Datas from developed countries indicate that the incidence of EPTB is increasing as a proportion of TB (5, 8). Since EPPB is much less infectious than PTB (16), it may not have received widespread attention from governments and researchers. However, EPTB can affect almost all organs in the human body and has a wide range of clinical implications (17). Datas from a national survey show that the prevalence of smear-positive TB in China decreased from 170 cases per 100,000 population in 1990 to 59 cases per 100,000 population in 2010 (18). Despite the success of the new integrated control model, limited epidemiological information suggests that the incidence of extrapulmonary tuberculosis in China may be increasing (3, 4). However, all over the world including China, the in-depth epidemiological and clinical information on RR/MDR-EPTB population are still lacking. In the present study, we included 5 years of datas on all well-documented MDR-TB, in which 17.76 % were EPTB and the most common site were pleura/chest wall (20.20 %) and lymphadenitis (19.21%). Consistent with existing studies on EPTB, the majority of RR/MDR-EPTB patients were predominately female (50.66%)、more less likely to develop diabetes (22.85%) and more likely to be newly diagnosed ( 56.95%) (4, 8). Notably, RR/ MDR-EPTB detection was more prone to delay, with a median time of 145 (14,341) days since the first visit to hospital .This is understandable because the microbiological diagnosis of EPTB presents challenges, with having difficulty obtaining bacteriological evidence in the early stages of consultation, and some even requiring invasive biopsies or even surgery. Moreover, most of the extrapulmonary specimens were oligosaccharides at the initial stage of the disease, making the diagnosis of various tests less sensitive. For example, MTB culture reduces sensitivity to paucibacillary infection and take several weeks to produce results (19). We also found that, unlike RR/MDR-PTB, RR/MDR-EPTB relies more on Xpert to establish the diagnosis. In the study, Xpert was positive in 91.70 % cases of RR/MDR-PTB and 93.71% cases of RR/MDR-EPTB, while the culture positive rate of MDR/RR-EPTB was significantly lower than that of RR/MDR-PTB. (56.95% Vs 79.21%, P < 0.01). Previous study shown that Xpert should be used as a primary diagnostic tool for the detection of EPTB, especially in tuberculous lymphadenitis. However the added value of diagnosing pleural or peritoneal tuberculosis may be limited (20) .Existing studies, however, have focused on the microbiological diagnosis of EPTB, rather than on drug-resistant populations. Effective treatment of MDR-TB is based on accurate detection of drug resistance, but microbiological data and related studies on drug-resistant EPTB were still lacking. Delayed initiation of RR/MDR- EPTB treatment are likely to be associated with an increase in bacterial load and progression of the disease. Inaccurate treatment may acquire more resistance, leading to further spread of the disease (21). Rapid molecular diagnostic tests such as Xpert significantly reduce the time to diagnosis, and thus the time to treatment, compared to traditional DST (22). In our study, we found that Xpert could detect most drug-resistant EPTB and had good performance in all kinds of specimens. We believe that the main reason lies in the general lack of bacteria in conventional extrapulmonary specimens, and the development of drug-resistant MTB or infection with drug-resistant MTB may alter the nature of the oligosaccharides in the specimens. Therefore, both the culture positive rate (56.95%) and the Xpert positive (93.71%) rate were relative high.
Fluoroquinolones(FQs)have long been considered the cornerstone of treatment regimens for MDR-TB (23) and listed as Group A recommended drugs in the latest guidelines (15). Increased second-line drug resistance was associated with a higher rate of treatment failure (23). However, FQS has been widely used to treat bacterial infections of respiratory tract、gastrointestinal tract and urinary tract in China over the past decades (25). Improper use of FQs may lead to acquired resistance in TB patients, which in turn leads to the spread of strains that are already resistant to FQs. Molecular epidemiological studies have shown that resistance to moxifloxacin increased significantly in China between 2000 and 2010 (26). In our study, we also found 32.54% cases of pre-XDR/XDR-EPTB, which was significantly higher than that in MDR/RR-PTB༈18.88 %, P < 0.01༉, especially in osteoarticular༏spinal TB༈61.54%༉and genitourinary TB (50%). Our results have revealed that the majority of RR / MDR-EPTB were newly diagnosed. Because the early manifestations of EPTB are indistinguishable from common bacteria infection (genitourinary infection、bone and joint infection, etc.), patients may often first referred to non-TB specialist hospitals, so antibiotics may be administered while waiting for definition. In the present study, the treatment success rate after 18 months was 69.56% in MDR/RR-EPTB, significantly lower than that of RR/MDR-PTB ( 79.21%) in the same period. Among them, the treatment success rate was lower in osteoarticular/spinal TB (51.28%) and genitourinary TB (56.25%), which were also the two groups with the highest incidence of pre-XDR /XDR-EPTB. Our results also revealed that the prognosis of RR/MDR-EPTB may be worse than that of RR/MDR-PTB, and FQS resistance may be one of the main reasons. Clinicians should recommend Xpert early and use FQs cautiously in cases suspected TB.
Our study had some limitations. EPTB was not included in routine infectious disease reports in China CDC due to its relatively low infectivity. Our retrospective study only collected datas from Shanghai pulmonary Hospital. Although the specialized hospital is the only MDR-TB designated treatment hospital in Shanghai. Our data may not be representative of the whole country. However, our findings highlight the need for rigorous management and monitoring of RR/MDR-EPTB.