Primary Drug-Resistant Tuberculosis in the Elderly in Shandong,China,from 2004 - 2019.

Background: With an aging population, China is facing a huge buedern of elderly patients with drug resistant tuberculosisi (DR-TB), which has become an signicant obscale for the global TB control targets. There is still few study on DR-TB among China so far.Thus, more researches on the epidemiological characteristics and trend of primary DR-TB among the elderly will be necessary. Methods: A retrospective study was conducted in Shandong, China from 2004-2019, 12661 primary TB and 4368 elderly ( ≥ 60 years of age) primary TB cases were involved. Clinical characteristics including age, sex, Cavity, Smoking, drinking, comorbidity and drug susceptibility data were included. Descriptive statistical analysis, Chi-square and linear regression were used for analyzing. Results: Among 4368 elderly patients with primary TB, the DR-TB and MDR-TB accounted for 17.19% and 2.29% respectively. During 2004 to 2019, the proportions of MDR-TB, PDR-TB, RFP-resistance increased by160.00%, 18.18%, 231.82%, and the rate of DR-TB among elderly patients with primary cavitary TB increased by 255%.Among the elderly with primary DR-TB, the proportion of male (from 85.19 to 89.06), cavity (from 7.41 to 46.88), RFP (from 3.70 to 21.88), SM (from 37.04 to 62.5) increased signicantly(P<0.05) . And the proportion of female (from 14.81 to 10.94), non-cavity (from 92.59 to 32.81 ), INH (from 66.67 to 57.81 ) decreased signicantly. (P<0.05) . Conclusion: Among the elderly, the proportions of MDR-TB, PDR-TB,RFP-resistance and cavitary DR-TB increased signicantly. The pattern of DR-TB changed from female, non-cavity and INH-resistant groups to male, cavity and RFP, SM-resistant groups. For a better control on the elderly DR-TB in the future, we should pay more attention to, male, smoking, drinking, COPD and diabetes subgroups. especially the primary drug resistant tuberculosis to face the problem which the population aging will bring. Nevertheless, the studies on drug resistant tuberculosis in the elderly are few. We collected 12661 primary TB cases with drug susceptibility test results. Meanwhile,Chi-square and linear regression were carried out to assess the epidemiological characteristics and trend of primary DR-TB among the elderly in Shandong, China, from 2004–2019. Otherwise, we divided the primary DR-TB among the elderly into some groups separated by drug-resistnt proles, sex, smoking, drinking, cavity and diabetes for further analysis. This retrospective cohort study collected 12661 primary TB case-patients in Shandong, the second largest province in China, from 2004 to 2019, to evaluate the epidemiological characteristics and trend among the elderly DR-TB. We have some ndings in this study. Among the elderly, the proportions in these subgroups including MDR-TB, PDR-TB, RFP-resistance and cavitary DR-TB increased signicantly. The pattern of DR-TB shifted into male,cavity and RFP, SM-resistant groups. Male,smoking,drinking, COPD and diabetes subgroups.subgroups should get more attention.


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All sputum samples were adopted from patients conforming to the conditions by suspected site. Then these samples were sent to the TB Reference Laboratory of SPCH for further detection. Samples were cultured on Löwenstein-Jensen (LJ) culture medium,and then growing colonies were sent for further identi cation and DST.Para-nitro benzoic acid (PNB) and Thiophene-2carboxylic acid hydrazide (TCH) medium tubes were used for identi cation of the species M. tuberculosis. The susceptibility to four rst-line drugs (rifampicin, isoniazid, streptomycin, and ethambutol) was tested by the proportional method on Löwenstein-Jensen (LJ) culture medium according to the WHO guidelines. [11] The concentration of drugs were as follows: 0.2 µg/mL (isoniazid, INH), 40 µg/mL(rifampin, RFP), 10 µg/mL (streptomycin, SM), 2 µg/mL (ethambutol, EMB). [12] Quality Control Quality assessment and data extraction were complicated by two professional investigators respectively. Superior TB National Reference laboratory in SPCH implemented the external quality assessment regularly for all laboratories in our study.
Data Inclusion And De nitions TB patients with a positive M. tuberculosis culture were included, DST results, demographic information, and clinical information of the patients were available .
Drug-resistant tuberculosis (DR-TB) include acquired and primary drug resistance according to whether having a history of previous treatment. [13] The elderly primary TB refers to a patient ≥ 60 years of age with primary TB.
Drug-resistant tuberculosis (DR-TB): Resistance to any drugs. [14] Mono-resistance (MR): Resistance to one rst-line anti-TB drug only. [15] Polydrug resistance (PDR): Resistance to more than one rst-line anti-TB drug, other than both isoniazid and rifampicin. [15] Multidrug resistance (MDR): Resistance to at least both isoniazid and rifampicin. [15] Rifampicin resistance (RR): Resistance to rifampicin detected using phenotypic or genotypic. [15] Statistical Analysis Chi-square test for trends and linear regression in line charts and stacked bar charts were used to analyze the changes and temporal trend in quantity and proportions of the different resistance patterns over time. Odds ratios (ORs) and 95% CIs for the comparisons of speci c characteristics between the non elderly (< 60 years) and the elderly (≥ 60 years)were acquired by Pearson Chi-square test. P < 0.05 was considered to be signi cant statistically. All analyses were implemented by using SPSS software (version 20.0).

