Risk factors for physical disability in patients with leprosy disease in Yunnan, China: Evidence from a retrospective observational study

Background Leprosy is potentially debilitating. The risk factors related to physical disabilities associated with leprosy disease in Yunnan, China was not clear. Methodology/Principal findings We studied 10644 newly detected leprosy patients from Yunnan, China, from 1990 to 2019. Factors associated with Grade 1 (G1D) and Grade 2 (G2D) physical disabilities or overall physical disabilities (combined G1D and G2D) associated with leprosy were analyzed using multinomial and ordinal logistic regression analyses. The following factors were associated with the development of physical disability in these patients with leprosy: delayed diagnosis [odds ratio (OR): 5.652, 4.399, and 2.275; 95% confidence intervals (CIs): 4.516–7.073, 3.714–5.212, and 2.063–2.509; for ≥ 10, 5–10 y, and 2–5 years, respectively], nerve damage (OR: 3.474 and 2.428; 95% CI: 2.843–4.244, and 1.959–3.008; for 2 and 1 damaged nerves, respectively), WHO classification of PB (OR: 1.759; 95% CI: 1.341–2.307), Ridley-Jopling classification (OR: 1.479, 1.438, 1.522 and 1.239; 95% CI: 1.052–2.079, 1.075–1.923, 1.261–1.838, and 1.072–1.431; for TT, BT, BB, and BL when compared with LL, respectively), advanced age (OR: 1.472 and 2.053; 95% CI: 1.106–1.960 and 1.498–2.814; for 15–59 and over 60 years old, respectively), zero skin lesions (OR: 1.916; 95% CI: 1.522–2.413), leprosy reaction (OR: 1.528; 95% CI: 1.195–1.952), rural occupation (OR: 1.364; 95% CI: 1.128–1.650), Han ethnicity (OR: 1.268; 95% CI: 1.159–1.386), and male sex (OR: 1.128; 95% CI: 1.024–1.243). Conclusions Delayed diagnosis, nerve damage, no skin lesions, WHO and Ridley-Jopling classifications, leprosy reactions, advanced age, rural occupation, Han ethnicity, and male sex were associated with disability in leprosy patients. Identifying risk factors could help to prevent physical disability.


Introduction
Leprosy, caused by Mycobacterium leprae (M. leprae), is a potentially disabling infectious disease. When M. leprae settles into skin tissues and human peripheral nerves, the development of an immunologic response is induced. The action of the bacillus in the body and the inflammatory process lead to neuritis, which compromises autonomous, sensory and/or motor neural function. When neuritis impacts individuals who do not receive proper treatment, the process may become chronic, thus leading to the characteristic physical disabilities of the disease [1].
In 2019, 10813 leprosy cases with Grade 2 disabilities at diagnosis (G2D) were reported globally, and the proportion of G2D cases was 5.3% among new cases, corresponding to 1.2 per million population [2]. However, disability is unevenly distributed, with a relatively high rate of G2D continuously reported in recent years in India [3], Brazil [4,5], and China [6]. In India, 5245 leprosy cases with G2D were identified in 2016, corresponding to 2.9 per million population [3]. In Brazil, the proportion of new leprosy cases with G2D was 7.9%, and the rate was 8.42 per 1 million population in 2016 [4]. From 2012 to 2016, the mean rate of leprosy new case detection with G2D in Brazil was 10.5 per 1 million inhabitants [5]. In China, a relatively high level of G2D has been continuously reported in recent years. The percentage of G2D in newly detected cases was 19.0% in 2018, similar to the data in 2017 [6]. In the absence of verifiable data, it is estimated that 3-4 million people are living with visible impairments or deformities due to leprosy [7].
Due to the large number of people with disability/deformity due to leprosy, the World Health Organization (WHO) launched a 5-year global leprosy strategy in 2016 to reduce the disease burden and the prevalence of deformities [8]. Disabilities/deformities can lead to problems such as decreased ability to work, limited social life, and psychological problems, and they are responsible for stigma and prejudice against individuals with the disease [9,10]. Therefore, monitoring the prevalence and evaluating the risk factors for disabilities associated with leprosy are needed.
Yunnan Province is located in southwestern China and has the highest burden of leprosy in China. In the past 30 years (from 1990-2019), 11052 newly diagnosed leprosy patients were registered in the Leprosy Management Information System (LEPMIS), and the percentage of those with a disability at diagnosis ranged from 10.34% to 32.02% for G2D [11]. These numbers call attention to the need to perform studies evaluating epidemiological and clinical prevalence associated with physical impairment. This study aims to assess the characteristics and risk factors associated with physical disability and deformity in leprosy patients based on newly diagnosed leprosy patients in Yunnan, China.

