavorable outcomes—especially in older people—are scarce. This study aims to utilize national surveillance data to characterize treatment outcomes among older aTB patients, identify determinants of unfavorable outcomes, and compare these findings with those from symptomatic tuberculosis (sTB) patients. The results are expected to inform early screening and clinical intervention strategies for aTB in older people, and to support the optimization of treatment and care for this vulnerable population.
Methods
Study design and data source
A nationwide, retrospective cross-sectional study was conducted based on Chinese TB surveillance data from 2021 to 2024. The study aimed to evaluate treatment outcomes and identify determinants of unfavorable treatment among older asymptomatic pulmonary tuberculosis (aPTB) patients, with a comparative analysis performed against their symptomatic pulmonary tuberculosis (sPTB) patients. Data were obtained from the Chinese Information System for Disease Control and Prevention, the nationwide mandatory TB surveillance platform.
Study population and inclusion/exclusion criteria
Eligible participants were identified as older patients (≥ 65) with aPTB. Given its pathogenic transmissibility and status as a mandatory reportable disease, pulmonary tuberculosis (PTB) remains a critical public health priority. Our analysis specifically focused on rifampicin-susceptible cases to isolate the determinants of unfavorable treatment from the influence of drug resistance, thereby reducing statistical noise. A total of 2,144,150 patients with drug-susceptible tuberculosis (DS-TB) were registered between January 1, 2021 and December 31, 2024. After excluding records with incomplete symptom data (n = 1,178,564), extrapulmonary involvement, nontuberculous mycobacteria (NTM) infection, or logical inconsistencies (n = 9,190), 956,396 drug-susceptible -pulmonary tuberculosis (DS-PTB) patients remained. Of these, 320,432 (33.5%) were aged ≥ 65 years. Further exclusions were made for patients with incomplete treatment (e.g., untreated, waiting for treatment, or still on treatment), diagnostic changes, or transition to RR-TB treatment (n = 72,692). Missing data were handled using a stratified approach based on the missing proportion: variables with > 20% missing were excluded; those with 10–20% missing were imputed using the mice R package; and for variables with < 10% missing, cases with missing values were removed (n = 24,726) (Supplementary Table 1). The final analytic cohort comprised 223,014 patients, including 25,735 (11.54%) aPTB cases and 197,279 (88.46%) sPTB cases (Fig. 1).
Fig. 1.
Flowchart of the study population selection. Abbreviation: DS-TB=Drug-susceptible tuberculosis; EPTB=extrapulmonary tuberculosis; NTM=nontuberculous mycobacteria; DS-PTB=Drug-susceptible pulmonary tuberculosis; RR-TB=rifampicin-resistant tuberculosis; aPTB=asymptomatic pulmonary tuberculosis; sPTB=symptomatic pulmonary tuberculosis
Study definition and variables
The aPTB was operationally defined for this study as a registered PTB case without a recorded of cough. This definition, adopted for feasibility and consistency with surveillance data, was informed by the WHO conceptual definition of asymptomatic TB as “a person with TB disease who did not report symptoms suggestive of TB during screening” [10]. Given the lack of a globally symptom standard, the central role of cough as a key screening and transmission-related symptom for PTB, and in conjunction with existing authoritative research [11], this pragmatic definition was applied. It is a pragmatic surveillance-based definition and not a full clinical definition of asymptomatic TB and that patients classified as aPTB may have had other TB-related symptoms (coughing up phlegm, hemoptysis, chest pain, fever, fatigue, night sweats). Treatment outcomes were classified according to national and WHO guidelines [12, 13]. Treatment success was defined as the sum of “cured” and “treatment completed”. Unfavorable outcomes were defined as the sum of “treatment failed”, “died”, “lost to follow-up”, and “not evaluated” (Table 1).
Table 1.
Definition of treatment outcome for tuberculosis
| Outcome | categories | definition |
|---|---|---|
| Treatment success | cured | A pulmonary TB patient with bacteriologically confirmed TB at the beginning of treatment who completed treatment as recommended by the national policy with evidence of bacteriological response and no evidence of failure. |
| treatment completed | A patient who completed treatment as recommended by the national policy whose outcome does not meet the definition for cure or treatment failure. | |
| Unfavorable outcomes | treatment failed | A patient whose treatment regimen needed to be terminated or permanently changed to a new regimen or treatment strategy. |
| died | A patient who died before starting treatment or during the course of treatment. | |
| lost to follow-up | A patient who did not start treatment or whose treatment was interrupted for 2 consecutive months or more. | |
| not evaluated | A patient for whom no treatment outcome was assigned. |
We collected a comprehensive set of variables from the national TB surveillance system and used for subsequent analyses, which were categorized into three domains: sociodemographic characteristics, clinical characteristics and treatment management characteristics. Sociodemographic characteristics included sex, age, ethnicity, household registration, and region. Clinical characteristics encompassed the diagnosis result, presence of comorbidities, and baseline sputum smear microscopy result at month 0. Treatment management characteristics comprised case discovery mode, treatment mode, treatment type, specific treatment plan, use of fixed-dose combination (FDC) drugs, regular medication adherence rate, regular visit adherence rate, completion of initial follow-up visit, and occurrence of adverse drug reactions (ADRs) during treatment.
Statistical analysis
Data management and analysis were performed using Excel 2021 (version 2021, Microsoft, Redmond, USA, https://www.microsoft.com/) and R 4.4.3 (Version 4.3.3, Vienna, Austria, https://www.r-project.org/). Categorical variables were described using frequencies and proportions. The mice package in R was used for multiple imputation of missing data. Variables with a P < 0.05 in univariate analyses were included in a multivariable logistic regression model using a stepwise selection method to identify factors independently associated with unfavorable treatment outcomes.
