Lepr Rev (2019) 90, 46–56

Spatial-temporal dynamics of in Wuhan, , 1950–2017

LIANG CHEN*, JIAN CHEN**, MAN-QING LIU**, XIA GAO*, JUN GAO* & QUAN HU* *Wuhan Institute of Dermatology and Venereology, Wuhan, China **Wuhan Centers for Disease Prevention and Control, Wuhan, China

Accepted for publication 14 January 2019

Summary Aim: In the past 60 years, the number of registered leprosy patients has decreased significantly in Wuhan, China. However, the process behind this remains unknown. Thus, the aim of this study is to analyse the spatial-temporal dynamics of leprosy in Wuhan from 1950 to 2017. Methods: The data of leprosy patients from 1950 to 2017 in Wuhan city was downloaded from Leprosy Management Information System (LEPMIS) in China. By using Arcgis (Version 9.3) and Satscan (version 9.4), we analysed the spatial- temporal dynamics of leprosy, including multibacillary and paucibacillary types. Results: 3655 leprosy patients including 1201 with multibacillary leprosy (32·9%) and 2454 with paucibacillary leprosy (67·1%) were enrolled in this study, which showed a significant decrease from 1950 to 2017, and marked transformation of the majority type of leprosy from multibacillary to paucibacillary (p , 0·0001) in Wuhan city. The spatial-temporal analysis of leprosy patients indicated that the distribution changed gradually from clusters in the urban areas to scattered cases in the suburban areas. There has been no cluster of leprosy patients since 2000 in Wuhan. Conclusions: The results of this study suggest great changes within Wuhan, implying that within the low endemic areas of leprosy in China, the focus should be on strengthening systems for monitoring early symptoms.

Keywords: Leprosy, Spatial-temporal analysis, Geographical distribution, Paucibacillary, Multibacillary

Introduction

Leprosy, a chronic infectious disease caused by , was a major public health problem and a concerning social issue.1 In 2015, a total of 136 countries or regions

Correspondence to: Quan Hu, Wuhan institute of Dermatology and Venereology, Wuhan, Hubei China (e-mail: [email protected]) Liang Chen and Jian Chen contributed equally to this work. Health Commission of Hubei Province funded project:WJ2019M017.

46 0305-7518/19/064053+11 $1.00 q Lepra Spatial-temporal dynamics of leprosy 47 had reported leprosy, and 210,758 cases of leprosy were newly diagnosed, with , Brazil and Indonesia and 11 other countries contributing more than 94% of all new cases. The registered prevalence was 174,608 cases [http://www.who.int/gho/neglected_diseases/ leprosy/en/], of which 678 were in China [http://www.who.int/lep/resources/who_wer9135/ en/]. At the end of 2017, there were 2925 leprosy registered patients in China, and 718 leprosy patients were newly identified, with , , and four other provinces contributing more than 73% of new cases.2 The occurrence of leprosy seems to follow specific patterns. Leprosy mainly affects the skin, the peripheral nerves, the mucosa of the upper respiratory tract and the eyes, thus easily causing disability. The World Health Organization (WHO) divided leprosy into multibacillary leprosy and paucibacillary leprosy.3,4 In order to reinvigorate efforts to control leprosy and avert disabilities, especially among children affected by the disease in endemic countries, WHO launched a new global strategy 2016– 2020 “Accelerating towards a leprosy-free world”.5–9 One of the goals of the strategy is to reduce the number of newly diagnosed patients with leprosy-related disabilities to less than one per million. China had issued the “National Programme for Elimination of Leprosy in China, 2011–2020” in 2011, which aimed to reduce the proportion of newly diagnosed patients with grade 2 disabilities to less than 23%. However, due to the low incidence of newly diagnosed leprosy patients in Wuhan, (less than one per million population) and the long delay in the diagnosis of leprosy (about 2–3 years),10 –13 newly discovered patients have had various degrees of disability. Here there is one person with disability in every four newly diagnosed patients, and the previously set goal has not been achieved. In recent years, the number of newly diagnosed patients was less than four per year in Wuhan, creating great difficulty in achieving the goals. Therefore, it is necessary and very important to retrospectively analyse the epidemic of leprosy in Wuhan and to find new ways of preventing new patients with leprosy-related disabilities.

