research paper on leprosy disease

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Leprosy: A Review of Epidemiology, Clinical Diagnosis, and Management

Kou-huang chen.

1 School of Mechanical and Electronic Engineering, Sanming University, Sanming, Fujian, China

Cheng-Yao Lin

2 Division of Hematology-Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, Tainan, Taiwan

3 Department of Senior Welfare and Services, Southern Taiwan University of Science and Technology, Tainan, Taiwan

4 Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan

Shih-Bin Su

5 Department of Occupational Medicine, Chi-Mei Medical Center, Tainan, Taiwan

Kow-Tong Chen

6 Department of Occupational Medicine, Tainan Municipal Hospital (Managed By Show Chwan Medical Care Corporation), Tainan, Taiwan

7 Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Associated Data

Data sharing is not applicable to this article as no dataset was generated or analyzed during the current study.

Leprosy is a neglected infectious disease caused by acid-fast bacillus Mycobacterium leprae . It primarily affects the skin and then progresses to a secondary stage, causing peripheral neuropathy with potential long-term disability along with stigma. Leprosy patients account for a significant proportion of the global disease burden. Previous efforts to improve diagnostic and therapeutic techniques have focused on leprosy in adults, whereas childhood leprosy has been relatively neglected. This review aims to update the diagnostic and therapeutic recommendations for adult and childhood leprosy. This review summarizes the clinical, bacteriological, and immunological approaches used in the diagnosis of leprosy. As strategies for the diagnosis and management of leprosy continue to develop better and more advanced knowledge, control and prevention of leprosy are crucial.

1. Introduction

Leprosy, or Hansen's disease, is a chronic bacterial infection caused by Mycobacterium leprae ( M. leprae ) infection [ 1 ]. M. leprae , the taxonomic order Actinomycetales, family Mycobacteriaceae, is an acid-fast, gram-positive obligate intracellular bacillus that demonstrates tropism for phagocytes in the skin and Schwann cells within peripheral nerves [ 2 ]. Although the 9-banded armadillo infects the wild in the southern United States, M leprae grows in the footpads of mice, which is the main method of growing M leprae in laboratories around the world [ 3 ].

Leprosy is ubiquitous in tropical countries, particularly underdeveloped and developing countries. In 1990, the World Health Organization (WHO) proposed the global goal of eliminating leprosy by the end of the 20th century [ 4 ]. Despite the commitment of governments, researchers, and healthcare workers worldwide, disease control has not yet been achieved. Between 1900 and 2000, although the number of new leprosy cases remained relatively constant or slightly increased owing to intensified case-finding efforts, a significant reduction in the number of registered cases for treatment and prevalence of cases was observed during this period because of the effectiveness of multidrug therapy (MDT) and improvement in the quality of health care in patients with leprosy worldwide [ 5 ]. Figure 1 shows the geographical distribution of new leprosy cases worldwide in 2020 [ 6 ]. This indicates that the highest rates for the detection of new cases are reported by countries in the African region (AFR) and Southeast Asia region (SEAR). Of the 127 countries that reported in 2020, India, Brazil, and Indonesia continued to report the highest number of new cases (>10,000); of the 124 countries that provided data on child cases, SEAR accounted for 62% of all new-child cases. In 2016, the WHO launched a new global strategy entitled “The Global Leprosy Strategy 2016–2020: Accelerating toward a leprosy-free world” with the main objectives of reducing the number of children diagnosed with leprosy and presenting visible physical deformities to zero, all countries enacting specific legislation against discrimination, and the reduction of new leprosy cases with grade 2 disability to less than one case per million [ 7 ].

Global distribution of new leprosy cases in 2020 (source: World Health Organization/National Leprosy Program, WHO 2021) [ 6 ].

