Association between body mass index and newly diagnosed drug-resistant pulmonary tuberculosis in Shandong, China from 2004 to 2019

Tuberculosis (TB), is caused by Mycobacterium tuberculosis (MTB), contributes to a largest number of deaths from infectious diseases (more than HIV/AIDS) [1, 2]. According to WHO Tuberculosis Report, approximately 10.0 million population suffered from TB globally in 2018, and the prevalence was 132 cases per 100,000 people [1]. Additionally, nearly 1.2 million HIV-negative and 251, 000 HIV-positive patients died from TB in 2018 [1]. Nine percent of the overall TB burden worldwide were from China, only second to India (27%) [1].

Multidrug-resistant tuberculosis (MDR-TB) is defined as TB with resistance to at least isoniazid (INH) and rifampin (RFP), which is usually associated with longer hospitalization, more expensive treatment, and higher mortality [3]. The bacteriological cause is the transmission of MDR-TB strains in new cases or the acquired resistance through de novo mutation during TB treatment [2, 3]. The emergence and spread of rifampin-resistant (RR-TB) or MDR-TB has brought grim challenge to TB control, and threatens the health of human being. The estimated proportions of RR-TB/MDR-TB among previously treated and newly diagnosed cases were 18% (95% confidence interval [CI] 7.6–31%) and 3.4% (95% CI 2.5–4.4%) respectively [1]. Despite recent advances in early diagnosis of MDR-TB such as GeneXpert MTB/RIF, laboratories in many low-income countries are still unable to carry out routine bacterial culture and drug susceptibility testing (DST), thus clinical predictors of DR-TB especially MDR-TB may contribute to the early discovery and timely treatment of suspected cases [4, 5]. The identification of clinical risk factors for the development of drug-resistant tuberculosis (DR-TB) will also benefit the management of TB patients and facilitate tuberculosis control programs [1, 5].

The critical influences of diverse nutritional status on TB infection have been recognized for decades [6]. Recent years, there were more and more researches focused on body mass index (BMI, usually used as one of the indicators to judge nutritional status) and TB, for example, the impact of BMI on TB incidence, TB treatment outcomes, TB-related mortality, or negative conversion rate of new sputum among MDR-TB patients [7‐9]. Lower BMI is a recognized risk factor for active tuberculosis infection [10]. The main causes of malnutrition were poverty and food shortages [7, 8]. Malnutrition could damage the immunity of human body by decreasing the concentration of T-cell subset (including T-cytotoxic-suppressor cell, T helper cells, and natural killer cells), immunoglobulins, and interleukin-2 receptor, making them more vulnerable to infections such as TB and HIV [11]. Although, former researches revealed that the increased incidence of different infections such as hospital-acquired or postoperative infections might be attributable to obesity [12], available evidence on obesity and risk of active tuberculosis infection indicated an inverse relationship [6]. Interestingly, a study in rural China found that BMI more than 28.0 kg/m² was independent risk factor of latent tuberculosis infection (LTBI, adjusted odds ratio (aOR) 1.17, 95% CI 1.04–1.33) [13]. In summary, BMI have an influence on the infection of MTB strains, and it may also affect the infection of resistant strains. However, no previous publications seem to have examined the impact of different BMI levels on primary drug resistance among TB cases [7‐9].

This research intended to explore the association between BMI and primary DR-TB in the aspects as follows: (1) to describe the clinical characteristics of TB cases with four different BMI status (underweight/normal weight/overweight/obese); (2) to illustrate the drug resistant profiles of TB cases subgroups stratified by BMI; (3) to analyze the relative risk of DR-TB including DR-TB (total), MDR-TB (total), mono-resistant tuberculosis (MR-TB, total), polydrug resistant tuberculosis (PDR-TB, total), RFP-related resistance, INH-related resistance, streptomycin (SM)-related resistance, MR-TB (INH), INH + RFP + SM resistance (MDR3), INH + SM resistance (PDR2), Any INH + SM resistance among subgroups with different BMI; (4) to investigate the risk factors of DR-TB among TB cases subgroups stratified by BMI.

