Analysis of Clinical Characteristics of 556 Spinal Tuberculosis Patients in Two Tertiary Teaching Hospitals in Guangxi Province

Spinal tuberculosis (STB), which accounts for half of musculoskeletal tuberculosis, is among the leading causes of extrapulmonary tuberculosis. Guangxi Province, located in southern China, is among the most severely affected provinces in China. In this study, we collected and analyzed data from 2 Class-A tertiary teaching hospitals in Nanning City, Guangxi Province, from 2011 to 2019, with the aim of providing reference points for the prevention, diagnosis, treatment, and prognosis analysis of STB, using the epidemiological characteristics of 556 STB cases. Our results revealed that males had a slightly higher incidence (50.17%) compared to females (49.83%), with 64.93% of cases falling between the ages of 18 and 45 years. Cases from rural communities accounted for 63.49% of the reviewed cases. The average time between onset of symptoms and hospitalization was 18.0 months (range: 1 day-220 months). The most commonly reported symptoms were lower back pain (78.60%), radicular pain (51.98%), and systemic toxemia (43.53%). Additionally, 53.98% of the reviewed cases had varying degrees of neurological impairment. The main pathological lesion locations were the lumbar spine (43.53%) and thoracic spine (32.55%). Among them, 72.66% of cases involved at least 2 vertebral segments, and 62.77% of cases presented with paravertebral abscesses. Among the cases reviewed, 90.65% underwent antituberculosis chemotherapy prior to surgery. Following treatment, the cure rate was 78.41%, while 3.78% of patients had postoperative relapse. There were cases of concomitant illnesses among the cases reviewed, 40.65% of patients also had pulmonary tuberculosis, 15.29% had hepatitis B, 13.30% had diabetes, and 7.91% had hypertension. Our results still demonstrate that spinal tuberculosis remains a serious public health problem in Guangxi Province. Thus, preventive measures should be directed towards rural residents with comorbidities such as the elderly and diabetic.


Introduction
Tuberculosis (TB) continues to be an infectious disease nightmare in developing countries. Late treatment of pulmonary tuberculosis still continues to pose a serious threat to public health and socioeconomic development in the developing world as it leads to incapacitation and uncontrolled spread [1]. Spinal tuberculosis (STB), which accounts for approximately 50% of musculoskeletal tuberculosis, is the most common extrapulmonary tuberculosis [2]. The diagnosis of spinal tuberculosis is relatively difficult. Pathological evidence from tissue samples is the gold standard for diagnosis, but in fact, it is very difficult to identify Mycobacterium tuberculosis from the lesion [2].
In addition, because of the vague nature of the presenting symptoms and paucity of neurological symptoms and signs in the early stages of the disease, most patients report serious manifestations like irreversible neurological impairments such as paralysis at the time of reporting, which increases the length of stay and treatment costs, resulting in serious financial burden [3].
Antituberculous chemotherapy remains the fundamental treatment modality for STB, with surgery as an adjuvant [4,5]. According to the World Health Organization report, although the incidence and mortality rates of tuberculosis (TB) in China have been declining steadily in recent years, China still remains one of the countries with the highest TB burden in the world [6]. There were approximately 833,000 new tuberculosis cases in China in 2019, with a reported 388,000 mortalities, demonstrating that tuberculosis is still a serious public health problem among Chinese people [6].
The epidemiology of tuberculosis is influenced by factors such as geographic location, lifestyle, socioeconomic development, and the availability of good medical services. Guangxi Province, located in southern China, has a population of over 50.12 million, with a rural population of 33.22 million according to 2021 population data. Guangxi Province is among the provinces with the highest tuberculosis burden in China, with a 2019 annual incidence of 81.12/ 100,000 compared to the national incidence of 44.45/ 100,000. This therefore necessitates more studies into the prevention and treatment measures of tuberculosis-related diseases in the province. There are currently few epidemiological investigations into spinal tuberculosis in Guangxi; thus, this study investigates this common extrapulmonary disease in order to better understand the incidence, as well as provide references for prevention and treatment in the province and beyond. This study collected and analyzed inpatient data such as clinical symptoms, diagnosis, treatment, and prognosis of 556 confirmed spinal TB cases from 2 tertiary teaching hospitals in Nanning City, in order to investigate the stated goals.

Materials and Methods
2.1. Patient Data. We retrospectively analyzed the medical records of STB patients admitted to 2 tertiary teaching hospitals from January 2011 to December 2019 using the medical record retrieval code . The collected data included  clinical features such as pain, radiculopathy, systemic  symptoms, neurological manifestations, imaging features,  pathologic vertebrae, treatment options, and posttreatment  complications. Other clinical data such as comorbidities, as well as prognostic indicators, were also analyzed. Personal information such as gender, age, residence (rural or urban), and occupation was also analyzed. The Frankel grading system was used to assess the grades of the neurological manifestations in the reviewed patients; grade A: complete neurological deficit; grade B: sparing of sensation; grade C: sparing of sensation but no useful motor function; grade D: sparing of sensation and useful motor function; and grade E: no deficits. Since pulmonary tuberculosis (PTB) and diabetes are common comorbidities of STB, we analyzed the correlation between PTB, diabetes, and STB. Guangxi Province also has a high incidence of hepatitis B and hypertension; hence, their correlations were also analyzed.