Despite control efforts, including the widespread use of MDT and stabilization of reported new case detection rates in the last few years, leprosy remains endemic in many developing countries [ 8 , 9 ]. The number of patients undergoing treatment at the end of 2019 was 202,256, with a corresponding prevalence rate of 22.9 per million people, of which 14,893 were children below 14 years of age [ 4 ]. In particular, cases still appear in various countries in Southeast Asia, America, Africa, the Eastern Pacific, and the Western Mediterranean [ 4 , 9 ]. Moreover, the high incidence rate in children under 15 years of age is important, indicating that there is early exposure of the population to the bacillus, which is associated with an elevated prevalence in the general population and is a good indicator of high transmission and poor quality of control programs [ 10 – 16 ]. In the absence of an effective vaccine, early diagnosis and treatment of the disease are important to stop the transmission of M. leprae, reduce the risk of physical disability and deformity, and reduce the physical, psychosocial, and economic burden of the disease [ 17 – 19 ]. Due to difficulties in diagnosis, lack of scientific studies on leprosy, and largely unknown outcomes in patients with leprosy, childhood leprosy reflects early exposure to M. leprae but remains neglected. Therefore, this review aimed to describe the recent advances in the epidemiology, clinical diagnosis, and management of leprosy.

2. Classification

Table 1 presents a comparison of the proposed leprosy classification. Leprosy was first classified by Rabello, and the characteristics of disease polarity have been established [ 4 , 20 ]. In 1966, Ridley–Jopling introduced a classification method for clinical leprosy based on the patient's clinical characteristics and immune status [ 21 ]. According to this classification system, the disease is divided into two poles and an intermediate state, including polar tuberculoid leprosy (TT) ( Figure 2 ), borderline tuberculoid leprosy (BT), mid-borderline leprosy (BB), borderline lepromatous leprosy (BL), and lepromatous leprosy (LL) ( Figure 3 ) [ 21 – 24 ].

Tuberculoid leprosy: lesion with a single, stable, hairless plaque, and well-defined borders (photograph courtesy of Eichelmann, et al.) [ 23 ].

Lepromatous leprosy: lesion with diffuse thickening, numerous discrete, and confluent nodules (photograph courtesy of White, et al.) [ 24 ].

Comparison of classifications of leprosy proposed by World Health Organization and Ridley–Jopling.

Note. 1+ or 2+: microscopic criteria when acid-fast bacilli were observed using Ziehl–Neelsen stain; negative, no acid-fast bacilli observed; BL, borderline lepromatous; BT, borderline tuberculoid; IND, indeterminate; LL, lepromatous leprosy; TT, tuberculoid leprosy.

Patients with a strong cell-mediated immune reaction had few lesions with low or undetectable mycobacteria and were classified as having tuberculoid forms, whereas patients anergic to M. leprae had multiple lesions with higher loads of mycobacteria and were classified as having lepromatous forms [ 21 ]. Where an affected person falls within the classification model depends on their immune response [ 22 ]. Tuberculoid forms show little evidence of M. leprae-specific antibodies but a vigorous T helper (Th)1 cytokine response, whereas lepromatous forms show a Th2 cytokine response with markedly high antibody titers but T-cell hypo-response (anergy) [ 19 , 25 ]. The balance of the Th1/Th2 response alone cannot fully explain the response to leprosy. Other T-cell subsets have been identified to play an important role in determining host immunity [ 25 ]. Tuberculoid leprosy is stable, rarely contagious, or self-limiting. The bacillus is not detectable by bacteriological analysis, but the Mitsuda reaction (lepromin test) is positive, and granulomas are typically found on biopsy. Borderline cases are classified as borderline lepromatous, borderline tuberculoid, or mid-borderline leprosy according to the pole (lepromatous or tuberculoid) they tend toward [ 21 , 22 ]. Patients who have not yet developed a cell-mediated immune response to organisms are classified as having indeterminate leprosy (IL) [ 26 ]. If left untreated, they can progress to either tuberculoid or lepromatous disease.