Ethics statement
The study design and data analysis were approved by the Ethics Committee of the Yunnan CDC, Yunnan, China. Individual identifying information was not available and therefore not used.

Data sources
The data for this retrospective observational study were collected from the LEPMIS in China. We systematically screened the case data of patients with leprosy from local hospitals and the Center of Disease Control and Prevention of Yunnan Province (CDC) in Yunnan, China. The inclusion criterion was newly detected leprosy cases from 1990-2019 in Yunnan, China. The diagnosis of leprosy by clinicians met the diagnostic criteria issued by the Ministry of Health of the People's Republic of China [12]. The exclusion criteria were relapsed, imported, or revisited leprosy cases and no information or unclear information on the disability status of the leprosy patients. The newly detected leprosy patients were diagnosed with no disability (G0D), Grade 1 disability (G1D) or Grade 2 disability (G2D) and formed the sample for this study.

Classification of disabilities and nerve involvement
All the patients included in this study with a confirmed diagnosis of leprosy disease were evaluated for physical impairment and nerve involvement based on the objective scale of physical impairment as defined by the WHO [13]. The classification related to physical impairment was as follows: Grade 0: no impairment, Grade 1: loss of sensation, and Grade 2: visible impairment.

Variables
The demographics and clinical data were collected for this study. The patients' basic demographic information included sex, date of birth, ethnicity, and occupation. The clinical characteristics included the age of diagnosis, date of symptom onset, date of diagnosis, detection mode, skin lesion, nerve damage, contact history, leprosy reaction, classification of disability (G0D, G1D, and G2D), Ridley-Jopling (clinical) classification, and WHO operational classification. Diagnosis duration was defined as the time duration between the onset of symptoms and the confirmed diagnosis.

Statistical analysis
The Kolmogorov-Smirnov test was used to test the distribution of the patient characteristics. The results of descriptive analyses are presented as the mean ± standard deviation (SD), min to max, and medians and interquartile ranges (IQRs) for continuous variables and as counts and percentages in each category for categorical variables. Chi-square tests were used to examine differences in proportions of categorical variables between different groups. To explore the risk factors associated with G1D and G2D separately and the overall risk of physical disability (combined G1D and G2D), multinomial and ordinal logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). All analyses were performed using SPSS, version 16.0 (SPSS Inc). P values �0.05 were considered significant.  were tuberculoid (TT), 9.82% were borderline-borderline (BB), and 1.53% were indeterminate (I) forms of leprosy ( Table 1). The median diagnosis durations were 13, 16, and 29 months for leprosy patients with G0D, G1D, and G2D, respectively.

Risk factors for leprosy disease with G2D
Advanced age, rural occupation, Han ethnicity, male sex, delayed diagnosis, nerve damage, zero skin lesions, WHO and Ridley-Jopling classifications, and leprosy reactions were also associated with a higher risk of G2D analyzed by multinomial logistic regression ( Table 2) Regarding diagnosis duration, 2-5 years (OR: 2.848; 95% CI: 2.531-3.206; P = 0.000), 5-10 years (OR: 5.752; 95% CI: 4.725-7.002; P = 0.000), and over 10 years (OR: 7.469; 95% CI: 5.790-9.637; P = 0.000) increased the risk of G2D compared with less than 2 years. Regarding nerve damage, damage to one (OR: 2.320; 95% CI: 1.775-3.031; P = 0.000) or 2 (OR: 3.686; 95% CI: 2.869-4.736; P = 0.000) nerves increased the risk of G2D compared with no nerve damage. Having zero skin lesions increased the risk of G2D compared with having more than 5 skin lesions (OR: 2.037; 95% CI: 1.552-2.675; P = 0.000). Regarding the WHO classification, the PB form (OR: 1.925; 95% CI: 1.389-2.667; P = 0.000) increased the risk of G2D compared with the MB form ( Table 2) Table 2). The I form (OR: 0.348; 95% CI: 0.159-0.761; P = 0.008) decreased the risk of G2D compared with the LL form (Table 2). Regarding leprosy reactions, patients with leprosy reactions had an increased risk of G1D compared with patients without leprosy reactions, but there was no impact on G2D (P = 0.563) ( Table 2). Similar to findings with G1D, no association of detection mode or contact history and risk of G2D was found ( Table 2). Table 2 also summarizes the results of risk factors associated with physical disabilities (combined G1D and G2D) by ordinal logistic regression. Advanced age, rural occupation, Han ethnicity, male sex, delayed diagnosis, nerve damage, zero skin lesions, WHO and Ridley-Jopling classifications, and leprosy reactions were associated with a higher risk of physical disability associated with leprosy disease.