Patients' Characteristics
We collected 12661 primary TB case-patients, and analyzed the demographic and clinical information of them from 2004 to 2019 in Shandong, China. 4368 primary TB case-patients were the elderly (≥ 60 years), which accounted for 34.50% of the total primary TB case-patients collected. There were 8183 primary TB case-patients were the non elderly (< 60 years),which accounted for 64.63% of the total primary TB case-patients collected. The elderly primary TB casepatients were more likely than the non elderly primary TB case-patients to be male

Drug-resistance Patterns
The elderly patients with primary DR-TB were 751, which accounted for 17.19% among the total primary TB-case-patients collected. Among 4368 the elderly primary TB patients, the highest number and proportion of resistance were SM 469 (10. PDR6(RFP + EMB + SM), which accounted for 0.11% (5), 3.16% (138),0.05% (2), 0.23% (10), 0.14% (6) and 0.02% (1) respectively. The elderly primary TB cases had lower rate of DR-TB (17.19% vs 19.55% P < 0.05), MDR-TB (2.29% vs 3.72% P < 0.001) than the non elderly. The proportion of resistance to RFP or SM was lower among the elderly than the non elderly(P < 0.001). The proportion of resistance only to RFP, SM was lower among the elderly than the non elderly.(P < 0.05). The proportion of resistance only to INH, EMB was higher among the elderly than the non elderly(P < 0.05). (Table 2)   According to the WHO report, TB prevalence increased with age in Asia and some African countries (e.g. Ghana, Malawi,Rwanda, the United Republic of Tanzania and Zimbabwe), the peak of prevalence in some Africa countries (e.g. Ethiopia, Gambia, Namibia, Nigeria, Sudan, Uganda and Zambia) were among those people aged 35-54 years.
[15] And there is a estimated that the elderly population will come up to 400 million by 2030. 2 The prevalence of tuberculosis in aged 65 years and older was more than twice as high than that in younger adults.
[16] Elderly patients have been repeatedly reported to have a lower treatment completion rate and are less health awaeness than younger patients .That means the diagnosis and treatment in elderly TB is very di cult for us.
[17],[18] So the TB in the elderly should be appreciated. Meanwhile we found that the elderly (≥ 60 years) primary TB patients accounted for about one third(4368/12661, 34.50%)of the total new TB cases.
Besides, we found that the elderly with TB were more likely to be male, to have habits of smoking or drinking, and to develop complications such as COPD or diabetes than the non-elderly .We found that there was no statistical signi cance between elderly DR-TB cases and elderly susceptible TB cases in our statistical data. But we found that elderly DR-TB cases are more likely to be male and to like smoking than non elderly DR-TB cases. Some surveys showed a systematically higher burden of TB disease among men, with M:F (Male/Female) ratios ranging from 1.2 ( in Ethiopia) to 4.9 ( in Viet Nam). The M:F ratios were generally higher in Asia than in Africa, that was in the range 2-4. [2] In 2017 ,TB cases in all EU/EAA (European Union/East Asian Area) member States tended to be male. In Poland, men was the biggest in older age groups with TB. [19] This phenomenon may be associated with Social behavior factors and biological sex-related factors, such as sex steroid hormones, the genetic makeup of the sex chromosomes, and sex-speci c metabolic features. [20] Risk factors are also very important in the control of tuberculosis. Diabetes, alcohol use, and smoking all accounted for about a quarter of tuberculosis deaths and DALYs (disability-adjusted life years )around the world in 2015. [7] These factors may increase the risk of TB by impairing the immune system of human. [21]- [23] Smoking made it easy to develop TB which is related to ciliary dysfunction, to a reduced immune response, and to defects in the immune response of macrophages, with or without a decrease in the CD4 count. [24] Some evidence suggested that drinking was linked to tuberculosis treatment compliance and may lead to subsequent acquired drug resistance.besides it might be related to the sequelae of AUD (Alcohol Use Disorders), [21], [25] Diabetes leaded the susceptibility to tuberculosis to increase by a few mechanisms, including hyperglycemia and cellular insulinopenia, which have indirect effects on macrophage and lymphocyte function. [26] The study pointed out that factors impaired the innate defence mechanisms in the airways in COPD might increase the risk of TB infection or become activeTB. [27] Besides the study suggested that immunity declined and susceptibility to chronic disease increased with aging. [28] Taking some measures to prevent these risk factors may make cascade effect on the control of TB and DR-TB in the elderly.
