Epidemiology and grade 2 disability of leprosy among migrant and resident patients in Guangdong: an unignorable continued transmission of leprosy

Introduction Leprosy remains a major public health concern worldwide and one of the leading causes of disability. New cases of leprosy with grade 2 disability (G2D) often reflect delayed detection due to the limited capacity of the health system to recognize leprosy early. This study aimed to describe the epidemiology and G2D of leprosy among migrant and resident patients with leprosy in Guangdong province, China. Methods Data on newly diagnosed cases of leprosy were collected from the leprosy management information system in China. Descriptive statistical analysis was used to describe the status of G2D. Joinpoint regression model and logistic regression were performed to analyze the temporal trends and influencing factors for G2D. Results The G2D rate among migrant, resident, and total patients with leprosy was 17.5%, 18.7%, and 18.4%, respectively. The total G2D rate increased significantly from 18.0% in 2001 to 25.7% in 2021 (average annual per cent change: 2.5%). Multivariate analysis revealed that factors that negatively influence G2D between migrant and resident patients included delayed discovery time (migrants: OR = 2.57; residents: OR = 4.99) and nerve damage when diagnosed (migrants: OR = 9.40; residents: OR = 21.28). Discussion Our findings indicate that the targeted intervention measures implemented by our health system are urgently needed to improve the current situation, such as programs to promote early detection, strengthen awareness and skills of healthcare workers, and rehabilitation for disabled patients to improve their quality of life.


Introduction
Hansen's disease or leprosy is a neglected tropical disease (NTD) mainly caused by Mycobacterium leprae, a slow-growing Mycobacterium discovered by Hansen, which predominantly affects the skin, peripheral nerves, mucous membranes, liver, and kidney (1,2).In 2008, Mycobacterium lepromatosis was identified as a new species and the second causal agent of leprosy.However, M. lepromatosis has been implicated in a small number of leprosy cases, and the clinical aspects of leprosy caused by M. lepromatosis are poorly characterized (3).Since 1982, the World Health Organization (WHO) has recommended multi-drug therapy (MDT), Chen et al. 10.3389/fpubh.2023.1275010Frontiers in Public Health 02 frontiersin.orgwhich has been used to treat more than 15 million patients in the last 30 years and has made leprosy a curable disease (4).
Although MDT has reduced the number of cases in treatment, it had less impact on the number of new cases.Despite the availability of health facilities, there continue to be barriers to early diagnosis and treatment of leprosy.The lack of awareness of the disease among the general population and many consultations-suggestive of ill-trained health staff in suspecting and managing a leprosy case-were associated with a longer diagnostic delay, thus contributing to the ongoing transmission and disability-related disease burden (5).There were 202,185 new cases of leprosy worldwide, with a new case detection rate of 25.9 per million population in 2019 (6).In China, according to statistics released by the National Center for Leprosy Control, a total of 521 new cases of leprosy were detected, with a new case detection rate of 0.037 per 100,000 population in 2018 (7).
Guangdong province is the most severe leprosy epidemic area, with the highest number of cases in history; records showed that 96,797 people were affected by leprosy by 2020, representing approximately one-fifth of all leprosy patients in China.Regarding the new cases reported in 2018, Guangdong province ranked third in the number of new cases reported (57 cases), trailing Yunnan (174 cases) and Guizhou province (61 cases).These three provinces accounted for 56.0% of newly detected cases in China (7).The epidemic has the potential to be underestimated.There may be cases of oligosymptomatic leprosy with subclinical infection without diagnosis.This underdiagnosis may lead to underreporting to the leprosy surveillance system.
As the first province in China in terms of floating population and GDP, Guangdong province has great attraction and development potential in household registration immigration.According to the Guangdong Statistical Yearbook 2021, approximately 28.15 million migrants live in Guangdong province, representing 22.3% of the total permanent population (8).Movement can be a strategy to achieve a higher standard of living and access to better employment, education, and health service infrastructure, mainly among resource-poor rural areas and urban centers (9).Migration can lead to changes in circumstances that influence the conditions and risks associated with disease transmission, particularly among the poor, who are disproportionately affected (9,10).Therefore, migration has been identified as one of the social determinants that influence the transmission dynamics of NTDs, including leprosy, which was identified as an infection risk factor associated with poverty (11,12).
To improve our understanding of the epidemic situation of leprosy between migrant and resident populations, we detailed the demographic, clinical, geographic characteristics, and temporal trend of patients with leprosy in Guangdong province, China, 2001-2021.We also evaluated the status of grade 2 disability (G2D) and its associated influencing factors among migrant and resident patients with leprosy.

