Epidemiological Characteristics and Factors Associated with Cure of Leprosy in Chongqing, China, from 1949 to 2019

. Chongqing is one of the focuses of leprosy control in China. Although leprosy control in Chongqing has achieved remarkable results over the years, there are also some problems, such as recurrent epidemics and insuf ﬁ cient early detection in some areas. The aim of this study was to analyze the epidemiological characteristics of leprosy in Chong-qing, from 1949 to 2019 and explore the potential factors sociated with cure of leprosy to provide a basis for improving leprosy prevention and treatment strategies in Chongqing. Epidemiological indicators such as incidence and prevalence rates were used to evaluate the prevalence of leprosy. The epidemiological characteristics and control situation of leprosy in patients were analyzed using demographic characteristics, diagnosis, and treatment. Survival analysis was conducted to explore factors associated with the cure of leprosy. From 1949 to 2019, 3,703 cases of leprosy were registered in Chongqing. The incidence of leprosy in the city peaked at 0.853/10 5 in 1960 and remained below 0.100/10 5 after 2003. The number of high incidence areas decreased signi ﬁ cantly, but they were mainly concentrated in the northeast and south-east regions. The early detection rate increased yearly from 1949 to 2019, and the rate of grade 2 disability ranged from 38.2% to 21.7%, with a ﬂ uctuating downward trend after 1960. Male, young age, employment as a farmer, delayed diagnosis, and multibacillary leprosy were risk factors for leprosy cure. Chongqing should continue to strengthen leprosy monitoring to improve the early detection of leprosy and focus on sociated risk factors to carry out multiple strategies.


INTRODUCTION
Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M.leprae), mainly affecting the skin and peripheral nerves.If early detection and timely treatment are not available, patients' skin, nerves, limbs, and eyes will suffer progressive irreversible damage, and it is one of the main diseases leading to human disability. 1 After years of prevention and treatment, in 2000, the world achieved the leprosy elimination target (the prevalence rate is less than 1/10,000) set by the WHO. 2 Since then, new cases have decreased yearly, but the leprosy epidemic remains.WHO data show that 202,166 new cases were detected worldwide in 2019. 3eprosy remains a prominent public health and social problem, especially in Southeast Asia, South America, and Africa. 4,5eprosy has been prevalent in China for more than 2,000 years, with 55.9% of provinces having a leprosy prevalence rate of 10/10 5 or more in the 1950s and 1960s. 6Over the years, leprosy has been effectively controlled in China through strategic measures such as sustained support and investment from the government, the establishment of an effective surveillance system, and the management of leprosy patients.Since 2013, the WHO has no longer listed China as a country with a high incidence of leprosy, but in 2019, China still ranked 23rd in the world and eighth in Asia in terms of new cases of leprosy. 3In general, leprosy in China remains in a low epidemic state, but its spatial distribution varies widely, concentrated in the southwest and southcentral regions, 7,8 especially Yunnan, Guizhou, Sichuan, and Chongqing, which are the focus of leprosy control.Chongqing is one of the largest cities in southwestern China, and its leprosy control efforts have made remarkable achievements over the past 60 years.However, the epidemic is recurrent, with new patients occurring in districts that have not had cases in the past 10 years, and leprosy has not been completely eliminated.Meanwhile, due to the long incubation period of leprosy, the increasingly mobile population, and the fact that patients mainly live in remote and poor areas with poor health conditions, it is difficult to detect patients early, and control work needs to be continued.
Therefore, we review the surveillance data of leprosy in Chongqing from 1949 to 2019, analyze the epidemic trend and characteristics, and explore factors associated with the cure of leprosy to provide a strong scientific basis for the follow-up prevention and treatment of leprosy in Chongqing.