Results
Demographic characteristics
A total of 223,014 older pulmonary tuberculosis patients were included in the study, comprising 25,735 (11.54%) aPTB and 197,279 (88.46%) sPTB cases. Among aPTB patients, the majority were male (70.98%) and aged 65–69 years (35.00%), with Han ethnicity predominating (86.04%) and most having local household registration (96.35%). Geographically, 38.84% resided in central China, 34.47% in western, and 26.70% in eastern regions. Compared to sPTB patients, aPTB patients had a slightly higher proportion of males (70.98% vs. 69.58%, P < 0.001) and were more concentrated in the 65–69 age group (35.00% vs. 32.34%, P < 0.001). The proportion of Han ethnicity was also significantly higher among aPTB patients (86.04% vs. 83.50%, P < 0.001). In contrast, sPTB patients were overrepresented in the west (26.70% vs. 23.67% and 38.84% vs. 33.45% for eastern and central, respectively; P < 0.001). Notably, household mobility—including intra-city, intra-provincial, and extra-provincial migration—was slightly higher among aPTB patients (all P < 0.001) (Table 2).
Table 2.
Characteristics of study population
| Variable | Category | Total [n (%)] | aPTB [n (%)] | sPTB [n (%)] | χ2 | P |
|---|---|---|---|---|---|---|
| Sex | Male | 155,527 (69.74) | 18,267 (70.98) | 137,260 (69.58) | 21.28 | < 0.001 |
| Female | 67,487 (30.26) | 7468 (29.02) | 60,019 (30.42) | |||
| Age group | 65–69 | 72,804 (32.65) | 9008 (35.00) | 63,796 (32.34) | 75.40 | < 0.001 |
| 70–74 | 65,438 (29.34) | 7315 (28.42) | 58,123 (29.46) | |||
| 75–79 | 45,766 (20.52) | 5141 (19.98) | 40,625 (20.59) | |||
| ≥ 80 | 39,006 (17.49) | 4271 (16.60) | 34,735 (17.61) | |||
| Ethnicity | Han | 186,875 (83.80) | 22,143 (86.04) | 164,732 (83.50) | 108.19 | < 0.001 |
| Others | 36,139 (16.20) | 3592 (13.96) | 32,547 (16.50) | |||
| Household type | Local | 217,418 (97.49) | 24,796 (96.35) | 192,622 (97.64) | 201.33 | < 0.001 |
| Intra-city mobility | 2432 (1.09) | 345 (1.34) | 2087 (1.06) | |||
| Intra-provincial mobility | 1425 (0.64) | 229 (0.89) | 1196 (0.61) | |||
| Extra-provincial mobility | 1739 (0.78) | 365 (1.42) | 1374 (0.70) | |||
| Region | Eastern | 53,567 (24.02) | 6870 (26.70) | 46,697 (23.67) | 664.89 | < 0.001 |
| Central | 75,988 (34.07) | 9995 (38.84) | 65,993 (33.45) | |||
| West | 93,459 (41.91) | 8870 (34.47) | 84,589 (42.88) | |||
| Diagnosis result | Pathogen positive | 157,391 (70.57) | 15,161 (58.91) | 142,230 (72.10) | 2644.79 | < 0.001 |
| Pathogen negative | 57,832 (25.93) | 8608 (33.45) | 49,224 (24.95) | |||
| No pathogen result | 219 (0.10) | 35 (0.14) | 184 (0.09) | |||
| Tuberculous pleurisy | 7572 (3.40) | 1931 (7.50) | 5641 (2.86) | |||
| Comorbidity | Yes | 44,684 (20.04) | 6396 (24.85) | 38,288 (19.41) | 421.36 | < 0.001 |
| No | 66,601 (29.86) | 7208 (28.01) | 59,393 (30.11) | |||
| Unknown | 111,729 (50.10) | 12,131 (47.14) | 99,598 (50.49) | |||
| 0-month sputum smear result | Positive | 91,987 (41.25) | 7048 (27.39) | 84,939 (43.06) | 2324.55 | < 0.001 |
| Negative | 130,646 (58.58) | 18,606 (72.30) | 112,040 (56.79) | |||
| No result | 381 (0.17) | 81 (0.31) | 300 (0.15) | |||
| Discovery mode | Active | 8088 (3.63) | 1896 (7.37) | 6192 (3.14) | 1164.72 | < 0.001 |
| Passive | 214,926 (96.37) | 23,839 (92.63) | 191,087 (96.86) | |||
| Treatment classification | Initial treatment | 203,648 (91.32) | 23,854 (92.69) | 179,794 (91.14) | 69.33 | < 0.001 |
| Re-treatment | 19,366 (8.68) | 1881 (7.31) | 17,485 (8.86) | |||
| Treatment mode | Outpatient treatment | 203,772 (91.37) | 23,256 (90.37) | 180,516 (91.50) | 37.25 | < 0.001 |
| Inpatient treatment | 19,242 (8.63) | 2479 (9.63) | 16,763 (8.50) | |||
| Treatment plan | 2HRZE/4HR | 151,926 (68.12) | 15,580 (60.54) | 136,346 (69.11) | 816.31 | < 0.001 |
| 2HRZE/7-10HRE | 18,743 (8.40) | 2438 (9.47) | 16,305 (8.26) | |||
| 2HRZE/10HRE | 24,097 (10.81) | 3630 (14.11) | 20,467 (10.37) | |||
| 6-9RZELfx | 27,677 (12.41) | 4010 (15.58) | 23,667 (12.00) | |||
| Other sensitive plans | 571 (0.26) | 77 (0.30) | 494 (0.25) | |||
| FDC usage | Yes | 184,005 (82.51) | 20,044 (77.89) | 163,961 (83.11) | 430.65 | < 0.001 |
| No | 39,009 (17.49) | 5691 (22.11) | 33,318 (16.89) | |||
| Regular medication adherence rate | < 70% | 4553 (2.04) | 557 (2.16) | 3996 (2.03) | 7.18 | 0.127 |
| 70 ~ 79% | 342 (0.15) | 46 (0.18) | 296 (0.15) | |||
| 80 ~ 89% | 570 (0.26) | 62 (0.24) | 508 (0.26) | |||
| 90 ~ 99% | 7229 (3.24) | 783 (3.04) | 6446 (3.27) | |||
| 100% | 210,320 (94.31) | 24,287 (94.37) | 186,033 (94.30) | |||
| Regular visits adherence rate | < 70% | 3656 (1.64) | 423 (1.64) | 3233 (1.64) | 0.25 | 0.993 |
| 70 ~ 79% | 385 (0.17) | 45 (0.17) | 340 (0.17) | |||
| 80 ~ 89% | 414 (0.19) | 45 (0.17) | 369 (0.19) | |||
| 90 ~ 99% | 411 (0.18) | 49 (0.19) | 362 (0.18) | |||