Materials and methods

DATA COLLECTION AND CLEANING

All individuals in China who were diagnosed with leprosy were reported to LEPMIS at the Chinese Center for Disease Control and Prevention (China CDC) within 24 hours, which was mandatory. The data regarding leprosy patients from 1950 to 2017 in Wuhan were downloaded from LEPMIS. We conducted a spatial analysis based on the addresses of leprosy patients from the medical records. Cases without addresses or where the addresses could not be verified were excluded.

DESCRIPTIVE STATISTICAL ANALYSIS

For the basic information of leprosy patients, statistical analyses were performed with GraphPad Prism (GraphPad Software, San Diego, CA), and the Chi-Square test was applied. The clustering analysis was conducted with Arcgis and Satscan softwares. Statistical significance was defined as p , 0·05. 48 L. Chen et al.

THE ANALYSIS OF SPATIAL-TEMPORAL DYNAMICS

The software of Arcgis (version 9.3) and Satscan (version 9.4) were used for the analysis of spatial-temporal dynamics. A global spatial autocorrelation analysis and a space-time rearrangement scanning statistic method14 – 17 were used for the study. The Moran index was used to measure the spatial autocorrelation of global indicators, which reflected the degree of similarity of the spatial unit attribute values of spatial adjacency or spatial proximity. The global Moran index was calculated as follows: P P n n n w ðx 2 xÞðx 2 xÞ Pi¼1 Pi¼1 ij Pi j I ¼ n n n 2 i¼1 i¼1wij i¼1ðxi 2 xÞ where n is the number of observations, xi and xj are the observed values at position of xi and xj where i – j. x is the mean of the observed values (x) for all positions (n). {wij} is the spatial weight matrix.18 The space-time rearrangement sweep statistic method was proposed by Kulldorff et al.19 Analysis of time and spatial, scan the different time and area with a dynamically changing cylindrical scanning window, which achieve the purpose of detecting the temporal and spatial aggregation. The specific formula was: P ! P C 2 Czd P z[A z[CA Czd A d[ACzd 2 CA PðCAÞ¼ P C d[ACzd where mA is the expected number of occurrences of each cylinder A. X mA ¼ mzd ðz;deAÞ

Z represents the area, and d represents the day, CA is the actual incidence in each cylinder A, and C is the total incidence.19

Results

CHARACTERISTICS OF COHORT

Data of 3,655 eligible leprosy patients were downloaded from LEPMIS, including 3,447 adults (94·31%) and 208 children (5·69%). Classified by gender, the cases included 2923 males (80·0%) and 732 females (20·0%). According to the bacillary load, it included 1201 cases of multibacillary leprosy (32·9%) and 2454 cases of paucibacillary leprosy (67·1%). Table 1 showed the marked decrease of incidence of leprosy and significant changes in the composition ratio of sex (p ¼ 0·0265) as well as leprosy types (p , 0·0001) in the past 60 years in Wuhan city. We also found that most leprosy patients were farmers (27·2%) and were infected with Mycobacterium leprae through an unknown transmission route (46·0%) (Table 2). In 1950–2017, 208 cases (5·69%) were children under 14 years and half of them were discovered in the department of dermatology, among whom 27·88% was infected possibly by family members (Table 3). Spatial-temporal dynamics of leprosy 49

Table 1. The distribution of leprosy patients registered in different periods in Wuhan, China

Sex Leprosy type

Male Female Multibacillary Paucibacillary Years No. of Cases (%) (%) p (%) (%) p

1950–1959 1567 1281 (81·7%) 286 (18·3%) 0·0265 551 (35·2%) 1016 (64·8%) ,0·0001 1960–1969 1445 1148 (79·4%) 297 (20·6%) 429 (29·7%) 1016 (70·3%) 1970–1979 448 355 (79·2%) 93 (20·8%) 124 (27·7%) 324 (72·3%) 1980–1989 97 69 (71·1%) 28 (28·9%) 36 (37·1%) 61 (62·9%) 1990–1999 56 40 (71·4%) 16 (28·6%) 35 (62·5%) 21 (37·5%) 2000–2017 42 30 (71·4%) 12 (28·6%) 26 (61·9%) 16 (38·1%)