MATERIALS AND METHODS
Ethical considerations.Ethical approval was not required because the analysis of the data from Leprosy Management Information System in China (LEPMIS) is a routine public health practice.Individual identification information was not available and therefore not used.
Data sources.Data for leprosy cases (1949-2019) were collected from the LEPMIS.The dataset comprises basic information on newly detected and relapsed leprosy cases, including patients' basic demographic information (sex, date of birth, ethnicity, education, occupation, and geographic information) and clinical information (age at confirmed diagnosis, date of symptom onset, date of confirmed diagnosis, onset to diagnosis time, grade of disability, Ridley-Jopling classification, and WHO operational classification).All leprosy cases were initially diagnosed by clinical symptoms and confirmed by laboratory examination.They were reported jointly through self-report, dermatological department visit, contact examination, epidemic site investigation, team examination, clue investigation, census, and other means.
Population data comprised the total population in major years, which was obtained from The Statistical Yearbook of Chongqing in 2020. 9tatistical analysis.Epidemiological indicators such as the incidence and prevalence rates were used to evaluate the prevalence of leprosy.Because leprosy is a chronic disease with a low fatality, it is of little practical significance to evaluate its mortality rate, which was described in only a temporal epidemiological profile.Incidence (per 100,000) and prevalence (per 100,000) are calculated by dividing the number of new leprosy cases per year, and the number of leprosy cases registered for treatment per year respectively by the size of the population at the end of the year.
Epidemiological characteristics and control situation of leprosy patients were analyzed using demographic characteristics, diagnosis, and treatment.Descriptive analyses were mainly applied to the data.Chi-square tests were used to compare rates.
To explore the potential factors associated with cure of leprosy further, survival analysis was conducted.Clinical cure was defined as main outcome of the survival analysis.Clinical cure refers to patients with no active symptoms (active skin lesions or peripheral nerve pain and tenderness), no leprosy reaction or neuritis, and negative skin bacteria.Considering that multidrug therapy (MDT) is the major factor affecting the cure rate, patients who were treated by MDT were included in the survival analysis to explore other factors.The other factors under consideration were sex (male and female), age group (0-29, 30-59, and $ 60 years), education (illiterate/semiliterate), occupation (farmer and others), marriage (unmarried and married), area of residence (rural versus urban area), onset to diagnosis time (0-1, 2-4, and $ 5 years), disability (no disability, grade 1 disability, grade 2 disability, and other disabilities), and leprosy classification (paucibacillary [PB] and multibacillary [MB]).The Kaplan-Meier method was used to draw the cumulative incidence curve, and the two-stage method was used if the curve crossed.The log-rank test was used to compare the cure probability among different groups.Because the leprosy classification did not meet the proportional hazards assumption, the influence of each factor on the cure probability was analyzed by time-dependent Cox regression.The test level was set at 0.05.R 4.2.1 was used for data analysis and graph construction, and ArcGIS was used to generate a heatmap of the incidence rate.