| 100% | 218,148 (97.82) | 25,173 (97.82) | 192,975 (97.82) | |||
| Initial follow-up visit completed | Yes | 221,388 (99.27) | 25,518 (99.16) | 195,870 (99.29) | 5.23 | 0.022 |
| No | 1626 (0.73) | 217 (0.84) | 1409 (0.71) | |||
| Presence of ADRs | Yes | 2613 (1.17) | 406 (1.58) | 2207 (1.12) | 41.40 | < 0.001 |
| No | 220,401 (98.83) | 25,329 (98.42) | 195,072 (98.88) |
Clinical and treatment management characteristics
The aPTB patients had a lower rate of pathogen-positive diagnosis (58.91% vs. 72.10%, P < 0.001) and more frequently presented with pathogen-negative results (33.45% vs. 24.95%). Documented comorbidities were more common in the aPTB group (24.85% vs. 19.41%, P < 0.001). Sputum smear positivity at 0-month was lower in aPTB (27.39% vs. 43.06%, P < 0.001), while negative results were higher (72.30% vs. 56.79%). Furthermore, aPTB patients exhibited a higher rate of active discovery (7.37% vs. 3.14%, P < 0.001), less often received re-treatment (7.31% vs. 8.86%, P < 0.001) and FDC therapy use (77.89% vs. 83.11%, P < 0.001). The proportion of outpatient treatment was slightly lower in aPTB patients (90.37% vs. 91.50%) and correspondingly higher inpatient treatment (9.63% vs. 8.50%, P < 0.001). Treatment regimens differed markedly (P < 0.001): the 2HRZE/4HR regimen was less frequent in the aPTB group (60.54% vs. 69.11%), while longer regimens (2HRZE/10HRE: 14.11% vs. 10.37%; 6‑9RZELfx: 15.58% vs. 12.00%) were more common. Adherence to medication and visits was similarly high in both groups (medication adherence ≥ 100%: 94.37% vs. 94.30%, P = 0.127; visit adherence ≥ 100%: 97.82% vs. 97.82%, P = 0.993) (Table 2).
Treatment outcomes
The overall success rates were comparable between the aPTB and sPTB groups (90.83% vs. 90.55%, respectively), with no statistically significant difference observed in the incidence of unfavorable outcomes (χ² = 2.16, P = 0.142). However, the specific composition of unfavorable outcomes differed significantly between the two cohorts (χ² = 63.99, P < 0.001). Within the unfavorable outcome subgroup, aPTB patients had higher proportions of loss to follow-up (18.52% vs. 13.69%) and non-evaluated cases (6.61% vs. 5.06%), whereas sPTB patients had higher proportions of death (76.87% vs. 72.15%) and treatment failure (4.38% vs. 2.71%) (Fig. 2). When considering all patients, the overall rates of treatment failed, died, lost to follow-up, not evaluated were (aPTB: 0.25%, 6.61%, 1.70%, 0.61%; sPTB: 0.41%, 7.27%, 1.29%, 0.48%) (Supplementary Table 2).
Fig. 2.
Treatment outcomes of asymptomatic and symptomatic pulmonary tuberculosis patients
Determinants of unfavorable treatment outcome
Univariate analysis was initially performed, and variables with P < 0.05 were included in the multivariate logistic regression models for both groups (Supplementary Tables 3 and 4). In the aPTB group, demographic analysis identified advanced age (e.g., ≥ 80 years: AOR = 3.30, 95% CI: 2.87–3.80) and western residence (AOR = 1.38, 95% CI: 1.21–1.56) as factors associated with increased odds of unfavorable outcomes, while female sex (AOR = 0.78, 95% CI: 0.70–0.88) was associated with lower odds. Clinical and treatment management risk factors comprised pathogen-positive diagnosis (AOR = 1.35, 95% CI: 1.18–1.55), presence of comorbidities (AOR = 1.72, 95% CI: 1.50–1.97), positive baseline smear (AOR = 1.48, 95% CI: 1.32–1.67), retreatment (AOR = 1.27, 95% CI: 1.07–1.51), extended/alternative regimens (e.g., 2HRZE/10HRE: AOR = 1.81, 95% CI: 1.57–2.09), non-FDC regimens (AOR = 1.18, 95% CI: 1.04–1.34), absent initial follow-up visit (AOR = 1.80, 95% CI: 1.16–2.81), and ADRs (AOR = 6.58, 95% CI: 5.16–8.39). Conversely, active case finding (AOR = 0.64, 95% CI: 0.50–0.82) and escalating medication/visit adherence were associated with substantially lower odds of unfavorable outcomes, with ≥ 100% adherence showing the strongest inverse associations (AOR = 0.02, 95% CI: 0.01–0.03, and AOR = 0.06, 95% CI: 0.04–0.10, respectively) (Table 3). The sPTB group presented a largely consistent profile, where advanced age (e.g., ≥ 80 years: AOR = 3.07, 95% CI: 2.92–3.23), extended/alternative regimens (e.g., 2HRZE/10HRE: AOR = 1.99, 95% CI: 1.88–2.10), and other factors remained significantly associated with increased risk. Similar to the aPTB group, female sex, active case finding, and high treatment compliance retained their significant inverse associations (all P < 0.05). Inter-group comparisons revealed two distinct divergences: central region residence was associated with lower odds (AOR = 0.82, 95% CI: 0.78–0.86) and inpatient treatment was a risk factor (AOR = 1.26, 95% CI: 1.19–1.34) exclusively in the sPTB group, with neither showing statistical significance in the aPTB group (Table 4).