In 1982, the World Health Organization (WHO) established a simplified classification based on the bacterial index (BI) (density of leprosy bacilli in slit-skin examination) to access medical care in regions where medical resources are insufficient and divided the disease into paucibacillary (PB) and multibacillary (MB) cases. PB indicates those who have a BI lower than 2+, and MB patients have a BI higher than or equal to 2+ [ 27 ]. In 1988, the WHO Expert Committee on Leprosy recommended that treatment should be initiated prior to smear tests; thus, practical and rapid methods of classification were developed that do not require expensive diagnostic equipment and do not put first-line healthcare workers at risk [ 22 ]. According to this classification, PB cases are defined as those in which less than five skin lesions and/or only one nerve trunk is involved, whereas MB cases involve more than five skin lesions and/or more than one nerve trunk. However, this classification system is not perfect, because most MB cases are misclassified as PB cases with unsuitable treatment. The classification of leprosy patients into multibacillary and paucibacillary groups determines the duration of treatment. Misclassification leads to an increased risk of relapse due to insufficient treatment if a multibacillary patient is classified as having paucibacillary disease. This prolongs the time at which a patient is infected. There are reports in which the results of serological and bacteriological approaches have been found to agree substantially [ 28 ]. Slit-skin smears (SSS) with a demonstration of bacilli in biopsies (bacterial index of granuloma or BIG) are the most sensitive and effective method for identifying multibacillary cases [ 29 ]. Ridley's logarithmic scale or bacterial index was used to interpret the test results, which were recorded as a number followed by a plus mark to express the degree of abundance or scarcity of bacteria per field [ 23 ]. It has been suggested that the bacterial index of granulomas should be estimated during the diagnostic workup of paucibacillary patients.

All the above-mentioned classifications were also used to classify the clinical forms of childhood leprosy [ 20 ]. It is assumed that the largest number of childhood leprosy cases is in the indeterminate clinical form; however, there was an average proportion (23%) of this form of the disease in a study of the Brazilian childhood population [ 10 ]. A delayed diagnosis may be the reason for this paradox.

3. Leprosy Reactions

Leprosy reactions are caused by an immune response between the host and M. leprae. Leprosy reactions are an important consequence of permanent nerve damage during leprosy [ 30 ]. Leprosy reactions include acute/subacute inflammatory processes that mainly involve the skin and nerves and are the primary cause of morbidity and neurological disability. They may occur regularly at any stage of the disease, even without treatment [ 30 ]. However, this reaction can also be initiated or aggravated by effective chemotherapy due to the active destruction of bacilli during or after treatment, thereby producing an abundance of antigenic material in the immune system [ 31 , 32 ]. Leprosy reactions can be subdivided into types 1 and 2.

Type 1 reactions ( Figure 4 ) are type IV cell-mediated allergic hypersensitivity reactions that most commonly occur in the BT, BB, and BL forms [ 20 , 33 ]. This was also described as a reversal reaction. The mechanisms of these reactions involve cellular immune responses against mycobacterial antigens [ 32 , 33 ]. Type 1 reactions can be improved (reversal reactions) or worsened (degradation reactions). In these cases, the common clinical manifestations are hyperesthesia, erythema, edema, subsequent scaling, and sometimes ulceration and neuritis [ 32 , 34 ]. Approximately 95% of type 1 reaction cases occur in the first 2 years after starting MDT [ 35 ]. Timely and effective treatment before irreversible damage occurs is important in patients with type 1 reactions.

Type 1 reaction: lesions with erythema, swelling, papules, and plaques (photograph courtesy of Oliveira, et al.) [ 20 ].

A type 2 reaction ( Figure 5 ), erythema nodosum leprosum (ENL), is a type III humoral hypersensitivity reaction [ 36 , 37 ]. The ENL reaction is immunologically characterized by immune complex deposition in the tissues, blood, and lymphatic vessels [ 38 ]. It usually occurs most frequently in patients with LL and occasionally in those with BL. ENL can occur at any time during the course of leprosy but usually occurs in the first year after MDT treatment [ 39 ]. The most common manifestation of type 2 reactions is the rapid appearance of painful erythematous subcutaneous nodules that may ulcerate [ 37 ]. Type 2 reactions are accompanied by systemic symptoms such as fever, with changes in the patient's general health status. Approximately 60% of patients with lepromatous leprosy develop type 2 reactions that may recur several times during the course [ 37 ]. Physical and mental stress, multiple drug therapy, vaccines, pregnancy, surgical procedures, injuries, intercurrent infections, and other antibacterial treatments are exacerbating factors [ 36 ].