Total 3655 2923 (80·0%) 732 (20·0%) 1201 (32·9%) 2454 (67·1%)

CHANGING EPIDEMIOLOGY OF LEPROSY IN WUHAN, 1950–2017

Figure 1 shows the distribution changes of leprosy patients in 13 districts of Wuhan from 1950s to 2010s, which was unbalanced in different districts and also decreased in different years. We can also find that, in the 1950s, leprosy patients in Wuhan were distributed mainly in the urban Huangpi district. In the 1960s, the distribution of leprosy patients in Wuhan was almost the same as that in 1950s, but had spread from the urban area to its surrounding environs (Figure 1). From the 1970s, the number of leprosy patients decreased significantly

Table 2. The clinical characteristics of leprosy patients from 1950–2017 in Wuhan, China

Characteristics n %

Sex Male 2923 80·00% Female 732 20·00% Leprosy type Multibacillary 1201 32·90% Paucibacillary 2454 67·10% Occupation Worker 76 2·10% Farmer 995 27·20% Other 40 1·10% Missing data 2544 69·60% Transmission route Couples 10 0·30% Parents 66 1·80% Home 400 11·00% Outside 1078 29·50% Neighbor 61 1·70% Relative 20 0·50% Unknown 1679 46·00% Missing data 341 9·30% Discovery methods Dermatology 2417 66·13% Professional clinic 417 11·41% National census 314 8·59% Other methods 507 13·87% 50 L. Chen et al.

Table 3. The characteristics of leprosy in children under 14 years of age from 195022017 in Wuhan, China

Characteristics n %

Sex Male 142 68·27% Female 66 31·73% Leprosy type in male Multibacillary 49 34·51% Paucibacillary 93 65·49% Leprosy type in female Multibacillary 49 74·24% Paucibacillary 17 25·76% Transmission route Parents 26 12·50% Home 58 27·88% Outside 37 17·79% Neighbor 1 0·48% Unknown 63 30·29% Missing data 23 11·06% Discovery methods Reported illness 1 0·48% Contact inspection 35 16·83% Dermatology 104 50·00% National census 13 6·25% Clues investigation 2 0·96% Medical unit 12 5·77% Professional clinic 31 14·90% Self report 10 4·81%

(Table 1). In the 2010s, leprosy patients were mostly distributed in the suburbs and there were almost no leprosy patients in the central Wuhan city (Figure 1). The newly diagnosed cases of children under 14 years old in Wuhan were mainly concentrated in 1952–1991. This number increased up to 33 in 1960. At the highest level, children accounted for 25% of newly diagnosed cases in the year (Figure 2 and Figure 3).

GLOBAL SPATIAL AUTOCORRELATION ANALYSIS OF LEPROSY IN WUHAN

Based on the address of each leprosy case, the global spatial autocorrelation analysis was performed in Arcgis and Satscan. The results showed that the cases of leprosy in Wuhan had significant spatial aggregation (p , 0·05), especially in 1950s and 1960s (p , 0·01, Table 4). As the number of leprosy patients decreased from the 1980s, the epidemic of leprosy in Wuhan was sporadic, and no cluster has occurred since 2000. As the distribution of leprosy patients in Wuhan had significant spatial aggregation, we further analysed the characteristics of clusters. According to the location information of leprosy patients (including multibacillary leprosy and paucibacillary leprosy), five clusters of leprosy (Figure 4) were identified by spatial scanning statistical method: (1) The first cluster (T1) occurred from 1951 to 1956, and was an area with a radius of 8·45 km and comprised of 658 cases. The cases were located mostly in Wuhan city, especially around the wharf. (2) The second cluster (T2) was identified in 1957, which was located in Huangpi district with a radius of 27·42 km and comprised of 94 cases. T2 may be associated with the construction of Spatial-temporal dynamics of leprosy 51 Wuhan Hospital for Leprosy Prevention and Control. (3) The third cluster was found in 1960, where there were 121 leprosy patients registered. (4) The forth (T4) and fifth (T5) clusters were found in 1966–1995 and 1976–2000 respectively, and were highly sporadic in the suburban area of Wuhan city (Figure 4).