Table 3.
Multivariable analysis of factors associated with unfavorable treatment outcome among aPTB
| Variable | Category | Treatment outcome [n (%)] | COR (95% CI) | P-value | AOR (95% CI) | P-value | |
|---|---|---|---|---|---|---|---|
| Successful | Unfavorable | ||||||
| Sex | Male | 16,517 (90.42) | 1750 (9.58) | 1.00 | |||
| Female | 6859 (91.85) | 609 (8.15) | 0.84 (0.76–0.92) | < 0.001 | 0.78 (0.70–0.88) | < 0.001 | |
| Age group | 65–69 | 8483 (94.17) | 525 (5.83) | 1.00 | |||
| 70–74 | 6722 (91.89) | 593 (8.11) | 1.42 (1.26–1.61) | < 0.001 | 1.45 (1.26–1.67) | < 0.001 | |
| 75–79 | 4610 (89.67) | 531 (10.33) | 1.86 (1.64–2.11) | < 0.001 | 1.89 (1.63–2.19) | < 0.001 | |
| 80- | 3561 (83.38) | 710 (16.62) | 3.22 (2.86–3.63) | < 0.001 | 3.30 (2.87–3.80) | < 0.001 | |
| Region | Eastern | 6210 (90.39) | 660 (9.61) | 1.00 | |||
| Central | 9208 (92.13) | 787 (7.87) | 0.80 (0.72–0.90) | < 0.001 | 0.90 (0.79–1.02) | 0.111 | |
| Western | 7958 (89.72) | 912 (10.28) | 1.08 (0.97–1.20) | 0.163 | 1.38 (1.21–1.56) | < 0.001 | |
| Diagnosis result | Pathogen negative | 8041 (93.41) | 567 (6.59) | 1.00 | |||
| Pathogen positive | 13,521 (89.18) | 1640 (10.82) | 1.72 (1.56–1.90) | < 0.001 | 1.35 (1.18–1.55) | < 0.001 | |
| No pathogen result | 35 (100.00) | 0 (0.00) | 0.00 (0.00–0.00) | 0.938 | |||
| Tuberculous pleurisy | 1779 (92.13) | 152 (7.87) | 1.21 (1.01–1.46) | 0.046 | 1.04 (0.84–1.30) | 0.711 | |
| Comorbidity | No | 6667 (92.49) | 541 (7.51) | 1.00 | |||
| Yes | 5595 (87.48) | 801 (12.52) | 1.76 (1.57–1.98) | < 0.001 | 1.72 (1.50–1.97) | < 0.001 | |
| Unknown | 11,114 (91.62) | 1017 (8.38) | 1.13 (1.01–1.26) | 0.031 | 1.27 (1.12–1.45) | < 0.001 | |
| 0-month sputum smear result | Negative | 17,158 (92.22) | 1448 (7.78) | 1.00 | |||
| Positive | 6141 (87.13) | 907 (12.87) | 1.75 (1.60–1.91) | < 0.001 | 1.48 (1.32–1.67) | < 0.001 | |
| No result | 77 (95.06) | 4 (4.94) | 0.62 (0.26–1.78) | 0.529 | 1.04 (0.33–3.29) | 0.947 | |
| Discovery mode | Passive | 21,577 (90.51) | 2262 (9.49) | 1.00 | |||
| Active | 1799 (94.88) | 97 (5.12) | 0.51 (0.42–0.64) | < 0.001 | 0.64 (0.50–0.82) | < 0.001 | |
| Treatment type | Initial treatment | 21,732 (91.10) | 2122 (8.90) | 1.00 | |||
| Retreatment treatment | 1644 (87.40) | 237 (12.60) | 1.48 (1.28–1.71) | < 0.001 | 1.27 (1.07–1.51) | 0.007 | |
| Treatment mode | Outpatient treatment | 21,091 (90.69) | 2165 (9.31) | 1.00 | |||
| Inpatient | 2285 (92.17) | 194 (7.83) | 0.83 (0.71–0.97) | 0.014 | 0.99 (0.83–1.19) | 0.932 | |
| Treatment plan | 2HRZE/4HR | 14,484 (92.97) | 1096 (7.03) | 1.00 | |||
| 2HRZE/7-10HRE | 2221 (91.10) | 217 (8.90) | 1.29 (1.11–1.51) | 0.001 | 1.31 (1.08–1.58) | 0.005 | |
| 2HRZE/10HRE | 3174 (87.44) | 456 (12.56) | 1.90 (1.69–2.13) | < 0.001 | 1.81 (1.57–2.09) | < 0.001 | |
| 6-9RZELfx | 65 (84.42) | 12 (15.58) | 2.44 (1.37–4.63) | 0.011 | 1.97 (0.96–4.04) | 0.066 | |
| Other sensitive plans | 3432 (85.59) | 578 (14.41) | 2.23 (2.00-2.48) | < 0.001 | 1.67 (1.44–1.93) | < 0.001 | |
| Fdc usage | Yes | 18,365 (91.62) | 1679 (8.38) | 1.00 | |||
| No | 5011 (88.05) | 680 (11.95) | 1.48 (1.35–1.63) | < 0.001 | 1.18 (1.04–1.34) | 0.010 | |
| Regular medication adherence rate | < 70% | 39 (7.00) | 518 (93.00) | 1.00 | |||
| 70 ~ 79% | 12 (26.09) | 34 (73.91) | 0.21 (0.10–0.43) | < 0.001 | 0.35 (0.15–0.81) | 0.015 | |