Data sources and diagnosis standard
Information on newly diagnosed leprosy cases were collected from the leprosy management information system (LEPMIS) in China.LEPMIS was designed by the Chinese government in 2010 and reports data on new, recurrent, and prevalent cases of leprosy (13).LEPMIS includes not only related information on disease discovery, diagnosis, and treatment, but also information on all aspects of leprosy management, including basic demographic information, source of infection, close contacts, follow-up after cure, etc.Therefore, LEPMIS was a detailed and comprehensive database that achieved lifelong leprosy cases and even contained information on death.Data from patients with leprosy from 2001 to 2021 were collected from paper files and uploaded to LEPMIS by staff from municipal, county, and district-level professional leprosy prevention and control institutions.Oral consent was obtained from each participant before the interview and each participant could decline to participate in this survey at any step.
The diagnosis of new leprosy was based on the Leprosy Diagnosis Standard WS291-2018 (14).Patients with clinical manifestations (skin lesions or peripheral nerve lesions) and positive laboratory tests for leprosy (skin smear test for bacteria or histological examination) were diagnosed as confirmed cases.Disability classification was based on the Disability Classification Standard for Leprosy, WHO, 1998 (15).In 1988, the WHO Expert Committee on Leprosy substantially simplified the disability grading system into a three-grade (0, 1, and 2) classification system (16).Patients with G2D have visible deformities (i.e., hand ulcers, absorption or contractures of the digits, plantar ulcers, callosities, foot drop, or claw) or severe visual impairment (i.e., cannot read the fingers at a distance of 6 m).Patients with grade 1 disability have loss of sensation or eye problems (irregular blinking) due to the presence of leprosy, but no visible deformities, including muscle weakness without clawing.Nerve involvement in leprosy is considered to occur when there are signs of pain or nerve thickening on palpation of the nerves, when there is loss of sensation according to the monofilament test, or when motor impairment is observed (17).Patients with grade 0 disability have no loss of sensation, no visible deformity, and no eye problems due to leprosy.In 1997, the eighth report of the WHO Expert Committee on Leprosy endorsed this grading system with the amendment that lagophthalmos, iridocyclitis, and corneal opacities should be included in the grade 2 criteria (18).

Statistical methods
A newly diagnosed leprosy case database was established in Excel 2010 (Microsoft Corp., Redmond, WA, United States), and the data were cleaned by logical error detection.Statistical analyses, including descriptive statistical analysis, chi-square test, bivariate and multiple logistic regression analysis, were performed using IBM SPSS Statistics 24.0 (IBM Corp., Armonk, NY, United States).Basic descriptive analyses, including frequency, percentage, and mean (SD), were used to describe demographic and clinical characteristics.Geographic distribution analysis was performed using MapInfo Professional version 11.0 (Pitney Bowes Software Inc.).Joinpoint regression analysis was performed using the Joinpoint Regression Program version 4.9.1.0(Statistical Research and Applications Branch, National Cancer Institute).

Ethics statement
No personally identifiable information was included in the database used for the analysis.All data included in the study were stored on a removable hard disk and unauthorized access to them was not possible.

