A Study On The Influencing Factors Of Cascade Losses In Latent Tuberculosis Infection And Health Benefits Of Preventive Therapy Among College Students

BackgroundIn 2021,the number of new tuberculosis(TB)cases worldwide reached 10.6 million.TB incidence increased from 127 per 100,000 population in 2020 to 134 per 100,000 population.The global TB incidence in 2021 was 3.6%higher than in 2020,breaking a downward trend of about 2%a year over the past two decades.In recent years,the TB epidemic in China has shown a downward trend.The number of new TB cases in 2021 was 780,000,down about 14%from 2015.But China still faces huge challenges to achieve a 50%reduction by 2025.The reported TB incidence among Chinese students decreased from 20.6 per 100,000 population in 2010 to 13.4 per 100,000 population in 2015,but rose again to 17.5 per 100,000 population in 2019.The Guidelines for Tuberculosis Prevention and Control in Chinese Schools(2020 Edition)indicates that the age of high TB incidence is around 18 years old.With the increasing enrollment scale of colleges,the number of students on campus has risen sharply in China.The number of students with TB and rifampicin-resistant TB in colleges has increased significantly.Latent tuberculosis infection(LTBI)is a state of persistent immune response to stimulation by Mycobacterium tuberculosis(MTB)antigens with no clinical manifestation or imaging evidence of active TB.About a quarter of the world’s population is infected with MTB,and about 5-10%of those infected may develop active TB in their lifetime.Evidence suggests China has the highest burden of LTBI,with nearly 350 million people infected with MTB.Strategy shift,gateway advance.TB preventive therapy(TPT)is an important component of the goal of ending TB.Recently,TB outbreaks still occur from time to time in Chinese colleges.LTBI management is an important means for TB prevention and control in colleges.College students are in the age group with high TB incidence.Early detection of LTBI population and early TPT are of great significance for the prevention and control of TB clusters in colleges,as well as the promotion of physical and mental health among college students.Since 2015,TPT has been piloted in many high schools and colleges in China.The relevant documents on school TB prevention and control have standardized and detailed the TB prevention and control measures and implementation suggestions in colleges.However,the specific steps of LTBI management,losses and the facilitators and barriers in Chinese colleges are not clear at present.In addition,few studies evaluated the impact of TPT on the physical and mental health of LTBI population.Therefore,we conducted a study on the factors influencing cascade losses of LTBI and the health benefits of TPT among college students,which will help Chinese colleges to formulate LTBI management strategies and provide decision-making basis for public health practitioners to carry out TB prevention and management.Objectives1.To quantify the LTBI cascade steps among college students,describe the characteristics of cascade losses,and explore the factors influencing cascade losses.2.To describe the acceptance and initiation rates of TPT among LTBI college students,and explore the influencing factors of accepting and starting TPT,as well as the facilitators and barriers to initiation.3.To describe the completion rate of TPT and the average time of last treatment among LTBI college students,explore the factors influencing non-completion,and explore the facilitators and barriers to completion.4.To measure the quality of life and mental health among LTBI college students,compare the difference of the quality of life and mental health between baseline and follow-up,and evaluate the impact of TPT on the quality of life and mental health.Methods1.Data collectionThis study was conducted in Shandong Province.Sixteen colleges in Jinan,Qingdao,Yantai,Rizhao,Linyi and Zibo were selected as research sites according to the TB incidence and regional medical conditions.From September to November 2020,the cluster random sampling method was adopted to randomly select the freshmen of Class 2020 by school/department in each college.All participants underwent symptom screening and chest X-ray and a tuberculin purified protein derivative(PPD)test(50IU/ml).Baseline surveys were then conducted.The inclusion criteria were:(1)18 years old and older;(2)a positive PPD result.Exclusion criteria were:(1)patients diagnosed with active pulmonary TB or extrapulmonary TB;(2)patients with a history of mental illness or epilepsy.The information collected in baseline surveys included household and personal basic information,knowledge of TB prevention and control,health status and health behavior.From November 2020 to January 2021,research groups were conducted.The inclusion criteria for the treatment group and control group were:(1)18 years old and above;(2)a positive PPD result.Exclusion criteria for the treatment group were:(1)patients diagnosed with active pulmonary TB or extrapulmonary TB;(2)patients with a history of mental illness or epilepsy;(3)allergic to isoniazid and rifamycin antibiotics;(4)liver and kidney function damage or poor,biliary obstruction disease;(5)patients with diabetes,alcoholism,or low body weight,etc.Respondents who met the inclusion and exclusion criteria and agreed to accept TPT were included in the treatment group after the acquisition of written informed consent.Exclusion criteria for the control group were:(1)patients