| 80 ~ 89% | 21 (33.87) | 41 (66.13) | 0.15 (0.08–0.27) | < 0.001 | 0.29 (0.15–0.59) | 0.001 | |
| 90 ~ 99% | 661 (84.42) | 122 (15.58) | 0.01 (0.01–0.02) | < 0.001 | 0.04 (0.03–0.06) | < 0.001 | |
| 100% | 22,643 (93.23) | 1644 (6.77) | 0.00 (0.00-0.01) | < 0.001 | 0.02 (0.01–0.03) | < 0.001 | |
| Regular visits adherence rate | < 70% | 34 (8.04) | 389 (91.96) | 1.00 | |||
| 70 ~ 79% | 4 (8.89) | 41 (91.11) | 0.90 (0.29–2.29) | 0.776 | 0.49 (0.13–1.89) | 0.303 | |
| 80 ~ 89% | 16 (35.56) | 29 (64.44) | 0.16 (0.08–0.32) | < 0.001 | 0.33 (0.13–0.86) | 0.023 | |
| 90 ~ 99% | 30 (61.22) | 19 (38.78) | 0.06 (0.03–0.11) | < 0.001 | 0.16 (0.07–0.39) | < 0.001 | |
| 100% | 23,292 (92.53) | 1881 (7.47) | 0.01 (0.00-0.01) | < 0.001 | 0.06 (0.04–0.10) | < 0.001 | |
| Initial follow-up visit completed | Yes | 23,203 (90.93) | 2315 (9.07) | 1.00 | |||
| No | 173 (79.72) | 44 (20.28) | 2.55 (1.84–3.58) | < 0.001 | 1.80 (1.16–2.81) | 0.009 | |
| Presence of ADRs | No | 23,147 (91.39) | 2182 (8.61) | 1.00 | |||
| Yes | 229 (56.40) | 177 (43.60) | 8.20 (6.71–10.03) | < 0.001 | 6.58 (5.16–8.39) | < 0.001 | |
Table 4.
Multivariable analysis of factors associated with unfavorable treatment outcome among sPTB
| Variable | Category | Treatment outcome [n (%)] | COR (95% CI) | P-value | AOR (95% CI) | P-value | |
|---|---|---|---|---|---|---|---|
| Successful | Unfavorable | ||||||
| Sex | Male | 122,891 (89.53) | 14,369 (10.47) | 1.00 | |||
| Female | 55,743 (92.88) | 4276 (7.12) | 0.66 (0.63–0.68) | < 0.001 | 0.60 (0.58–0.63) | < 0.001 | |
| Age group | 65–69 | 59,804 (93.74) | 3992 (6.26) | 1.00 | |||
| 70–74 | 53,454 (91.97) | 4669 (8.03) | 1.31 (1.25–1.37) | < 0.001 | 1.34 (1.28–1.41) | < 0.001 | |
| 75–79 | 36,311 (89.38) | 4314 (10.62) | 1.78 (1.70–1.86) | < 0.001 | 1.87 (1.78–1.97) | < 0.001 | |
| 80- | 29,065 (83.68) | 5670 (16.32) | 2.92 (2.80–3.05) | < 0.001 | 3.07 (2.92–3.23) | < 0.001 | |
| Ethnicity | Han | 149,061 (90.49) | 15,671 (9.51) | 1.00 | |||
| Other | 29,573 (90.86) | 2974 (9.14) | 0.96 (0.92-1.00) | 0.034 | 1.01 (0.96–1.07) | 0.605 | |
| Region | Eastern | 42,142 (90.25) | 4555 (9.75) | 1.00 | |||
| Central | 60,739 (92.04) | 5254 (7.96) | 0.80 (0.77–0.83) | < 0.001 | 0.82 (0.78–0.86) | < 0.001 | |
| Western | 75,753 (89.55) | 8836 (10.45) | 1.08 (1.04–1.12) | < 0.001 | 1.21 (1.16–1.27) | < 0.001 | |
| Diagnosis result | Pathogen negative | 46,309 (94.08) | 2915 (5.92) | 1.00 | |||
| Pathogen positive | 126,969 (89.27) | 15,261 (10.73) | 1.91 (1.83–1.99) | < 0.001 | 1.42 (1.35–1.50) | < 0.001 | |
| No pathogen result | 172 (93.48) | 12 (6.52) | 1.11 (0.65–2.05) | 0.641 | 0.96 (0.39–2.37) | 0.923 | |
| Tuberculous pleurisy | 5184 (91.90) | 457 (8.10) | 1.40 (1.26–1.55) | < 0.001 | 0.89 (0.79–1.01) | 0.062 | |
| Comorbidity | No | 54,622 (91.97) | 4771 (8.03) | 1.00 | |||
| Yes | 33,187 (86.68) | 5101 (13.32) | 1.76 (1.69–1.83) | < 0.001 | 1.45 (1.38–1.53) | < 0.001 | |
| Unknown | 90,825 (91.19) | 8773 (8.81) | 1.11 (1.07–1.15) | < 0.001 | 1.17 (1.12–1.22) | < 0.001 | |
| 0-month sputum smear result | Negative | 103,569 (92.44) | 8471 (7.56) | 1.00 | |||
| Positive | 74,788 (88.05) | 10,151 (11.95) | 1.66 (1.61–1.71) | < 0.001 | 1.41 (1.35–1.47) | < 0.001 | |
| No result | 277 (92.33) | 23 (7.67) | 1.01 (0.68–1.58) | 0.913 | 1.47 (0.76–2.84) | 0.257 | |
| Discovery mode | Passive | 172,804 (90.43) | 18,283 (9.57) | 1.00 | |||