The results of the National Prevalence Survey showed China has 5.7% of new and 25.6% of previously treated cases of MDR-TB. [29] In addition, the DR-TB and MDR-TB were accounted for 18.10% and 2.89% respectively among the elderly with TB in our study. Meanwhile, we found that the annual drug resistant rate of MDR-TB, PDR-TB,RFP-resistance and cavitary DR-TB increased signi cantly in our study. The increment of MDR-TB were also be found in previous studies in Beijing(from 2005 to 2008) [30], in Korea [31], in Taiwan [32] et al. And in Zhejiang province the drug resistant rate of MDR-TB decreasedvery slowly.
[33] China has the world's largest number of patients with MDR -TB. Inadequate treatment in both the public health system and the hospital system may induced the MDR-TB.The treatment of MDR-TB/RR-TB is di cult, complicated and costly. [9], [34] All of these alarm us that the MDR-TB plays a key role in the burden of DR-TB disease. We found that the elderly had a higher resistantce rate only to INH or EMB and a lower resistance rate to any one of INH, RFP, EMB, and SM compared to that in non elderly. These could be found in TaiWan [35]- [38], in United Kindom [39]. And we also found that the drug resistant patterns changed into male, cavitary TB, RFP-resistant and SM-resistant among the elderly. Although we found that the drug resistant rates of different subgroups(MR-TB, male, cavity, smoking, drinking, INH-resistant, RFP-resistant, EMB-resistant, SM-resistant) declined and became very low during 2008-2010.We speculated that may be related to the policies China carried out before those years and the delayed action. [40]- [42]Some previous studies suggested that the cavity of tuberculosis could lead to an increased possibility of DR-TB during treatment. [43] the prevalence of DR-TB was signi cantly higher among males illuminated in some study. [44]- [47] It had been noticed that cavities were more common in DR-TB cases than in susceptible TB cases, and this phenomenon may be caused by limited drug penetration into cavities, the suitable environment provided by cavities for bacili, patients' immunity et. al. [45]- [51] Elderly patients were more probably to get RR-TB than the younger patients which was stated in some surveis. [45], [47] These may be the reasons that DR-TB pattern changed The change of DR-TB pattern will bring us a huge challenge to control the DR-TB in the elderly.
There were several advantages in our study. Firstly, the study were conducted in Shandong province, the second largest province in China ,from 2004 to 2019. All DST data were involved in our study. The research time span is large and the scope is wide So that our ndings are more likely to be generalized throughout the country. Secondly, we screened out the elderly with TB,and divided the elderly with TB and DR-TB into different subgroups according to sex, smoking history, drinking history, cavity, COPD, diabetes and so on.
Our study also had some limitations. Firstly, DST were not regularly executed among all TB patients, TB surveillance stations had differences in screen density and medical conditions, which might induce selection bias in our data. Secondly, there were some unavoidable bias induced by different technical levels and experimental conditions in TB surveillance. Lastly, the statistical data on smoking and drinking from 2004 to 2007 is missing in our study, thus we could not analyze the subgroups among the elderly with DR-TB including smoking, drinking et. al very well .

Conclusion
The study presented the epidemiological characteristics and trend of primary DR-TB among the elderly in Shandong, China, from 2004-2019. We found that the proportion of MDR-TB, PDR-TB and RFP-resistance and the rate of cavitary DR-TB among the elderly increased signi cantly, drug resistance patterns among the elderly modi ed from female, non-cavity and INH-resistant to male, cavity and RFP, SM-resistant. The elderly primary TB case-patients were more common in male, having history of smoking or drinking, having COPD or diabetes. We should pay more attention to these subgroups including male, smoking, drinking, COPD and diabetes subgroups. groups to prevent DR-TB in the elderly. Besides, support of government, improvement of medical, enhancement of public awareness are also very important. Older adults play very important roles in nowadays society in China, understanding the epidemiological characteristics and trend of primary DR-TB among the elderly will make the control of DR-TB more easier.  Ethics approval and consent to participate The protocols applied in this study were approved by the Ethics Committee of Shandong Provincial Hospital, a liated with Shandong University (SPH) and and the Ethic Committee of Shandong Provincial Chest Hospital (SPCH), China. Before analysis, patient records were anonymized and deidenti ed.

Consent for publication
Not applicable.