RESULTS
Epidemic overview.Time distribution.A total of 3,703 cases of leprosy were registered in Chongqing from 1949 to 2019.The incidence of leprosy in the whole city increased rapidly from a low level and then decreased to a low and stable state, as shown in Figure 1A.The incidence of leprosy increased rapidly from 0.006/10 5 in 1949 to a peak of 0.853/10 5 in 1960.It then fluctuated within the range of 0.085/10 5 and 0.673/10 5 from 1961 to 2002 and decreased to 0.048/10 5 in 2003.After that, the incidence of leprosy remained below 0.100/10 5 .The mortality rate of leprosy remained below 0.100/10 5 , and the change trend was consistent with the incidence rate.
The prevalence increased rapidly in 1958 and peaked at 3.927/10 5 in 1977, with the number of cases reaching 1,018.By 2003, the prevalence decreased to 0.521/10 5 .After that, the prevalence remained below 0.500/10 5 , as shown in Figure 1B.By the end of 2019, there were 99 leprosy patients in the city.
Regional distribution.A heatmap based on the 5-year average incidence of leprosy in each region from 1949 to 2019 is shown in Figure 2. The 5-year average incidence of leprosy was low (, 0.100/10 5 ) in most regions during 1949 and 1958.It was higher than 2.000/10 5 in many regions from 1959 to 1973, mainly in the northeast and southeast regions of Chongqing-namely, Wuxi, Fengjie, and Youyang.The 5year average incidence of leprosy dropped below 0.100/10 5 in most regions until 2003, after which a slight rebound from 2014 to 2018.
Population distribution.As shown in Table 1, there were 2,934 registered cases in males and 769 registered cases in females, and the sex ratio was 3.8:1.According to data characteristics and common international standards, the age of the cases was divided into three groups: 0-29 (1,229, 33.2%), 30-59 (2,213, 59.8%), and 60 and more years (261, 7.1%).There were 1,314 people whose education level was recorded (the rest were missing), among whom 519 were illiterate or semiliterate and 795 were literate.In terms of occupation, 96.3% of patients were farmers.There were 1,635 cases whose marriage condition was recorded (the rest were missed), including 282 unmarried people and 1,353 married people.In terms of residential area, 38.1% of the patients lived in the central areas, whereas the rest lived in the remote areas.
Diagnosis and treatment of leprosy.With regard to diagnosis, the median time between the onset and diagnosis of leprosy in the whole city was 3 years, with 1,161 (31.4%) cases diagnosed within 2 years of onset, 1,171 (31.6%) diagnosed within 2 to 5 years of onset, and 1,371 (37.0%) diagnosed .5 years after onset.There was a significant difference in the distribution of leprosy patients with different delay periods across years (x 2 5 99.61, P , 0.001).As shown in Table 2, the proportion of patients diagnosed within 2 years fluctuated greatly during the first 12 years and showed an upward trend from 1979.The proportion of patients with a delayed diagnosis of $ 5 years reached a maximum of 44.5% from 1979 to 1984, followed by a downward trend.
Of the leprosy patients registered from 1949 to 2019, 1,713 (48.0%) patients had no disability at diagnosis, 595 (16.7%) had grade 1 disability, 1,089 (30.5%) had grade 2 disability, and 174 (4.9%) had other disabilities.The distribution of leprosy patients with different grades of disability was significantly different across years (x 2 5 199.18,P , 0.001), and 132 patients with unknown conditions were not included in the analysis.As shown in Table 2, the proportion of patients with no or grade 1 disability fluctuated from 1949 to 2019 but showed an overall upward trend, whereas the proportion of patients with grade 2 disability reached a maximum of 38.2% during 1955-1960 and then showed a downward trend.
With regard to treatment, from 1949 to 1973, the overall 5-year cure rate of leprosy patients in Chongqing was lower than 20%.After 1978, it began to rise rapidly until 1989-1993, when the maximum 5-year cure rate of leprosy reached 74.4% and then fluctuated around 60%, as shown in Figure 3.
Before 1981, the treatment of leprosy mainly consisted of monotherapy with dapsone (DDS).In 1981, the WHO issued a standard regimen for the treatment of leprosy: MDT. 10 Therefore, considering 1981 as the boundary, the data were analyzed by leprosy classification and treatment in each period.As shown in Table 3, among the 3,703 registered patients, the majority (3,272, 88.4%) were classified as Survival analysis.Analysis of between-group differences.The between-group differences analysis took clinical cure as the main outcome to draw Kaplan-Meier cumulative incidence curves of different groups and performed the log-rank test, as shown in Figure 4.The clinical cure probability was significantly higher for female patients than for male patients (P 5 0.042).For patients of different occupations, the cure probability of farmers was significantly lower than that of other occupations (P 5 0.035).For patients of different age groups, the cure probability was significantly lower for patients aged 0 to 29 years than for those aged 30 to 59 years and .59 years (P , 0.0001).The cure probability was significantly lower for patients diagnosed 5 years or more than for those diagnosed within 5 years after onset (P 5 0.0074).For patients with different conditions of disability at diagnosis, the cure probability was significantly higher for patients without disability than for those with disability (P 5 0.005).For patients with different leprosy classifications, the cure probability was significantly lower for patients with MB leprosy than for those with PB leprosy (P 5 0.0092).
The cumulative incidence curves for education was plotted using the time value at the intersection of the curves as the landmark, as shown in Figure 5.The cumulative incidence curve of patients with different educational level was bounded at Time 5 80; when Time # 80 or Time .80, there was no significant difference in the probability of cure between patients who were illiterate/semiliterate compared with those who were literate (P .0.05).
Multivariate Cox regression analysis On the basis of the results of the Kaplan-Meier method and proportional hazards assumption judgment, six factors were screened into the time-dependent Cox regression model, including sex, age, occupation, onset to diagnosis time, disability, and leprosy classification.Considering the correlation between the onset to diagnosis time and disability (Spearman r 5 0.32, P , 0.001), the model was adjusted, as shown in Table 4.Among them, the cure probability was 1.24 (95% CI: 1.07-1.43)times higher for female patients than for male patients.The cure probability was 1.57 (95% CI: 1.36-1.82)and 2.77 (95% CI: 2.18-3.52)times higher for middle-aged and elderly cases than for young cases, respectively.The cure probability was 1.40 (95% CI: 1.07-1.84)times higher for other occupations compared with farmers.There was no significant difference between the cure probability for diagnosis within 2 to 5 years and the cure probability for those diagnosed within 2 years.The cure probability for delayed diagnosis of 5 years or more was 0.81 (95% CI: 0.70-0.94)times higher than for those diagnosed within 2 years.The cure probability for patients with PB was 2.06 (95% CI: 1.39-3.04)times higher than for patients with MB.The time-dependent covariable of leprosy classification was significant, suggesting time dependence, and its hazard ratio varied with time at Exp(2.06 1 0.99t).