| Active | 5830 (94.15) | 362 (5.85) | 0.59 (0.53–0.65) | < 0.001 | 0.67 (0.59–0.76) | < 0.001 | |
| Treatment type | Initial treatment | 163,653 (91.02) | 16,141 (8.98) | 1.00 | |||
| Retreatment treatment | 14,981 (85.68) | 2504 (14.32) | 1.70 (1.62–1.77) | < 0.001 | 1.36 (1.29–1.44) | < 0.001 | |
| Treatment mode | Outpatient treatment | 163,601 (90.63) | 16,915 (9.37) | 1.00 | |||
| Inpatient treatment | 15,033 (89.68) | 1730 (10.32) | 1.11 (1.06–1.17) | < 0.001 | 1.26 (1.19–1.34) | < 0.001 | |
| Treatment plan | 2HRZE/4HR | 126,251 (92.60) | 10,095 (7.40) | 1.00 | |||
| 2HRZE/7-10HRE | 14,397 (88.30) | 1908 (11.70) | 1.66 (1.57–1.75) | < 0.001 | 1.46 (1.37–1.55) | < 0.001 | |
| 2HRZE/10HRE | 17,508 (85.54) | 2959 (14.46) | 2.11 (2.02–2.21) | < 0.001 | 1.99 (1.88–2.10) | < 0.001 | |
| 6-9RZELfx | 440 (89.07) | 54 (10.93) | 1.53 (1.17–2.05) | 0.004 | 1.23 (0.89–1.70) | 0.219 | |
| Other sensitive plans | 20,038 (84.67) | 3629 (15.33) | 2.27 (2.17–2.36) | < 0.001 | 1.61 (1.52–1.70) | < 0.001 | |
| Fdc usage | Yes | 149,524 (91.19) | 14,437 (8.81) | 1.00 | |||
| No | 29,110 (87.37) | 4208 (12.63) | 1.50 (1.44–1.55) | < 0.001 | 1.10 (1.05–1.15) | < 0.001 | |
| Regular medication adherence rate | < 70% | 285 (7.13) | 3711 (92.87) | 1.00 | |||
| 70%~79% | 58 (19.59) | 238 (80.41) | 0.32 (0.23–0.43) | < 0.001 | 0.46 (0.32–0.64) | < 0.001 | |
| 80%~89% | 149 (29.33) | 359 (70.67) | 0.18 (0.15–0.23) | < 0.001 | 0.34 (0.27–0.44) | < 0.001 | |
| 90%~99% | 5617 (87.14) | 829 (12.86) | 0.01 (0.01–0.01) | < 0.001 | 0.03 (0.02–0.03) | < 0.001 | |
| ≥ 100% | 172,525 (92.74) | 13,508 (7.26) | 0.01 (0.00-0.01) | < 0.001 | 0.02 (0.02–0.02) | < 0.001 | |
| Regular visits adherence rate | < 70% | 402 (12.43) | 2831 (87.57) | 1.00 | |||
| 70%~79% | 60 (17.65) | 280 (82.35) | 0.66 (0.49–0.89) | 0.008 | 0.76 (0.51–1.12) | 0.168 | |
| 80%~89% | 96 (26.02) | 273 (73.98) | 0.40 (0.31–0.52) | < 0.001 | 0.68 (0.48–0.95) | 0.025 | |
| 90%~99% | 173 (47.79) | 189 (52.21) | 0.15 (0.12–0.20) | < 0.001 | 0.54 (0.40–0.74) | < 0.001 | |
| ≥ 100% | 177,903 (92.19) | 15,072 (7.81) | 0.01 (0.01–0.01) | < 0.001 | 0.11 (0.10–0.13) | < 0.001 | |
| Initial follow‑up visit completed | Yes | 177,522 (90.63) | 18,348 (9.37) | 1.00 | |||
| No | 1112 (78.92) | 297 (21.08) | 2.58 (2.27–2.94) | < 0.001 | 1.68 (1.42–1.99) | < 0.001 | |
| Presence of ADRs | No | 177,390 (90.94) | 17,682 (9.06) | 1.00 | |||
| Yes | 1244 (56.37) | 963 (43.63) | 7.77 (7.13–8.46) | < 0.001 | 6.28 (5.68–6.94) | < 0.001 | |
Discussion
Based on data from the Chinese Information System for Disease Control and Prevention from 2021 to 2024, this study evaluated treatment outcomes and risk factors among 223,014 older pulmonary tuberculosis patients, with asymptomatic patients accounting for 11.54%, indicating that asymptomatic tuberculosis constitutes a significant proportion among the older population and deserves adequate attention in clinical practice and public health interventions. Although treatment success rates were similar between asymptomatic (90.83%) and symptomatic (90.55%) patients, the types of unfavorable outcomes differed significantly. Multivariate analysis identified multiple risk factors associated with unfavorable outcomes, supporting targeted interventions for high-risk asymptomatic older individuals.