Type 2 reaction: lesions with erythema multiform-like bullous (photograph courtesy of Alemu Belachew, et al.) [ 36 ].

Lucio's phenomenon is a clinical variant of ENL or a third rare type of reaction. It usually occurs in Central and South America and in immigrants from these areas, although cases have also been reported in Europe and Asia [ 40 ]. The major clinical manifestations are red congestive macules that progress to blisters, hemorrhagic infarcts, and necrotic sloughs. Eventually, irregular atrophic scars are left behind [ 38 , 41 ]. Other findings include alopecia of the eyebrows and eyelashes, destructive rhinitis with nasal septal perforation, eruptive telangiectasia, hepatosplenomegaly, and lymphadenopathy [ 42 ]. If not treated immediately, patients can die owing to superinfection and sepsis [ 43 ].

Generally, children do not present with leprosy. Some studies have shown a low frequency of lepra reactions, varying between 1.36% and 29.7% [ 44 – 46 ]. Type 1 reactions were the most common, given that the most frequent clinical form is borderline BT [ 20 ]. Although children have a low risk of morbidity with leprae reactions, children with neural thickening have a higher risk of developing deformities (10–30%) than those without neural enlargement [ 47 – 49 ].

Taken together, leprosy reactions are consequences of the dynamic immune response to M. leprae that may occur before, during, or after the completion of MDT for leprosy. It is the main cause of nerve damage and disability in children with leprosy. Children are a vulnerable social group and cannot be expected to seek help from health professionals. Therefore, it is important to ensure that families are involved in monitoring the signs and symptoms of leprosy in their children.

4. Diagnosis

4.1. clinical findings.

Clinical evaluation is the first step in the diagnosis of leprosy and is generally sufficient in most cases. However, one of the challenges in diagnosing leprosy is simply to consider this disease in the list of differential diagnoses, particularly in developed countries where leprosy has almost been eradicated or is extremely rare [ 26 ]. Obtaining travel or family history (e.g., adopted or immigrated from an endemic area) is important when considering a diagnosis of leprosy. In addition, practical information about the protective measures of the care team (e.g., high index of suspicion and wearing gloves) to prevent transmission should be included.

Skin lesions are usually the first clinical manifestation observed. If appropriate medical treatment is not received, leprosy may progress to cause permanent damage to the skin, nerves, limbs, and other organs [ 36 ]. WHO experts have listed the main diagnostic criteria as follows [ 22 ]: (1) a hypopigmented or erythematous skin lesion or reddish skin patch with definite loss of sensation; (2) a thickened or enlarged peripheral nerve with loss of sensation and/or weakness of muscle supplied by the nerve; and (3) a positive acid-fast skin smear or bacilli observed in a skin smear/biopsy. When all three signs were present, diagnostic accuracy was as high as 95% [ 26 , 36 ].

The borderline TT form was the most common clinical type in children, followed by the borderline BT form [ 48 , 50 ]. In children, a single lesion exists in the exposed area, and a small portion of the lesions are present (<8%) in the gluteal region [ 51 – 53 ]. In other words, the entire body is likely to present leprosy lesions. Therefore, nerve endings may be involved in the early stages of leprosy. In some patients, M. leprae invades both sensory and autonomic nerves, causing a reduction in cutaneous sensation and absence of sweating [ 19 , 20 ]. However, musculoskeletal presentations also cause leprosy in the differential diagnosis of other autoimmune diseases such as juvenile idiopathic arthritis [ 54 ].