diagnosed with active pulmonary TB or extrapulmonary TB;(2)patients with a history of mental illness or epilepsy.Based on gender and age,students who refused TPT in each college were randomly matched with the treatment group in a ratio of 1:1.5,and were included in the control group after obtaining written informed consent.Three months of isoniazid plus rifapentine(3HP)was adopted twice a week.The dose was 600 mg/time for isoniazid and 600 mg/time for rifapentine if the body weight was≥50 kg;500 mg/time for isoniazid and 450 mg/time for rifapentine if the body weight was<50 kg.TPT in each college was started from November 2020 to January 2021.During the TPT period,medication and examination results were recorded under the guidance of county or district TB prevention and control institutions.TPT was completed from February to April 2021.Six months after the end of TPT,the project team conducted on-site follow-up surveys in all colleges.Follow-up surveys increased the collection of information such as medication use,and qualitative data were collected through face-to-face,semi-structured interviews and focus group discussions.2.Data analysis(1)Using the prospective data of LTBI among college students,the LTBI cascade steps in colleges were quantified and the characteristics of cascade losses were clarified.The generalized linear mixed-effects model(GLMM)was used to analyze the factors influencing cascade losses.(2)Using the quantitative and qualitative data among LTBI college students,GLMM was used to analyze the factors influencing TPT acceptance and initiation after accepting it.The thematic analysis method was used to analyze the facilitators and barriers to starting TPT.(3)Using the quantitative and qualitative data among LTBI college students,the Kaplan-Meier method was used to estimate the completion rate and average time of TPT.The Cox proportional risk regression model was used to analyze the factors influencing TPT non-completion.The thematic analysis method was used to analyze the facilitators and barriers to TPT completion.(4)The quality of life and mental health among LTBI college students were measured using prospective cohort data of LTBI.The difference analysis was used to compare the health status among LTBI college students before and after TPT.GLMM was used to analyze the impact of TPT on all dimensions of quality of life.The linear mixed model was used to analyze the impact of TPT on quality of life utility value,self-rated health and mental health.Results1.20,330 college freshmen participated in the tuberculin skin test(TST)test.20,151 test results were effectively read.1,731 students had positive TST results,and 1,691 were were given medical evaluation.1,631 students were recommended for TPT,and 723 were willing to accept TPT.292 students started TPT,and 229 completed TPT.The cascade losses occurred in three main stages:from recommendation to acceptance of TPT(loss rate 52.4%),from acceptance to initiation of TPT(loss rate 24.9%),and from initiation to completion of TPT(loss rate 3.7%).The cascade losses rate from recommendation to completion of TPT was 86.0%.Multivariate GLMM results showed that female(OR=0.67,P=0.015),having boarding experience(OR=0.47,P=0.002),TB knowledge level(OR=0.97,P=0.003),and smoking(OR=0.57,P=0.021)were negatively associated with cascade losses.Father’s high school education level or above(OR=1.86,P=0.014)was positively associated with cascade losses.2.Among 1,631 LTBI college students,the acceptance rate of TPT was 44.3%.Among 723 LTBI students who accepted TPT,the initiation rate was 39.7%.Multivariate GLMM results showed that female(OR=1.43,P=0.001),having boarding experience(OR=1.45,P=0.010),a history of TB exposure(OR=1.86,P=0.036)and moderate physical activity level(OR=1.36,P=0.020)were positively associated with accepting TPT.Father’s junior high school education level(OR=0.70,P=0.023)was negatively associated with TPT acceptance.The highest annual household income(OR=0.56,P=0.037)was negatively associated with TPT initiation after accepting it.Having boarding experience(OR=2.45,P=0.003)and TB knowledge level(OR=1.03,P=0.039)were positively associated with TPT initiation after acceptance.Qualitative results showed that fear of TB,parental support,failure to distinguish between TB and LTBI,free medication and examination,and clinician approval were facilitators for starting TPT.Lack of knowledge about TB and LTBI,concerns about side effects of drugs,and lack of documentation were barriers to TPT initiation.3.Among 292 LTBI college students who started TPT,the completion rate of TPT was 78.4%.Kaplan-Meier analysis showed that the average time of last TPT was 75.9 days.Multivariate Cox regression model analysis showed that non-medical students(HR=0.17,P<0.001)and TB knowledge level(HR=0.96,P=0.012)were negatively associated with failure to complete TPT.Living in an urban area(OR=1.75,P=0.041)was positively associated with TPT non-completion.Qualitative results showed that fear of TB,medication reminders,and medication education were facilitators for TPT completion.Forgetting medication,adverse reactions,treatment program problems,discontinuity in medication management,lack of medication compliance and benefit education,and lack of professional management were barriers to TPT completion.4.Among 740 LTBI college students,the utility value of the Chinese version of the Five-level EuroQol five-dimensional questionnaire(EQ-5D-5L)and visual analogue scale(VAS)score were high(baseline utility