Discussion

Leprosy prevalence has decreased markedly since the introduction of multidrug therapy (MDT) at the beginning of the 1980s. In Wuhan, the government has made great efforts on leprosy control,20 and the number of registered cases of leprosy has significantly decreased from 1567 in 1950s to 42 in 2000s (Table 1), and the majority type of leprosy has changed gradually from paucibacillary leprosy in 1950s to multibacillary leprosy in 2000s, which is

1950˜ 1960˜

1970˜ 1980˜

Figure 1. Continued. 52 L. Chen et al.

1990˜ 2000˜

2010˜

Figure 1. Geographical distribution of leprosy patients in different districts of Wuhan, China in 1950–2017. similar to the global trend of leprosy21 –23 [http://www.chinalep.org/showNewsDetail. asp?nsId ¼ 29]. Between 1950 and 1970, the majority of leprosy patients were aged less than 14 years old, accounting for 90·38%. No leprosy occurred in children under 14 years of age after 1992. Most cases of male children with leprosy were paucibacillary while cases of female children were multibacillary (Table 3). Due to the high rate of transition by family members and the fact that not everyone became infected the disease pathogenesis was considered to be associated with genetic factors. Furthermore, as there were large numbers of child patients in 1950–1970, it was considered that the pathogenesis was related to an individual’s health condition and local medical level. This conclusion is in line with what Santos M J, Ferrari C K et al. came to.24 Leprosy endemicity is low in Wuhan, but as leprosy Spatial-temporal dynamics of leprosy 53

33 35

30

25

20 21 21 17 15 13 11 10 9 7 8 7 8 556 5 6 4 6 4 2 1 1 1 00 1 1 1 11 0 3 22 0 0 0 00 0 0 0 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 –5

Figure 2. New cases of leprosy in children under 14 years old in Wuhan from 1952 to 1991.

(particularly for multibacillary leprosy) is highly contagious, it has been possible for it to be spread in Wuhan during the past 60 years. Therefore, based on the data from LEPMIS, we retrospectively analysed the spatial-temporal distribution of leprosy in Wuhan city. Wuhan is located in central China, and two important rivers (Yangtze River and Han River) cross at the centre of Wuhan city. In the 1950s–1970s, Wuhan, especially at the confluence of the two rivers, developed rapidly in its economics, politics and culture. The spatial-temporal results of leprosy (Figure 4) showed that the first cluster (T1) was located at the centre of Wuhan city, as well as around the wharf of the two rivers, with the largest cluster of cases (658 patients). In 1953, the Wuhan Hospital for Leprosy Prevention and Control was set up in Huangpi district, which may have caused the second cluster of multibacillary leprosy

30∙00%

25∙00% 25∙00% 22∙22% 20∙00%

15∙00% 10∙94% 10∙00% 10∙00% 8∙71% 8∙33% 9∙09% 8∙21% 7∙34% 6∙51% 6∙41% 7∙25% 7∙14% 7∙14% 5∙06% 5∙26% 7∙47% 4∙88% 3∙92% 7∙14% 5∙00% 4∙92% 6∙31% 2∙38% 4∙83% 4∙38% 3∙20% 3∙28% 3∙06% 2∙07% 0∙00% 2∙41% 1950 1955 1960 19651970 1975 1980 1985 1990 1995 –5∙00%

Figure 3. Proportion of children under 14 years in new cases of leprosy in Wuhan from 1952 to 1991. 54 L. Chen et al.