Identifying novel risk factors or predictors for DR-TB will facilitate the implementation of TB termination strategies, but so far little studies have explored the relationship between different TB drug-resistance and BMI status. Our study was designed to compare clinical features and drug-resistant profiles of primary pulmonary TB cases with different BMI, thus to provide reference in clinics. We now report DST results and BMI status of 8957 newly diagnosed pulmonary TB patients, and found that abnormal BMI was related to the elevated risk of some drug-resistant sub-types. Meanwhile, BMI were positively associated with the incidence of accompanying diseases among TB cases. Male was a risk factor of DR-TB in underweight, overweight, or normal TB patients.

Obesity has become a global public health problem, and it’s reported that approximately 46% of adults and 15% of children China are overweight or obese [23]. Plenty of evidence have revealed that BMI is negatively associated with active tuberculosis [6, 24]. For instance, a study among 46 028 adult participants in Taiwan found that obesity (BMI ≥ 27 kg/m²) (aOR 0.43; 95% CI 0.28–0.67) and overweight (BMI = 24–26.9 kg/m²) (aOR 0.67; 95% CI 0.49–0.91) contributed to a lower risk of TB infection [24]. A study in rural China found that BMI ≥ 28.0 kg/m² was observed to be independently associated with LTBI (aOR: 1.17, 95% CI 1.04–1.33) [13]. Interestingly, our study indicated that overweight was a risk factor for MDR-TB, INH + RFP + SM resistance, Any INH + SM resistance. The explanation may be that MTB had a lower virulence due to high-fat exposure and immunoregulation of leptin, and the reproduction speed of MTB with lipid bodies were slower than those without such lipid bodies [25, 26]. Furthermore, MTB can survive without reproducing in fatty tissues, and may go some way towards explaining why higher BMI contributed to LTBI. As we know, primary drug-resistant TB was caused by the transmission of resistant MTB strains, and this resistance may come at a “fitness cost” through a decreased transmission rate, virulence and reproduction speed [27]. Therefore, we supposed that obesity may have a greater impact on reducing the transmission of susceptible MTB strain than some resistant strains, because the transmission of the resistant strains were already at a lower level due to the “fitness cost”, which may explain why there was a higher risk of falling ill with MDR-TB, INH + RFP + SM resistant TB, or Any INH + SM resistant TB among overweight population. Some overweight and obese patients can also be malnourished, since BMI is only one of prognostic factors for assessing malnutrition. Fat accumulation in overweight and obese individuals may induce additional nutritional derangements, both indirectly through acute and chronic diseases with negative impact on nutritional status and directly through metabolic and body composition changes [28]. Furthermore, skeletal muscle mass and function (sarcopenia) may also contribute to malnutrition. Malnutrition in obesity may be an important factor for some increased resistance among newly-diagnosed tuberculosis patient. The indicators for nutritional status include anthropometric index and laboratory parameters [29, 30]. The former mainly includes height, weight, body mass index and alternative indices, trunk measurements (waist and hip circumferences and sagittal abdominal diameter) and limb measurements (mid-upper arm and calf circumferences) and skinfold thickness [29], and the latter mainly includes albumin, prealbumin, urinary creatinine or 3-methylhistidine [30]. However, this retrospective study were not available for other nutritional indexes except BMI. Therefore, it may be a good idea to detect more indicators for nutritional status as above among TB cases to find those with both burden of obesity and malnutrition in future, and then explore their drug-resistant profiles.

Overweight TB cases had a higher possibility of suffering from co-morbidity including COPD, hypertension, diabetes, and cancer. Actually, previous studies have figured out that BMI was a reliable predictor of prevalent diabetes, hypertension, and COPD [31‐33]. A study in in South Asian cities among 31,118 participants found that every standard deviation higher of BMI was associated with 1.42 and 1.28 times higher probability of hypertension and 1.65 and 1.60 times higher probability of diabetes among 40–69 years men and women respectively [31]. A dose–response relationship between COPD and BMI has been observed among both males and females, for example the prevalence of COPD increased from 2.5 to 7.6% in men and from 3.5 to 13.4% in women when their BMI changed from normal to obese (BMI ≥ 40) [33]. Recent years, former studies have found that COPD (aOR 1.86, 95% CI 1.01–2.93, P = 0.041) and diabetes (aOR 1.59, 95% CI 1.04–2.44, P = 0.03) could increase the risk of MDR-TB and PDR-TB, respectively [34‐36]. Thus, it can be seen that screening for drug resistance among overweight TB cases, especially those combined with COPD or diabetes, may help monitor the development and guide the clinical diagnosis and treatment of DR-TB.

