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Prevalence of multidrug-resistant tuberculosis in suspected childhood tuberculosis in Shandong, China: a laboratory-based study

Objective Currently, the prevalence of multidrug-resistant tuberculosis (MDR-TB) in childhood tuberculosis (TB) in Shandong, China remains unclear. We retrospectively conducted laboratory-based surveillance in a high TB burden district, to analyze the local prevalence of MDR-TB in childhood TB. Methods We collected data, including microbiological results and demographic and disease information, using a questionnaire and medical records. We used the chi-squared test to compare the prevalence of MDR-TB in childhood TB between two periods: 2008 to 2013 and 2014 to 2018. Results In Shandong, the prevalence of MDR-TB in childhood TB was low, at 5.6%. Between 2008-2013 and 2014-2018 among children with TB, the prevalence of MDR-TB remained unchanged, the proportion with pulmonary TB decreased from 78.3% to 64.9%, and the proportion with a TB contact history decreased from 20.5% to 9.9%. Conclusions The prevalence of MDR-TB among childhood TB in Shandong, China was low and has remained stable over the past years. However, non-tuberculous mycobacterial diseases may be a new challenge in the management of suspected childhood TB.


Keywords
Childhood tuberculosis, multidrug-resistant tuberculosis, China, non-tuberculous mycobacteria, prevalence, surveillance Date received: 15 May 2019; accepted: 24 July 2019 Background Tuberculosis (TB) is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS. In 2016, there were an estimated 10.4 million TB cases and 1.6 million TB deaths. Childhood TB has been neglected by health professionals because children frequently have paucibacillary disease that is thought to be noninfectious. According to a World Health Organization (WHO) report in 2017, children account for 6.9% of new TB cases globally. The global health community has not set pediatric-specific targets for reducing the disease burden owing to the absence of clear pediatric targets; perceptions of low public health importance; and challenges in presentation, diagnosis, treatment, and reporting. 1 Furthermore, the disease burden has not been well characterized, such as the prevalence of multidrugresistant TB (MDR-TB).
Until now, several studies have investigated the prevalence of MDR-TB among children in China; however, the figures are highly unreliable and variable. According to previous reports, the prevalence of MDR-TB in childhood TB was between 4.6% and 22%. [2][3][4][5] However, the prevalence of MDR-TB among children in Shandong Province, China remains unclear. Therefore, we conducted laboratory-based surveillance in Shandong to evaluate the prevalence of MDR-TB among children age 15 years old, from 2008 to 2018.

Patients and methods
This retrospective study was conducted at Shandong Provincial Chest Hospital (SPCH), which has about 800 beds and attends approximately 1000 patients with culture-confirmed TB every year. Mycobacterial culture was performed using L€ owenstein-Jensen medium, and drug susceptibility assay was performed as previously reported. 6 We used the absolute concentration method (isoniazid: 1 lg/mL, rifampin: 50 lg/mL, ethambutol: 5 lg/mL, and streptomycin: 10 lg/mL) on L€ owenstein-Jensen medium to screen Mycobacterium tuberculosis (MTB) isolates. Quality control was conducted using inter-laboratory confirmation testing at reference laboratories recognized by the WHO in South Korea and Hong Kong, China. Non-tuberculous mycobacteria (NTM) were identified using p-nitrobenzoic acid and thiophene-2-carboxylic acid hydrazide tests and further identified with a Mycobacteria Identification Array Kit (CapitalBio, Beijing, China).
We collected data, including demographic and diseases information, using a questionnaire and medical records. The chi-squared test was used to compare the prevalence of MDR-TB in children between two periods: 2008 to 2013 and 2014 to 2018. This study was approved by the Human Research Ethics Committees of SPCH (ethics approval number: SPCHEC 2018-03-02). Written informed consent was waived owing to the retrospective design of the study and anonymous nature of the data collection.

Discussion
In the current study, we found that the overall rate of PTB among childhood TB decreased between 2008-2013 and 2014-2018. There are three reasons for this. First, although TB remains a major public health problem in China, the prevalence has steadily decreased. China has now fallen to second place worldwide in TB prevalence. 7 Second, as an important cause of PTB, the TB contact history was lower during 2014 to 2018 than in 2008 to 2013. Third, we found that the percentage of cases of EPTB has increased in recent years; this may have a large impact on the balance between PTB and EPTB.
In our study, the overall prevalence of MDR-TB among children in Shandong, China was 5.6%, similar to the findings of a previous data 2 and lower than that reported in another study (10.8%). 2,6 Moreover, we observed no substantial variations in the prevalence of MDR-TB among children between the two study periods. This is in contrast to the results of a previous study, 2 which showed that the percentage of MDR-TB in childhood TB increased significantly from 2006 to 2015. This difference may be owing to limitations in the previous research. First, the age criteria in that study was higher, from 15 to 18 years old, and most patients (76.1%) were !15 years old. Second, few MDR-TB cases were reported each year (usually <10 cases), so the prevalence could easily fluctuate because of the small sample size. Third, the statistical methods used in that previous study were inappropriate. In fact, only in the last 3 years (2012-2015), the prevalence of MDR-TB seemed to be increasing among children. 2 Therefore, assessing the prevalence rate over a longer period may provide better understanding regarding the situation of MDR-TB in children.
Our results indicated a decreasing trend in the prevalence childhood MDR-TB, although not statistically significant. This phenomenon may be explained by the contribution of recent transmission during an MDR-TB epidemic in China and the impact of TB contact on the risk of TB diseases. 8,9 Remarkably, a previous study showed an increasing prevalence of NTM infections in China. 10 In the present study, NTM isolates were detected in eight patients and the first isolate was detected in 2012. As far as we know, most NTM isolates were resistant to first-line anti-TB drugs. Therefore, greater attention must be given to this situation for better management of these infections in children.
Although we revealed important information in this study, some limitations exist. In our study, 12 MDR-TB patients were included, and the average annual number of patients with MDR-TB was fewer than two. If comparing results in each year from 2008 to 2018, statistical significance may never be achieved. For this reason, we divided the study into two periods: 2008 to 2013 and 2014 to 2018.

Conclusions
In Shandong, China, although the proportion of PTB among cases of childhood TB has decreased, the proportion of EPTB cases increased from 2008-2013 and 2014-2018. Moreover, the local prevalence of MDR-TB among children was not very high and remained unchanged between the two periods. However, NTM diseases may be a new challenge in the management of suspected childhood TB.