Demographic and clinical characteristics of leprosy from 2001 to 2021
Of the 1980 newly diagnosed cases of leprosy registered during the study period, 452 (22.8%) were migrant patients, while 1,528 (77.2%) were resident patients.The proportion of migrant cases increased from 9.0% in 2001 to 45.7% in 2021 in Guangdong, China (Figure 1).Among the 452 migrant patients, 328 from other provinces were relatively close in location [top five provinces: Hunan (74), Guizhou (55), Sichuan (48), Jiangxi (38), and Guangxi (34)], 116 from other areas of Guangdong, four from Hongkong, three from Indonesia, and one from Mali.Among 1,980 patients with leprosy, 1,302 (65.8%) were males.The vast majority (94.9%) were Han nationality and 1,105 cases were farmers or herders, representing 58.7%.Between 2001 and 2021, the average age of newly diagnosed patients with leprosy in Guangdong was 43.1 (SD = 18.0) years.During this period, 51 cases of pediatric patients (aged <14 years) were detected, with a male-tofemale ratio of 1:3 (Table 1).
The results of the chi-square test showed that there was a significant difference between migrant and resident patients from different groups of age, sex, nationality, occupation, education, delayed discovery time, skin lesions when diagnosed, nervous lesions when diagnosed, case classification, and BI (p < 0.05) (Table 1).

Geographic and temporal trend of G2D from 2001 to 2021
The G2D rate of newly diagnosed migrant leprosy patients was 17.5% between 2001 and 2021, ranging from 0 (Chaozhou and the other six cities) to 50.0% in Heyuan (northern Guangdong) (Figure 2).In contrast, the rate of G2D of newly diagnosed resident patients with leprosy was 18.7 between 2001 and 2021, ranging from 9.5% in Chaozhou (eastern Guangdong) to 32.4% in Shaoguan (northern Guangdong) (Figure 2).