People have found a significant association between underweight and higher risk of active TB, adverse TB treatment outcomes, tuberculosis-related mortality [7, 37‐39]. According to a study among the US population in 1971–1975, estimated TB incidence among adults who were underweight, normal, overweight, and obese was 260.2 (95% CI 98.6, 421.8), 24.7 (95% CI 13.0–36.3), 8.9 (95% CI 2.2–15.6), and 5.1 (95% CI 0.0–10.5) per 100,000 person-years, respectively [38]. Interestingly, we found underweight was associated with lower risk of SM-related resistance and co-morbidity, but contributed to a higher risk of MR-TB (INH). Studies have also shown that underweight is associated with abnormal cell-mediated immunity, phagocytic function, complement system, immunoglobulin A secretion, and cytokine production such as reduced secretion of Th1 cytokines (IL-2, TNF-α and interferon-γ), which may lead to more severe TB infection [40]. Moreover, malnourished animals have higher bacterial burdens and impaired immune system (e.g. reduction of reactive N intermediates) [37, 41], Underweight population may influence the infection INH-resistant or SM-resistant MTB strains through immune system, but the molecular mechanism remains to be further explored. Our findings would provide guidance for clinicians when treating underweight TB cases, for instance, they should maintain keen vigilance at INH resistance rather than SM resistance.

It has been observed that males were more likely to be affected with DR-TB among normal, underweight, or overweight population. However, there were inconsistent results in the previous literature about the influence of gender differences on vulnerability to MDR-TB [42‐44]. A study conducted in Lianyungang city, China found females were more likely to be infected with MDR-TB (aOR 1.763, 95% CI 1.060–2.934) [42], while Faustini stated that MDR-TB patients tended to be male (OR 1.38; 95% CI 1.16–1.65) in western Europe [43]. We assume that the heterogeneity on the susceptibility of DR-TB among males and females may be related to the their differences in airway structure and lifestyles such as smoking, drinking, stay up late.

This study had some strengths. Firstly, it’s the first study to investigate the effect of BMI on drug resistance among newly diagnosed pulmonary TB cases. Secondly, the relative risk of numerous drug-resistant sub-types including DR-TB (total), MDR-TB (total), MR-TB (total), PDR-TB (total), RFP-related resistance, INH-related resistance, SM-related resistance, IMR-TB (INH), INH + RFP + SM resistance (MDR3), INH + SM resistance (PDR2), Any INH + SM resistance among underweight, overweight, obese were analyzed, and could provide clinical reference for future pathologic and molecular studies on different resistant MTB strains. Thirdly, the large amount (DST results from a province of 100 million people) and long time span (from 2004 to 2019) of our data guaranteed the reliance of our findings.

This study also had some limitations. Firstly, drug resistance of second-line anti-TB drugs were not routinely examined in China unless at the initiative requirements of patients. Thus, the association between BMI and second-line anti-TB resistance remains to be discovered in future. Secondly, this was a retrospective study, and may have information bias. Thirdly, some obese patients can also be malnourished, since BMI is only one of prognostic factors for assessing malnutrition [28, 29, 45]. However, we were not available for other nutritional indexes except BMI due to its retrospective study model. This might be an important confounding factor in the obese group.

Our study has important implications on the global triple epidemics of underweight, obesity, and DR-TB. The positive effect of overweight on MDR-TB, INH + RFP + SM resistance, Any INH + SM resistance, and co-morbidity implies that routine screening for drug sensitivity and more attention on co-morbidity among overweight TB cases may be necessary. Although patients with normal weight had a lower proportion of drug-resistance than overweight or obese patients in Shandong, screening for drug resistance cannot be ignored either because patients with normal weight accounted for 74.64%. In addition, we found underweight TB cases have a higher risk of INH resistance, which provides a reference for clinical rational use of drugs. Our study suggests that an in-depth study of the interaction between host metabolic activity and infection of DR-TB may contribute more to novel treatment options or preventive measures, and accelerate the implementation of the STOP TB strategy.