Significant differences in demographic and clinical characteristics were observed between the asymptomatic and symptomatic groups. The asymptomatic group had a slightly higher proportion of males (71.0% vs. 69.6%), consistent with the gender distribution reported for older and general tuberculosis populations in China [14, 15]. Age was more concentrated in the 65–69year range, possibly due to greater social engagement and more health screening opportunities in this age group. Both groups showed higher prevalence in central and western regions, with asymptomatic patients more concentrated in the central region. This may reflect the relatively high tuberculosis burden in both regions, combined with better economic conditions and medical resources in the central region that facilitate detection through routine health checks. The proportion of cross-regional migrants was significantly higher in the asymptomatic group, likely related to employment-related screening opportunities such as pre-employment physical examinations. Clinically, asymptomatic patients had significantly lower rates of pathogen-positive and smear-positive results, possibly reflecting lower Mycobacterium tuberculosis loads [16, 17]. However, the proportion of patients with recorded comorbidities was significantly higher in the asymptomatic group, which may be explained by increased healthcare contact among those with comorbidities, leading to incidental tuberculosis detection. Regarding treatment management, active case finding was significantly higher in the asymptomatic group, while passive case finding was significantly higher in the symptomatic group. The absence of obvious tuberculosis-related symptoms means asymptomatic patients are often missed in symptom-based screening, underscoring the critical role of active screening strategies in improving detection [18]. This finding provides empirical support for the effectiveness of China’s active screening approach in key populations. The higher proportion of initial treatment cases in the asymptomatic group may be related to poorer baseline lung condition and greater likelihood of symptomatic presentation among retreatment patients.
This study shows that the treatment success rates for both asymptomatic and symptomatic older pulmonary tuberculosis patients exceeded 90%, meeting and surpassing the tuberculosis treatment success rate target proposed by the WHO [2], and are similar to findings from relevant studies in China [19]. However, despite the relatively high overall success rate, unfavorable outcomes still occur within a certain range, and the composition of unfavorable outcomes differs between the two groups. The proportion of loss to follow-up (18.52%) and not evaluated (6.61%) was significantly higher in the aPTB group compared to the sPTB group. This difference may involve several factors: first, asymptomatic patients, lacking obvious clinical symptoms, may have insufficient awareness of the disease and weaker motivation for treatment, making them more prone to interrupting treatment; second, preliminary findings from this study indicate a higher proportion of migrant populations among asymptomatic patients, and the cross-regional mobility of this group increases the difficulty of follow-up management and treatment continuity [20]; furthermore, the high proportion of comorbidities in asymptomatic patients, along with the burden of polypharmacy, may reduce treatment adherence [21, 22], not only increasing the individual’s risk of treatment failure, relapse, or death but also potentially inducing acquired drug resistance, posing a threat to public health. Therefore, for asymptomatic older patients, pre-treatment health education should be strengthened to help them establish a correct understanding of the need for complete tuberculosis treatment. Simultaneously, the cross-regional management mechanism for the migrant population should be improved to ensure treatment continuity during patient migration. Additionally, diversified supervision methods such as Short Message Service reminders, video observation therapy, and community home visits should be explored to enhance the management effectiveness of this high-risk group [23]. In contrast, the mortality rate and treatment failure rate were significantly higher in the sPTB group compared to the aPTB group. Death was the primary cause of unfavorable outcomes in both groups, accounting for 72.15% and 76.87% in the asymptomatic and symptomatic groups, respectively. This result highlights the risk of death faced by older tuberculosis patients, possibly related to factors such as the frequent presence of multiple chronic diseases, immune senescence, and poor nutritional status in older people [24, 25]. The higher bacterial load and higher proportion of retreatment cases in symptomatic patients may also contribute to their relatively higher mortality and treatment failure rates, suggesting the need to strengthen etiological and drug susceptibility monitoring and optimize treatment regimens promptly.
Through multivariate regression analysis, this study systematically identified, for the first time, risk factors for unfavorable treatment outcomes in older asymptomatic patients. Consistent with the sPTB group, advanced age was significantly associated with unfavorable outcomes in aPTB patients. Compared to the 65–69 age group, patients aged ≥ 80 years in the asymptomatic group had a 3.30-fold increased risk of unfavorable outcomes (AOR = 3.30), consistent with findings from multiple studies [26–28]. This association may be explained by multiple factors collectively contributing to an increased risk of unfavorable treatment outcomes in older people as age increases, including accelerated immune senescence, increased comorbidity burden, and diminished drug metabolism capacity. Residing in the western region was also an independent risk factor (AOR = 1.38), possibly related to the lower level of economic development, poorer accessibility of medical resources, and relatively lower health literacy in that region [29]. Notably, female sex was associated with a lower risk in this study (AOR = 0.78), consistent with findings from several domestic studies but differing from findings by Ereso et al. [30], this discrepancy may stem from differences in study populations, socioeconomic backgrounds, and cultural factors. Ereso et al. suggested that the higher risk of unfavorable outcomes in females might be related to household economic control, social status, and stigma. In China, however, males are the population that requires focused attention in tuberculosis control efforts [31].
From a clinical perspective, pathogen-positivity (AOR = 1.35), baseline sputum smear positivity (AOR = 1.48), and the presence of comorbidities (AOR = 1.72) were all significantly associated with a higher risk of unfavorable outcomes in aPTB patients. Pathogen-positivity typically implies a higher bacterial load and more severe pulmonary lesions, while the presence of comorbidities increases the complexity of treatment management and may affect drug metabolism and immune function, which may contribute to a worse prognosis [25]. In low- and middle-income countries, TB patients frequently suffer from coinfections with HIV, SARS-CoV-2, bacteria, fungi, or parasites, which serve as critical comorbidities that further complicate clinical management and increase the risk of unfavorable outcomes [8].