Diagnosis and Treatment.
The diagnostic criteria for STB are as follows: (1) clinical signs and symptoms, such as back pain, spinal deformity, neurological deficits (numbness, weakness, hypoesthesia, dyskinesia, and paralysis), and systemic toxemic symptoms (low-grade fever, night sweats), and weight loss; (2) CT and MRI findings: vertebral destruction, intervertebral space involvement, kyphosis, paravertebral abscess, etc.; (3) laboratory findings: anemia, elevated erythrocyte sedimentation rate (ESR) and Creactive protein (CRP), positive T-SPOT, tuberculosis antibodies (IgG and IgM), and positive tuberculin skin test; (4) diagnostic antituberculosis chemotherapy which was effective in difficult to diagnose cases; and (5) pathological evidence from tissue samples which is the gold standard for diagnosis.
All patients received the combination of the 4 antituberculosis chemotherapeutic agents HREZ (rifampicin (450 mg/ day), isoniazid (300 mg/day), ethambutol (750 mg/day), and pyrazinamide (750 mg/day)) for at least 18 months. All patients underwent rigorous monitoring of renal and liver functions during treatment. All patients and their immediate families were also educated and trained to understand the importance of early, regular, and full completion of the combined medication, and family members were urged to help patients adhere to their medications. Patients were also advised to rest and avoid strenuous activities. None of the patients included in the study were HIV positive.
Patients were evaluated by telephone follow-up and outpatient visitation to gather information on posttreatment prognosis. Patients were classified as "cured" if there is no recurrent TB lesion within 2 years after treatment, the ESR level remained within the normal range, bone healing is observed on follow-up imaging examinations, and the clinical symptoms have disappeared for at least 3 months [7]. Relapses were presented as postoperative recurrence of TB lesions, sinus formation, progressive kyphosis, abscess formation, or internal fixation fractures. Patients were classified as "other" because of incomplete follow-up data, loss of contact, failure to heal, transferred treatment, or death [8].

Statistical Analysis.
Demographic and clinical characteristics were collected and included gender, age, place of residence, degree of education, neurological deficit, pain, radiculopathy, systemic symptoms, neurological manifestations, imaging features, pathologic vertebrae, treatment options, posttreatment complications, Hb, and ESR. All statistical analyses were performed using SPSS statistical software version 26.0 (IBM, Chicago, USA). The chisquared (χ 2 ) test was used to analyze the collected data, with p < 0:05 considered statistically significant.

General Information.
A total of 556 eligible cases of confirmed STB were reviewed in this study (Table 1). Among them, there were 361 (64.93%) patients between the ages of 18 and 45 years and 98 (17.63%) patients between 46 and 60 years. There was a statistically significant difference between the age distribution of patients (p = 0:003) during the reviewed period. During this 9-year period, the incidence of STB was relatively stable (30-112 new cases per year), and the gender proportions, male (50.17%) and females (49.83%), remained virtually unchanged, without any statistically significant differences (p > 0:05). Among the cases reviewed, rural residents accounted for 63.49%, while urban residents accounted for 36.51%, but the difference was not statistically significant (p > 0:05). In terms of occupational distribution, there were 338 farmers (60.79%), 89 bluecollar workers (16.01%), 26 students (4.68%), and 103 (18.53%) in other forms of occupation. The result of our correlation analysis between occupation and years was statistically significant (p = 0:036). The average interval between onset of symptoms and hospitalization was 18.0 months (range: 1 day-220 months). The average intervals for rural patients were significantly longer (25.5 months) compared to urban patients (9.1 months) (p < 0:05). There is regional and local distribution of patients in the major cities of Guangxi Province. During the period studied, Nanning City had the highest incidence of STB (17.09%), followed by Guigang 15.83%, Chongzuo 12.95%, Wuzhou 9.17%, Yulin 6.47%, Laibin 6.29%, Baise 6.29%, Guilin 5.94%, etc. Figures 1(a) and 1(b). Table 2. Lower back pain was reported in 78.60% of patients, followed by radicular pain (51.98%) and systemic toxemic symptoms (43.53%). The results of our correlation analysis revealed no correlation between lower back pain, systemic poisoning, and annual incidence (years) during the period of the study (p > 0:05). However, there was a statistically significant correlation between radicular pain and annual TB incidence (p < 0:05).