Discussion
We report 3402 leprosy patients with G1D and G2D and confirmed physical disabilities due to leprosy disease during 1990-2019 in Yunnan, China. G1D and G2D accounted for 10.95% and 21.02% of the total sample of patients, respectively. Advanced age, rural occupation, Han ethnicity, male sex, delayed diagnosis, nerve damage, WHO and Ridley-Jopling classifications, zero skin lesions, and leprosy reactions were associated with a high risk of developing physical disability associated with leprosy disease.
Advanced age at diagnosis has been previously reported as a risk predictor for developing a physical disability associated with leprosy disease [14]. Age is known to be related to disease duration and diagnosis delay [15,16]. This study quantified the association of advanced age and physical disability since the study was conducted in Brazil [14]. Male patients were not associated with the risk of G1D but were 1.205-and 1.128-times more likely than female patients to have G2D and overall physical disabilities, respectively. Similar results were observed in studies conducted in China [17], Burkina Faso [18], Turkey [19], Zimbabwe [20], Bangladesh [21], India [22], Brazil [1,[23][24][25][26][27][28], Indonesia [9], and Nigeria [29]. Male patients were more likely to have physical disabilities than female patients [30], which may be due to social behaviors [31]. Our study also indicated that a rural occupation was associated with a risk of physical disability. which may be due to socioeconomic status, such as undernutrition, and be associated with a reduced expenditure on food, possibly brought on by increased unemployment and a loss of income [32,33].
In another study, an active detection mode was demonstrated to be associated with a higher risk of physical disability than a passive detection mode [14]. This finding was reported in the Brazilian population, and the diagnosis of leprosy using community surveys (e.g., schools, nurseries, small villages) increased the detection of G2D. This may reflect the better training of the examiners, with a defined focus on verifying leprosy complications [14]. Active and passive detection modes should not be compared competitively but rather need to be interpreted as mutually enhancing for the effective early detection of leprosy, which in turn can reduce G2D [34]. However, in this study, statistically significant differences were not found between the active and passive detection modes with regard to the presence of disabilities.
Early identification combined with the proper treatment of leprosy reactions can be an effective strategy to prevent disability in leprosy patients [23]. In contrast, a longer diagnosis duration was 2-5 times more likely to develop physical disabilities than a diagnosis within 2 years in this study. In our analysis, the variable of longer diagnosis duration presented the highest odds for developing physical disability. Similar trends were also found with G2D and G1D.
Nerve damage and leprosy reactions have been reported as risk factors for developing physical disability in previous studies [35][36][37][38]. The multinomial and ordinal logistic regression analysis findings support previous studies showing that the number of affected nerves upon diagnosis was associated with G1D, G2D, and combined physical disabilities (G1D and G2D). The presence of a leprosy reaction was associated with G1D and combined physical disabilities.
Regarding the WHO and Ridley-Jopling classifications, the PB and Ridley-Jopling classifications tended toward the TT form being associated with G2D and combined physical disabilities. The results showed that zero skin lesions was associated with a greater risk to develop G1D, G2D, and combined physical disabilities in Yunnan, China, which was different from findings in other studies [30]. Most studies have demonstrated that male sex, multibacillary leprosy, leprosy reactions, and lepromatous presentation were associated with the presence of physical disabilities associated with leprosy [30], but only a few studies showed the relationship between PB and physical disabilities [39]. As the epidemiology of the disease varies greatly worldwide, a certain population may present specific risk factors for disabilities, and there may be factors common to all populations. The different statistical analysis methods could be another probable cause of discrepancies among studies. In a previous study, only one factor based on prevalence was included in the model at one time. In this study, various factors were included, and logistic regression showed which of the various factors being assessed had the strongest association with an outcome and provided a measure of the magnitude of the potential influence. Logistic regression also has the ability to "adjust" for confounding factors, i.e., factors that are associated with both other predictor variables and the outcome, such that the measure of the influence of the predictor of interest is not distorted by the effect of the confounder [40].
This study should be interpreted within the context of its limitations. The main limitation of this study is that it was a retrospective observational study; therefore, the results relied on the accuracy and completeness of patient records. The LEPMIS was established by the National Center for Leprosy Control in 2010, and the data have since become more accurate and integrated. During the past several decades, the definitions for the WHO classifications of MB and PB have been continually adjusted. These classifications may have influenced the WHO operational classification indicators used in this study.

Conclusion
In conclusion, the most important risk factors for physical disability at diagnosis, in decreasing order of importance, were delayed diagnosis, nerve damage, paucibacillary leprosy, Ridley-Jopling classification as tuberculoid, advanced age, zero skin lesions, leprosy reactions, rural occupation, Han ethnicity, and male sex. The identification of risk factors associated with physical disability in this study could be helpful for disability prevention in the endemic population in Yunnan, China. Early detection and proper therapy with multidrug therapy (MDT) are necessary to reduce the burden of disability and deformity associated with leprosy disease.