At the treatment management level, retreatment (AOR = 1.27), receiving extended/alternative treatment regimens (e.g., 2HRZE/10HRE and 6-9RZELfx, with AOR up to 1.81), non-use of FDC (AOR = 1.18), absence of an initial follow-up visit (AOR = 1.80), and ADRs (AOR = 6.58) were all significantly associated with an increased risk of unfavorable outcomes. Retreatment patients often have a history of prior non-standard treatment or previous treatment failure, potentially accompanied by complex issues such as drug resistance or poor adherence, which may contribute to significantly higher risks of treatment failure and relapse. This is consistent with the conclusions of Woldesemayat et al. [32]; You et al. also found an increased risk in patients with a history of tuberculosis [33]. Regarding treatment regimens, compared to the standard regimen, other regimens were associated with a higher risk of unfavorable outcomes, suggesting that using standard treatment regimens for asymptomatic tuberculosis patients may correlate with better outcomes. The associated between non-use of FDC and worse outcomes further supports the potential value of FDC in simplifying the medication process and improving treatment adherence [34]. The association observed with absence of an initial follow-up visit highlights the importance of management at the start of treatment. The initial follow-up visit is not only the beginning of directly observed treatment, short-course (DOTS) but also a crucial opportunity to establish patient-doctor trust, complete health education, and identify early risks. ADRs were associated with a markedly higher risk in this study, likely contributing to treatment interruption or regimen adjustment, and severe cases may even result in death [15]. However, this strong association should be interpreted with caution. Differential recording bias may exist in a surveillance setting—patients who remain engaged with the healthcare system longer may have ADRs more systematically documented, whereas ADRs in those lost to follow-up early may go unrecorded. Furthermore, residual confounding by disease severity, comorbidity burden, and treatment complexity cannot be excluded, as patients with more severe underlying conditions or more complex regimens are both more susceptible to ADRs and independently at higher risk of unfavorable outcomes. Regardless of the mechanism, this emphasizes the necessity of conducting close drug safety monitoring for older tuberculosis patients. In contrast, active case finding (AOR = 0.64) and extremely high medication/follow-up adherence (AOR as low as 0.02 and 0.06, respectively) were associated with significantly lower risk of unfavorable outcomes. This supports the crucial role of strengthening active screening and standardized full-course management in improving the prognosis of older aPTB patients, especially for asymptomatic, hidden patients [18, 35]. However, active case finding accounted for only 7.37% of aPTB patients, and these individuals may inherently have milder disease or better health literacy; therefore, the observed association does not necessarily imply that active case finding per se improves prognosis. Similarly, the strong associations observed for extremely high adherence may partly reflect better baseline health status and engagement in care. These findings highlight a need for further prospective evaluation. It is worth noting that while hospitalization did not reach statistical significance in the aPTB group, it was a clear risk factor in the sPTB group (AOR = 1.26), which, to some extent, reflects the reality that hospitalized patients have more severe baseline conditions.
This study has certain limitations. First, the definition of asymptomatic adopted a single criterion—absence of cough. While this may modestly overestimate the proportion of aPTB compared with stricter definitions requiring the absence of all PTB-related symptoms, cough is the most common and characteristic symptom of pulmonary TB and the principal driver of healthcare-seeking. This operational definition therefore aligns with both public health priorities and clinical practice. Future research could explore the prevalence and treatment outcomes of aPTB using different defining criteria. Second, the analysis was restricted to registered tuberculosis cases with complete symptom records, potentially excluding cases missed due to lack of screening or incomplete documentation—this may introduce selection bias. Third, asymptomatic tuberculosis typically lacks tuberculosis-related clinical symptoms, and its detection relies more on active screening strategies. However, the data in this study, based on a surveillance system, primarily originated from passive case finding, implying that some patients might have been missed. Therefore, the results of this study cannot be directly extrapolated to all aPTB patients, but they can still reflect the current situation of aPTB in China to a certain extent.
Conclusions
This study systematically analyzed treatment outcomes among older asymptomatic pulmonary tuberculosis patients in China from 2021 to 2024, based on surveillance data from the national tuberculosis information system. Asymptomatic patients accounted for 11.54% of the study population, with a treatment success rate (90.83%) comparable to that of symptomatic patients (90.55%). However, the composition of unfavorable outcomes differed significantly: the asymptomatic group had a higher loss to follow-up rate, while mortality and treatment failure rates were higher in the symptomatic group. These findings suggest that, although the overall efficacy was met, challenges remain in the treatment management of older asymptomatic patients, possibly related to factors such as the absence of symptoms and the presence of multiple comorbidities. Within this surveillance cohort, the following variables were associated with unfavorable outcomes: advanced age, residence in western regions, pathogen/smear positivity, comorbidities, previous treatment history, use of non-standard or extended regimens, non-use of FDC, absence of an initial follow-up visit, and ADRs. Conversely, active case finding and high treatment adherence were associated with favorable outcomes. These findings provide an evidence base for identifying high-risk older individuals and optimizing standardized treatment management, although caution should be exercised when generalizing these findings to other populations or settings.
Supplementary Information
Acknowledgements
Not applicable.
Abbreviations
- ADRs
Adverse drug reactions
- AOR
Adjusted odds ratio
- aPTB
Asymptomatic pulmonary tuberculosis
- CI
Confidence interval
- COR
Crude odds ratio
- DOTS
Directly observed treatment, short-course
- DS-PTB
Drug-susceptible pulmonary tuberculosis
- DS-TB
Drug-susceptible tuberculosis
- EPTB
Extrapulmonary tuberculosis
- FDC
Fixed-dose combination
- NTM
Nontuberculous mycobacteria
- PTB
Pulmonary tuberculosis
- RR-TB
Rifampicin-resistant tuberculosis
- sPTB
Symptomatic pulmonary tuberculosis
- TB
Tuberculosis
- WHO
World Health Organization
Authors’ contributions
YX-W conceived, designed the study and wrote the draft of the manuscript. JH-L and FJ-G helped cleaned and analyzed the data. CH-X commented on and revised drafts of the manuscript. All authors read and approved the final report.
Funding
This work is financially supported by the National Science and Technology Major Project of China (2025ZD01901000) and National Key Research and Development Program of China (2024YFC2311204).
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
Approved by the China CDC Institutional Review Board (No. 202522).
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.