Treatment and Prognosis.
The treatment options administered are summarized in Table 4. In 504 (90.65%) of patients, preoperative antituberculosis chemotherapy was used prior to surgical treatment and achieved good efficacy (Figure 2), while 52 (9.35%) patients were treated with only antituberculosis chemotherapy. During the 9-year period, patients who underwent chemotherapy and surgery were greater than those treated with only chemotherapy; however, there was no statistically significant difference between them (p > 0:05). The primary surgical methods were anterior debridement, bone grafting, and internal fixation; anteriorlateral debridement, bone grafting, and internal fixation; and posterior debridement, bone grafting, and internal fixation.  BioMed Research International The summary of patients' prognoses is shown in Table 4. A total of 486 patients (78.41%) were classified as "cured" after receiving treatment. Local recurrence was observed in 21 patients (3.78%). Such patients received continued antituberculosis chemotherapy and underwent revision surgery. 49 (8.81%) patients were classified as "other" because of incomplete follow-up data, loss of contact, failure to heal, or transferred treatment. No patient died during the entire follow-up period.  (Figures 3(a)-3(d)).

Discussion
Tuberculosis continues to threaten public health, especially in developing countries. Spinal tuberculosis (Pott disease) was first described in 1782 by Percival Pott [9]. In developing countries, spinal tuberculosis mostly occurs among young and middle-aged people, while in the developed world, the elderly are the most affected [10,11]. An epidemiological survey of spinal tuberculosis in the United States between 2002 and 2011 revealed an average age of 51 years (35-65 years), with 24.5% of cases over the age of 65 years [12]. In this study, 64.93% of the patients were between the ages of 18 and 45 years, while 17.63% were between 46 and 60 years old. This is possible because patients in the age group of 18-60 years perform physical labor for a long time, which increases the load on the spine, which leads to chronic spinal injury, which can easily lead to infection of Mycobacterium tuberculosis. In this study, patients younger than 18 years accounted for only 7.01%, which may be explained by the fact that the protective effect of BCG vaccination con-tinues into the adolescence stage [13]. According to a 2020 report by the World Health Organization [2], the male to female ratio of newly diagnosed tuberculosis in China was 2.19 : 1. However, in this study, the male to female ratio was 1 : 1, with no statistically significant change in the 9year period of the study. In Guizhou, which is also an underdeveloped southwestern region of China, the ratio of male to female in STB is 1.1 : 1 [14]. This similarity in the sex ratio may be due to the similarities in the economic, medical, and educational levels of the two regions. In our study, the number of STB patients after 2016 has an increasing trend than before, but it is not statistically significant. This may be because in recent years, the country has strengthened poverty alleviation and the country has increased its medical insurance investment. The awareness of hospital visits has increased, so the number of visits has increased.
It is reported that 80% of STB patients worldwide are in poor and developing countries. Studies have also reported that 80% of STB patients in China are from rural areas [15]; however, in this study, the ratio was slightly lower at  The average interval between the onset of symptoms and hospitalization of rural patients was 25.5 months; on the contrary, that for the patient from urban areas was 9.1 months. This may be related to the low level of health awareness, education, and the overall level of socioeconomic development in Guangxi Province. According to the urban distribution of STB, Nanning City, Guigang City, and Chongzuo City have more STB patients than other major cities in China. These differences can be attributed to the lower standard of medical care and socioeconomic development in these cities. Unlike pulmonary tuberculosis, the most common manifestation of spinal tuberculosis is lower back pain [16]. Other major symptoms include systemic toxemic symptoms such as low-grade fever, night sweats, and weight loss. In this study, 78.60% of patients reported lower back pain, while 43.53% reported systemic toxemic symptoms. The main reason why STB patients seek medical evaluation and treatment is lower back pain. In this study, vertebral tenderness was reported in 68.17%, while vertebral percussion pain was reported in 66.01% of patients during physical examination. Kyphosis was also observed in 27.52% during the physical. The contiguous bone necrosis associated with tuberculosis coupled with psoas, paravertebral, or prevertebral abscess formation may result in neurological manifestations such as back pain and radiating pain. Studies have reported that delayed treatment of STB could result in neurological damage and even paralysis [17]. In this study, 51.98% of patients reported neuropathic pain. Varying degrees of neurological impairment were observed in 53.96% of cases. Severe neurological impairments were observed in 7.2% of cases (2.70% Frankel grade A; 4.50% grade B). Following surgical treatment, varying degrees of neurological function recovery were observed in such patients, confirming the poorer recovery rate among patients with severe neurological impairment on admission.