value:0.980±0.061,EQ-VAS score:92.6±111.1;follow-up utility value:0.976±0.097,EQ-VAS score:93.1±10.8).The score of mental health measured by the Chinese version of the 10-Item Kessler Psychological Distress Scale(K10)was low(baseline K10 score:14.0±7.8;follow-up K10 score:14.5±8.2).After half a year of TPT completion,the utility value of the treatment group increased from 0.977±0.060 to 0.982±0.065,and the EQ-VAS score increased from 91.6±12.1 to 93.41±9.9.In the control group,the utility value decreased from 0.983±0.061 to 0.973±0.113,and the EQ-VAS score decreased from 93.3±10.4 to 92.9±11.4.The mental health score of the treatment group increased from 14.5±8.0 to 14.5±8.2.The mental health score of the control group increased from 13.7±7.7 to 14.5±8.2.The difference in the difference of utility value and EQ-VAS score between the treatment group and the control group before and after TPT was statistically significant(Z=2.32,P=0.020;Z=2.40,P=0.016),while the difference in the difference of mental health score was not statistically significant.After adjusting for covariates,time weakened the positive impact of TPT on "anxiety or depression"(β=-0.741,P=0.043).Time weakened the negative impact of TPT on EQ-VAS score(β=2.112,P=0.023),but the impact of TPT on mental health was not significant.Conclusions1.The cascade steps of LTBI among college students were seven steps.The main cascade losses occurred from recommendation to acceptance of TPT(loss rate 52.4%),acceptance to initiation of TPT(loss rate 24.9%),and initiation to completion of TPT(loss rate 3.7%).Cascade losses were negatively associated with female,having boarding experience,TB knowledge level and smoking,and positively associated with father’s high school education level or above.It is recommended to quantify the cascade steps of LTBI and strengthen the publicity and education of those accepting TPT.2.The acceptance and initiation rates of TPT were low among LTBI college students.TPT acceptance rate was positively associated with female,having boarding experience,a history of TB exposure and moderate physical activity level,and negatively associated with father’s secondary education level.TPT initiation rate after accepting it was negatively associated with the highest annual household income,and positively associated with having boarding experience and TB knowledge level.The facilitators for starting TPT were fear of TB,family support,confusion between TB and LTBI,free treatment and examination,and clinician referrals.Barriers included lack of proper knowledge of TB and LTBI,side effects of drugs,and lack of documented guidelines.In the future,students and parents should be educated about TPT,and the integration of medical treatment and prevention should be strengthened.3.The completion rate of TPT was low among LTBI college students,and the average time of the last TPT was 75.9 days.TPT non-completion was negatively associated with non-medical specialty and TB knowledge level,and positively associated with urban residence.The facilitators for completing TPT were fear of TB,medication reminders,and education on LTBI medication.Barriers included forgetting to take medication,fear or experiencing adverse reactions,long duration of treatment,high quantity of medication,discontinuous management of medication,lack of education on medication compliance and benefit,and lack of professional management.Successful TPT needs the joint improvement of colleges,preventive institutions and medical institutions.4.The quality of life and mental health among LTBI college students were good.Before TPT,the quality of life and mental health of the treatment group were worse than those of the control group.After TPT,the quality of life in the treatment group improved,while the mental health of the control group became worse.Time weakened the negative impact of TPT on the quality of life.The evaluation and intervention of mental health among LTBI patients should be strengthened in the future.Innovations1.This study put forward the concept of LTBI cascade management in colleges,quantified the seven-step cascade of college students from LTBI detection to TPT completion,clarified the characteristics of cascade losses,and identified the factors influencing cascade losses and main losses.The research results are of great significance to further strengthen the LTBI management in colleges,and also provide new ideas for the management of LTBI in other high-risk groups in China.2.In this study,a mixed method was used to obtain quantitative and qualitative data.The qualitative data broke through the previous single perspective of focusing only on LTBI population,and integrated the views of both TB staff and LTBI population to expand the research conclusions of quantitative data.The combination of quantitative and qualitative methods comprehensively and deeply explored the factors influencing TPT initiation and completion among LTBI college students,which provides reference for the development of LTBI management strategies and intervention measures in colleges.3.Based on the prospective and follow-up data of LTBI population,this study evaluated the implementation process of 3HP regimen and the health benefits of TPT,which enriches relevant research on TPT evaluation.This study made up for the limitation that most of the previous domestic studies only focused on a certain link of TPT and less considered the whole process,and provides a decision-making basis for public health practitioners to carry out TB prevention and management.