DISCUSSION
The incidence rate is the most effective indicator to evaluate the prevalence of leprosy. 11From the existing leprosy data of the detection system, the incidence of leprosy in Chongqing increased rapidly and then decreased to a stable low level.][14] In the 1960s, the country strengthened efforts in the active From the perspective of regional distribution, the number of high leprosy incidence areas in Chongqing has decreased significantly in recent years, and they are mainly concentrated in the northeast and southeast regions, both of which are far away from the main urban areas, where factors such as inconvenient transportation, underdeveloped economy, and untimely allocation of health resources may affect leprosy control.7][18][19] This suggests that for the development of new leprosy prevention and treatment measures, priority should be given to strengthening the allocation of health resources in remote and economically underdeveloped areas to increase access to healthcare for patients.
In terms of population distribution, the sex ratio of leprosy patients in the whole city was 3.82:1, and there were far more males than females, which may be related to the fact that men had more opportunities for contact with infectious sources than women because of their more extensive social activities.Some scholars also believe that women had poorer access to health services than men and reported their illness later than men. 7,20Second, the incidence of leprosy in Chongqing was mostly concentrated in young and middle-aged people, the mainstay of social productivity, and leprosy often leads to multiple morbidities that make self-care impossible, 21 thus causing huge economic losses and medical burdens to leprosy families and society.Therefore, it is of great significance to provide effective rehabilitation for leprosy patients.In addition, almost all new cases were farmers, indicating that there may still be sources of infection in rural areas, coupled with the constraints of rural living environment and health conditions and more chances of trauma, making farmers a highrisk group for leprosy.On the other hand, because the most directly accessible health service personnel of farmers are the primary medical staff, raising awareness of leprosy prevention and treatment among primary medical staff also plays a significant role in the early detection and diagnosis of leprosy. 22he rate of early detection of leprosy in Chongqing increased yearly, whereas the rate of grade 2 disability fluctuated and declined after 1958, which was attributed to the strengthening of leprosy monitoring and management by the Chongqing health system in recent years.However, the rate of grade 2 disability still reached 24.6%, and the early detection rate was 49.2% during 2015-2019, both of which failed to meet the goals of lower than 20% and higher than 70% by the end of 2015 in The Plan for Elimination of Leprosy hazards in Chongqing (2011-2020). 235][26] Therefore, strengthening the detection of leprosy symptoms and achieving early detection, early diagnosis and early treatment of leprosy patients is still the primary task of leprosy prevention and control in Chongqing.
Survival analysis showed that sex, age, occupation, onset to diagnosis time, and leprosy classification had a significant influence on the probability of cure.In terms of demographic characteristics, the cure probability was higher for female than for male patients.This may be due to the higher risk factor exposure rate in men than in women, which also suggests that health services targeting men are inadequate. 27he cure probability was higher for middle-aged and elderly patients than for young patients due to the longer duration of the disease in young patients, with a median cure time of 72 months.Meanwhile, some studies have shown that the incubation period for leprosy is long-in some cases, up to 10 years-so that most cases are only clinically detectable in adulthood, which in turn affects the cure process for young leprosy patients. 28Rural residents' access to health services is much lower than that of urban residents, which in turn adversely affects the diagnosis and treatment of diseases and may result in lower cure probability for farmers than for other occupations.It is also associated with the prevalence of leprosy prevention and control knowledge in rural areas.Even in low epidemic areas, it is necessary to increase the publicity and education on leprosy prevention and control to raise awareness and self-care. 29n terms of diagnosis and treatment, the cure probability for patients with a delay in diagnosis of 5 years or more was significantly lower than for those diagnosed within 2 years, further confirming the role of prolonged delay in diagnosis as a hindrance to leprosy cure. 30The delay in diagnosis determines the disability degree of the patients to a certain extent.2][33] Therefore, it is still a priority to improve the ability of early diagnosis and reduce the incidence of deformity. 34Patients with MB leprosy were significantly less likely to be cured than those with PB leprosy, which is consistent with the results of existing studies. 35Patients with MB leprosy tend to have more severe symptoms and a longer course of disease.
The main limitation of this study is that it was a retrospective observational study; therefore, the results depended on  the accuracy and completeness of patient records.Data before the 1980s may be unreliable and incomplete due to failure to fill out the notification form correctly.
In summary, leprosy in Chongqing, a low-epidemic state, remains.The number of high incidence areas has decreased significantly, and they are mainly concentrated in the northeast and southeast regions, where the demographic characteristics of the incidence population were mostly male, young and middle-aged, and farmers.However, with the current status of eliminating the hazards of leprosy, diagnosis delay, and the incidence of disability at diagnosis are still challenging issues.Medical institutions at all levels should continue to strengthen leprosy surveillance, especially symptom surveillance, to improve the early detection of leprosy and reduce the incidence of disability in patients.Second, male, young age, farm labor, delayed diagnosis, and MB leprosy are risk factors for leprosy cure.Therefore, in future leprosy prevention and treatment, Chongqing should pay attention to health education and health services of key population, strengthen the accessibility of health resource allocation, improve the  detection awareness and diagnostic ability of medical personnel, and implement targeted measures, thereby eliminating the harm of leprosy, enhancing the quality of life and cure of leprosy patients, and further improving the management of combined health care and nursing services.