Table 4. Global spatio autocorrelation analysis of leprosy patients in Wuhan from 1950 to 2017

Years Moran I coefficient Expected index Variance z-score p-value

1950s 0·1399 20·0050 0·0001 12·4511 < 0·0001 1960s 0·0267 20·0050 0·0001 2·5970 0·0094 1970s 0·0217 20·0050 0·0002 2·1642 0·0304 1980s 20·0016 20·0050 0·0002 0·2779 0·7811 1990s 20·0022 20·0050 0·0001 0·2311 0·8172 2000s 20·0010 20·0050 0·0002 0·3283 0·7427 2010s 0·0129 20·0050 0·0001 1·5367 0·1244 Total 0·0705 20·0050 0·0001 6·3223 < 0·0001

(T2) in 1957 in Wuhan (Figure 4), as nosocomial infection was most likely to occur at that time. In 1960, the third cluster (T3) was located in Caidian district. From 1966 to 2000, as a result of the economic development and urban expansion of Wuhan city, the fourth and fifth clusters of leprosy (T4 and T5) were mostly scattered in the suburban areas, which might partly relate to the social discrimination of leprosy and the prejudice against leprosy patients. To our best knowledge, little research has been done on the spatial and temporal aggregation of leprosy in the world. Although the WHO’s annual report data has obvious geographical aggregation our spatial-temporal analysis of leprosy is based on the geographical distribution of the patients. This allows us to demonstrate the cognitive

T4 Coordinates: T2 Coordinates: 30∙796 N, 114∙843 E 31∙039 N, 114∙227 E Radius: 34∙42 km Radius: 27∙42 km Time frame: 1966–1995 Time frame: 1957 Number of cases: 116 Number of cases: 94 Test Statistic: 27∙96 Test Statistic: 34∙54 P-value: <0∙0001 P-value: <0∙0001

T3 Coordinates: 30∙520 N, 113∙889 E Radius: 21∙52 km Time frame: 1960 Number of cases: 121 Test Statistic: 81∙26 P-value: <0∙0001

T1 Coordinates: 30∙609 N, 114∙254 E Radius: 8∙45 km Time frame: 1951–1956 Number of cases: 658 Test Statistic: 76∙50 P-value: <0∙0001

T5 Coordinates: 30∙137 N, 114∙246 E Radius: 32∙92 km Time frame: 1976–2000 Number of cases: 59 Test Statistic: 47∙85 P-value: <0∙0001

Figure 4. Spatio-temporal Clusters of leprosy patients in Wuhan from 1950 to 2017. By using the softwares of Arcgis and Satscan, five significant clusters (p , 0·05) were identified from 1951 to 2000. Spatial-temporal dynamics of leprosy 55 process behind the spread of disease. Through our experience, we can divide the cognitive process of disease understanding into four stages:

1. Without adequate knowledge about leprosy, there are a large number of cases in densely populated areas. 2. In the preliminary understanding stage, centralised isolation was started, but the prevention and control of nosocomial infections was not perfect. 3. After the public was able to gain an understanding of leprosy, we were able to distribute the knowledge. This is the stage we are currently at. 4. Finally, to reach the stage of comprehensive control, it is necessary to fully explain the course of disease changes and achieve accurate medical treatment.

Our spatial-temporal results implied that, in order to achieve the target of interrupting the transmission of leprosy globally by 2020,25 it is necessary to emphasise the strengthening of the early symptoms monitoring system. This view has also been recommended by other experts in public health.26,27 In recent years, the downward trend of leprosy cases has slowed down, with global leprosy prevention and treatment reaching a bottleneck. Our research has important guiding significance regarding the trends within leprosy epidemics. In areas with fewer newly diagnosed patients, the aggregation is not obvious. For the global leprosy strategy 2016– 2020, to eliminate the hazards of leprosy, we are only able to achieve it through constant innovation. We will work to further improve the efficiency of the health system so that our hospitals, the CDC systems and primary health centers can work together, discover patients as soon as possible through early symptom monitoring and help to reduce the number of both misdiagnosis and missed-diagnosis. Furthermore, it is necessary and important to introduce new detection techniques28 – 31 to find patients earlier and reduce levels of disability.

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