According to the available literature, the most common site for spinal tuberculosis is the lumbar and thoracic spine [18]. In this study, lumbar tuberculous lesions accounted for 43.53%, while thoracic and thoracolumbar lesions accounted for 32.55% and 6.65%, respectively. This localization may be related to the anatomical factors of the high level of mobility and load forces in the lumbar region in the thoracic region. STB lesions usually involve two or more vertebrae. This is because the segmental arteries bifurcate to supply two adjacent vertebrae, making the hematogenous spread to adjacent vertebrae easy. MTB involvement of the anterior or posterior longitudinal ligament may also enable multiple adjacent vertebrae involvement [8]. In this study, 72.66% of cases involved 2 adjacent vertebrae, while 16.73% involved 3 or more vertebrae, while paravertebral abscesses were found in 62.77% of patients.
The hemoglobin level has been used as an indirect indicator of health and nutritional status, and studies have reported that tuberculosis causes weight loss and malnutrition [19]. Thus, in this study, we analyzed the hemoglobin levels to determine the nutritional status of patients. In this study, anemia was observed in 54.91% of patients, thus con-firming the high incidence of malnutrition in tuberculosis patients. Thus, our results also revealed that more attention should be paid to nutritional supplementation before, during, and after antituberculosis chemotherapy or surgical treatment for TB-related diseases. ESR and CRP, which are used as indirect indicators of inflammation and inflammatory reactions, have high sensitivity but low specificity. However, they can still be used to monitor disease activity during follow-up. The average ESR is 43.5 mm/h [20]; however, in this study, ESR ranged between 2 and 152 mm/h. The average CRP in STB patients has been reported to range between 6 and 197 mg/L [21]. However, in this study, it ranged between 0.11 and 204.31 mg/L. Thus, it confirms that inflammatory reactions are common in tuberculosis patients and that ESR and CRP can be used as indirect indicators of postoperative prognosis.
Antituberculosis drugs are currently the basis for spinal tuberculosis treatment. Surgical treatment on the other hand plays an important adjuvant role. This is because surgical risks such as loss of life, infection, metastasis, and postoperative recurrence are significantly increased in the absence of preoperative chemotherapy [22]. The American Thoracic Society recommends 6-9 months of chemotherapy for STB, and many studies have demonstrated the effectiveness of such a program [23]. Surgical indications for STB include spinal cord and nerve root compression or injury, severe kyphotic deformity or progressive kyphosis, spinal column instability, and abscesses. Surgical decompression is recommended as soon as possible following effective chemotherapy; this not only promotes recovery of nerve function and spinal column stability but also provides specimens for confirmatory pathological examination of surgical samples to help guide chemotherapy. In this study, 90.65% of patients received preoperative antituberculosis, with a cure rate of 78.41%. The recurrence rate was 3.78% (21 patients). Reasons for relapse may include unstable antituberculosis drug treatment, malnutrition, comorbidities, and lack of rest. Relapsed patients were cured by revision surgery, including debridement, drainage, and local catheter infusion of antituberculosis drugs.
Studies have reported that between 33% and 50% of STB patients have a history of pulmonary tuberculosis [24,25]. In this study, 40.65% of the STB patients reviewed had PTB history, the majority of them being males, who were also at risk of developing paravertebral abscess lesions and nerve damage. This could be attributed to the high incidence of smoking and drinking among Chinese men. Furthermore, the majority of patients reviewed in this study were farmers or had blue-collar jobs, where manual labor is the norm.
The immunosuppression observed in diabetes patients has been reported to result in increased susceptibility to infections and poor tissue repair abilities [26]. Active tuberculosis is an infection that can aggravate diabetes and may even induce acute ketoacidosis. Diabetes and tuberculosis patients usually have the characteristics of the long course, severe illness, rapid progress, slow recovery, etc., which are difficult to treat [27,28]. In addition, patients with diabetes and STB have impaired anti-infection and tissue repair capabilities, which affect the prognosis and sometimes lead to surgical failure. In this study, the majority of STB patients over 45 years with diabetes were treated conservatively unless necessary.
This study has several limitations. Firstly, it is a retrospective study of 556 inpatients in 2 tertiary hospitals. Thus, the sample size is relatively small. Secondly, this study did not include outpatients, which may lead to a high proportion of surgically treated patients and no HIV/ARDS cases. Finally, this study did not obtain the results of antituberculosis drug resistance.

Conclusion
Spinal tuberculosis is still a serious problem that endangers public health. Lower back pain is the most common clinical manifestation of STB, and the lumbar vertebrae are the most commonly affected. More attention should be paid to rural residents, farmers, blue-collar workers, elderly, and diabetic patients who should be the main focus of spinal tuberculosis preventive measures, especially in underdeveloped areas. Our results provided valuable information on the epidemiological characteristics of spinal tuberculosis in Guangxi Province, China, thus helping to raise local, regional, and national attention to it.

Data Availability
The data used to support the findings of this study are included within the article.

Conflicts of Interest
The authors have no conflicts of interest to declare.