FIGURE 1 .
FIGURE 1. Changes in leprosy indicators from 1949 to 2019.(A) The incidence rate and mortality rate of leprosy in Chongqing from 1949 to 2019.The solid line represents the incidence rate and the dashed line represents the mortality rate.(B) The prevalence rate of leprosy in Chongqing from 1949 to 2019.

FIGURE 2 .
FIGURE 2. The 5-year average incidence of leprosy in each region in Chongqing from 1949 to 2018.Darker color represents regions with higher incidence rate.

FIGURE 4 .
FIGURE 4. Kaplan-Meier cumulative incidence curves of eight variables including sex, age, occupation, marriage, residence, onset to diagnosis time, disability, and leprosy classification.The dashed line represents the median cure time, and the P value represents the log-rank test result.

FIGURE 5 .
FIGURE 5. Two-stage cumulative incidence curves for the variable of education.The dashed line represents the time division point, and the P value represents the log-rank test result.

TABLE 2
15layed diagnosis and disability of leprosy patients in Chongqing, 1949-2019, cases (percentage) ANALYSIS OF LEPROSY IN CHONGQING, CHINA detection of leprosy, and Chongqing actively implemented detection strategies, resulting in the detection rate peaking (0.853/10 5 ) in 1960.In the early 1950s, the resistance of M. leprae to DDS became common.Subsequently, the WHO recommended MDT consisting of rifampicin, DDS, and clofazimine in 1981.Since then, the leprosy cure rate has greatly improved,15so the leprosy cure rate in Chongqing also rose rapidly after 1984.The epidemic situation of leprosy from 2003 to 2019 was further analyzed, showing that the incidence rate was below 0.100/10 5 and the prevalence rate was below 0.6/10 5 in all years, indicating that leprosy in Chongqing was stable at the leprosy elimination standard stipulated by the WHO in recent years, which further reflected the achievements of leprosy prevention and control in Chongqing.
FIGURE 3. The 5-year cure rate of leprosy in Chongqing from 1949 to 2019.EPIDEMIOLOGICAL

TABLE 3
Leprosy classifications and treatment of leprosy patients in different periods in Chongqing, cases (percentage)