Discussion
With the worldwide implementation of WHO MDT in the 1980s, the global burden of leprosy has decreased.However, a certain number of new patients with leprosy with G2D are still found when diagnosed, reflecting a failure in early detection of leprosy and indicating that transmission continues (19).Of the 121 countries that submitted data to the WHO on G2D in 2020, 68 countries reported 7,198 new G2D cases, which represents 5.7% of 127,396 new cases of leprosy worldwide (20).Although leprosy has a steadily low prevalence in China, the rate of G2D among new cases of leprosy was 17.7% in 2020, while our research showed that the rate of G2D was 18.4% in Guangdong province, China, between 2001 and 2021.Although leprosy cases with G2D have been diagnosed and reported, cases of oligosymptomatic leprosy with subclinical infection can easily be overlooked.Therefore, it leads to underdiagnosis, underreporting to the surveillance system, and an underestimation of the leprosy epidemic.
Leprosy remains one of the leading causes of deformity and physical disability.Our study showed the same influencing factors for G2D among migrant and resident patients with leprosy, including delayed discovery and nervous lesions when diagnosed.The burden of leprosy G2D in new cases often indicates a delayed detection, often due to a lack of awareness in the community of early signs of leprosy, a delay in seeking care, or the limited capacity of the health system to recognize leprosy early (20).Srinivas et al. (21) found that delayed diagnosis is a major challenge in the leprosy program in India.Patient delay and healthcare provider delay have been significant risk factors for disability among adult cases of leprosy.Moreover, since a large proportion of cases with disabilities ignored initial symptoms as they believed that symptoms would disappear by themselves, patient delay became the main reason for the risk of disability.
Nervous lesions when diagnosed were another influencing factor for G2D among migrant and resident patients with leprosy.Due to bacterial proliferation or the immunologic response of the host to these bacilli or both, there is some degree of irreversible peripheral nerve damage in virtually all patients with leprosy.If not treated effectively, widespread destruction of the mixed peripheral nerve trunks can result in widespread skin anesthesia and widespread permanent muscle paralysis that affects the face, hands, and feet (22).Meanwhile, peripheral nerve trunks remove the sensation of pain.The lack of pain feedback allows patients with leprosy to damage and deform themselves.Most of the deformities attributed to leprosy are caused by this secondary damage (1).
Of the 1,980 cases of leprosy registered during the study period, 452 (22.8%) were migrant patients.Similarly to our previous research, the migrant cases originated mainly from two areas: the provinces surrounding Guangdong (Hunan and Jiangxi) and the southwestern provinces (Guizhou, Sichuan, and Guangxi), which have the highest incidence of leprosy in China (23).Due to the long incubation period of leprosy and the failure of current testing method to detect leprosy early, these migrants were identified and treated only after they migrated to Guangdong province, thus resulted in continued transmission between provinces in Chinese territory.We also found that the G2D rate among migrant patients with leprosy was 17.5%, which is related to delayed discovery and nervous lesions.Early diagnosis of leprosy can lead to breaking the chain of transmission and reducing the number of G2D cases (24,25).Thus, the key point of resolve epidemiological problem is to fix the inability to diagnose in early period of leprosy.However, an accurate and timely diagnosis of the disease is still a challenge (26).Skin slit smear acid-fast staining is rapid and economic but has very low sensitivity and specificity.Definitive diagnosis of leprosy by clinic and pathological features     Our study also found that all migrant patients with leprosy had skin or nervous lesion when diagnosed, nearly one quarter had leprosy reactions, and about one fifth had visible deformities.The pronounced damage and permanent disabilities frequently caused patients with leprosy to suffer stigma and prejudice.The management of migrant patients with leprosy has been an important issue for current leprosy prevention and control.Possible reasons for this are that patients with leprosy may fear discrimination to seek medical care.Otherwise, changing job and address frequently reduced the convenience to professional leprosy prevention and control institutions for treatment because of more time and transportation cost.
There are some limitations to this study.First, this study is a crosssectional study, therefore, we were unable to draw causal inferences.Second, the clinical histories of some participants were incomplete due to the loss of records throughout the 21 years period, and the information of treatment classification was collected from LEPMIS which followed the instruction of WHO-MDT classification of leprosy treatment and the Leprosy Diagnosis Standard WS291-2018 in China, which may outdated and reduces the complexity of the disease.Third, although patients claim that their current address is the place where they live, work, and receive treatment, we cannot exclude individuals who work only in places other than their municipality as migrants.Furthermore, it is not known whether the infection occurred at the place of primary residence or at the present address due to the long incubation period of leprosy.
To reduce delay and promote early diagnosis, we have implemented leprosy symptom monitoring programs in Guangdong province since 2017.We propose eight early symptoms of leprosy.If doctors in medical institutions find suspected cases of leprosy, the cases can be referred to a local leprosy-designated diagnosis and treatment center for professional diagnosis and treatment through the "Guangdong Suspected Leprosy Symptom Monitoring System." However, this is not enough; early case detection campaigns, such as active surveys in endemic areas, should be carried out periodically (21).Furthermore, continuing education programs for healthcare workers and the community should also place greater emphasis on raising awareness of the disease (19).Meanwhile, disability prevention and rehabilitation, even after effective treatment, remain essential for patients with leprosy with deformity to improve their quality of life, which is why we plan to establish a provincial-level leprosy correction surgery and rehabilitation center in the future.

FIGURE 1
FIGURE 1Trends of migrant and resident patients with leprosy in Guangdong province, China, 2001-2021.

FIGURE 2
FIGURE 2Geography distribution of the grade 2 disability rate between migrant and resident patients with leprosy in Guangdong province, China, 2001-2021.

TABLE 1
Demographic and clinical characteristics of migrant and resident patients with leprosy in Guangdong, China, 2001-2021 (N = 1,980).

TABLE 3
Bivariate and multiple logistic regression analysis of grade 2 disability among migrant and resident patients with leprosy in Guangdong province, China, 2001-2021 (N = 1,980).