Leprosy: A Disease That Has Never Gone Away

Leprosy, a disease caused by Mycobacterium leprae, can destroy susceptible individuals' skin and peripheral nerves, ultimately leading to disfigurement. Due to its symptoms, it has been stigmatized since ancient times. As recently as the 1950s, there were nearly 400,000 leprosy patients in China.[1] Since 1980s, however, the introduction of multidrug therapy (MDT) by the World Health Organization (WHO) has made leprosy a curable disease. By 2000, the implementation of MDT in China reduced the prevalence of leprosy to less than one case per 100,000 residents at the national level. In 2011, the number of newly detected leprosy cases was still more than 1,000, with a prevalence of 0.407/100,000 individuals in China. Thus, a national leprosy-control plan (2011–2020) was published by the Chinese Ministry of Health (MOH), seeking to reduce the number of newly detected leprosy patients and those with grade 2 disability (G2D). Despite the advances, nearly 200,000 new cases were reported globally in 2022, an increase of 23.8% from 2021.[2] Additionally, no vaccine is available for prevention of leprosy. New disease hosts have been reported, including water buffalo and Eurasian red squirrel.[3] As leprosy will not be eliminated in the foreseeable future, effective strategies for identifying and monitoring leprosy patients are needed. In particular, accurate diagnostic techniques need to be developed in area with a low disease prevalence. This report focuses on the progress of leprosy control in China. 1. Efficient Surveillance In 1990, the national leprosy recording and reporting system was initiated by the MOH in China, managed by the National Centre for STD and Leprosy Control.[4] Demographic and clinical data on leprosy patients were collected, making it easier to track patients, analyze epidemiological trends, and so on. Furthermore, the data collected by the system provide a basis for the government to develop more effective control programs. An active case-finding survey has also played a crucial role in detecting leprosy patients in recent decades. However, detecting new leprosy cases through surveys may not be effective since leprosy has become a low-endemic disease. A provincial alliance of dermatology departments, including departments in general hospitals and leprosy prevention and control institutions, was established by the Shandong Provincial Institute of Dermatology and Venereology (SPIDV) in 2017.[5] This led to the diagnosis of 39 cases of leprosy in 3,043 suspected leprosy patients from 2017 to 2020. Furthermore, it reduced delays in the diagnosis of leprosy and in the proportion of G2D decreased by 66.23 months and 38.08%, respectively, demonstrating that a provincial alliance could be an effective strategy for combatting leprosy in the low-endemic era. Currently, 65 leprosy cases have been identified among 4,885 referral patients. 2. Precise Prophylactic Measures Contacts of leprosy patients, especially household contacts (HHCs), are at high risk of developing the disease.[6] Single-dose rifampicin is used in an attempt to reduce the incidence of leprosy, but the success of this approach is limited.[7] Only a small proportion of leprosy contacts can be protected by long-term follow-ups because the incidence of leprosy among HHCs is less than 1%.[8] The host's genetic factors have been shown to play an important role in the pathogenesis of leprosy,[9] and SPIDV has reported 38 susceptible loci based on genome-wide association studies (GWAS).[10] Based on genetic variants and epidemiological risk factors, a model predicting leprosy risk was established, with an area under the curve (AUC) of 0.821[11] and a sensitivity and specificity of 73.6% and 75.4%, respectively, making it possible to identify individuals with a higher susceptibility to leprosy. Currently, contacts of all new diagnosed leprosy patients are identified, and whole blood is drawn from them after receiving written informed consent. Then, those who are determined to be at higher risk based on the risk prediction model are given a single dose of rifampicin. A single dose of rifapentine has been shown to have protective effects against leprosy among close contacts in China.[12] 3. Early Diagnosis Early diagnosis is crucial for preventing disability among leprosy patients. Clinically, patients are diagnosed with leprosy when the exhibit two of the three cardinal signs: 1. loss of sensation in a skin lesion; 2. enlarged peripheral nerve; 3. positive skin smears.[13] However, traditional diagnostic techniques, such as acid-fast bacilli staining and histopathological examination, have low sensitivity and specificity. In the past few years, some new methods enabling early diagnosis of leprosy have been established. For example, serological analysis to identify M. leprae antigen-specific immune responses has been performed by the Beijing Tropical Medicine Research Institute.[14–17] Moreover, a comprehensive study on the structure of the M. leprae genome along with the development of polymerase chain reaction (PCR) have made it possible to identify M. leprae DNA.[18] The specificity of DNA-based PCR assays is 100%, while the sensitivity ranges from 34% for paucibacillary (PB) patients to 80% to 90% or more for multibacillary patients (MB), indicating that the diagnosis of PB patients is still a challenge. The droplet digital polymerase chain reaction assay, targeting the RLEP and groEL genes of M. leprae, has been developed by SPIDV to support the early diagnosis of PB patients, exhibiting a sensitivity of 79.5%.[19] These diagnostic approaches have been applied for diagnosing leprosy in China.[20] 4. Management Once leprosy is diagnosed, PB patients must complete six course multi-drug therapy (including rifampicin and dapsone) within nine months, while MB patients are expected to complete 12 course multi-drug therapy (including rifampicin, dapsone, and clofazimine) within 24 months. Notably, anti-microbial resistance is a major challenge in leprosy treatment. In 2016–2019, 3.1% of patients who relapsed tested positive for rifampicin resistance, while 1.1% were positive in new cases.[21] Resistance to dapsone was also observed in both relapses (2.2%) and new (2.5%) cases. Resistance to ofloxacin, a second-line drug for leprosy treatment, was found in about 0.5% of leprosy patients. The discovery that CD8+ T cell exhaustion with high expression of inhibitory immune receptors results in lesions in MB patients has provided potential targets for leprosy treatment.[22] In addition, leprosy reaction is common. Corticosteroids and thalidomide remain the mainstays of reaction management. Anti-TNF-α therapy might be an alternative option for patients who do not respond to traditional treatment.[23] Due to the national strategy, the prevalence, incidence, and rate of G2D have reached historically low levels in China. However, 15 countries reported more than 1,000 new diagnosed leprosy cases in 2022. With increasing international travel, the risk of leprosy transmission from patients in endemic countries to individuals in low-endemic countries has increased. Nearly half of all reported leprosy cases in low-endemic countries are suspected to be imported.[24] To share experience of SPIDV with people living in countries facing challenges related to leprosy control, the International Training Program on Leprosy for Developing Countries was held in China in 2019 and 2023 (No. 2019-1972; 2023-2056). The program was funded by the Ministry of Science and Technology of China and organized by SPIDV, aiming to improve leprosy control in countries with a high disease burden. In conclusion, significant progress has been made in controlling leprosy in China. However, leprosy is an old disease that has never gone away. A national comprehensive elimination of leprosy hazards plan (2024–2030) has been published by the National Disease Control and Prevention Administration of China, aiming to achieve zero leprosy-related disability and a leprosy-free world. Funding This work was supported by grants from the Academic Promotion Programme of Shandong First Medical University (2019LJ002), National Natural Science Foundation of China (82103734), the Shandong Province Taishan Scholar Project (tsqn202211346), the China Postdoctoral Science Foundation (2023M732128), and Shandong Postdoctoral Science Foundation (SDCX-ZG-202301007). Author Contributions Furen Zhang and Hong Liu designed the study. Qing Zhao drafted the manuscript. All authors edited, read and approved the final version of the manuscript. Conflicts of Interest None.