The clinical diagnosis of leprosy is dependent on the recognition of disease signs and symptoms and is therefore only possible once the disease has manifested. Physical examination does not identify the early stages of the disease when clinical manifestations are rare [ 36 , 53 ]. Previous studies showed that untrained health practitioners may not be effective in recognizing early signs of the disease [ 36 , 55 ]. It is likely that clinical diagnosis is delayed or even missed, especially in regions where leprosy is controlled [ 56 ]. This finding might be related to a long delay between disease onset and diagnosis as well as a high rate of disability in grade 2 among new-child patients. In addition, it is difficult to conduct a thermal reaction test in younger children, which is necessary for the differential diagnosis of other childhood cutaneous lesions. Simple and objective tests to detect leprosy infection are necessary to assist clinicians in the early diagnosis of leprosy and to detect leprosy before its clinical signs manifest.

4.2. Slit-Skin Smear Test

Bacilloscopic examination is an important method for accurate diagnosis. The preferred sites for sample collection are active lesions or lesions with altered sensitivity, as well as the ear lobes and contralateral elbow [ 57 ]. In the absence of injury, intradermal shaving can be performed in both the ear lobes and elbows [ 50 ]. The slit-skin smear test has a specificity of 100% and sensitivity of 50% [ 57 – 59 ]. A smear from the nasal mucosa, ear lobe, forehead, chin, extensor surfaces of the forearms, knee, cooler parts of the body, and/or skin lesions was the preferred site for sample collection. After collection, Fite staining or modified Ziehl–Neelsen staining was used to examine acid-fast bacilli (AFB) and calculate the Ridley logarithmic scale or bacterial index (BI) score [ 23 , 60 ]. A positive result indicated that the patient had MB. However, a negative result does not rule out a clinical diagnosis of leprosy and does not necessarily classify the patient as having PB. The AFB staining technique requires the presence of at least 10 4 organisms per gram of tissue for reliable detection under a microscope; thus, organisms have a very low sensitivity of detection [ 60 ].

Microscopic examination revealed positive bacilli (9.3%–25%) in children [ 12 , 44 ]. Household contact is an important risk factor for infection in children [ 61 ]. According to Cuba's experience, 89% of diagnosed cases have at least one case of leprosy in their family [ 62 ]. Therefore, a family history can be used as a diagnostic tool.

4.3. Skin Biopsy and Histopathologic Examination

Skin biopsy is an important diagnostic tool for leprosy. A biopsy was obtained from the leading margins of the most recent and active skin lesions with the entire thickness of the dermis, at least a portion of the subcutaneous fat lesion, and stained according to the Fite-Faraco method [ 63 , 64 ]. Tissue samples were used for the diagnosis. They were collected from lesions on the body, stained with hematoxylin-eosin and Fite tissue stains, and examined for the type, extent of involvement, infiltrate characteristics, and AFB. Biopsy specimens may be further analyzed for granuloma fraction, bacterial index of granuloma (BIG) for grading AFB in tissues, and histopathological index [ 23 ]. BIG is a method used to detect AFB bacilli in a given tissue volume [ 26 , 29 ]. Histopathological examination can be useful for verifying the type of leprosy and differentiating a leprosy reaction [ 23 , 64 ]. Histopathological findings are used as criteria in the Ridley–Jopling spectral classification that defines five spectral types of leprosy (TL, BT, BB, BL, and LL) [ 21 ]. At the tuberculoid pole, bacilli are scarce, whereas at the lepromatous pole, an inflammatory infiltrate containing Virchow's cells is replete with bacilli.

The specificity of skin biopsy specimens and histopathological examination ranges from 70% to 72%, but the sensitivity ranges from 49% to 70% [ 65 , 66 ]. Among the 100 newly diagnosed untreated leprosy patients classified into the PB and MB groups according to the WHO classification, the sensitivity and specificity of the WHO classification were 63% and 85%, respectively, using the results of the slit-skin smear test and skin biopsy examination as gold standards [ 66 ]. This indicates that the accuracy of the present clinical classification can be further improved by adding more knowledge of diagnostic criteria.

The accuracy of skin biopsy examination depends on the appropriate selection of the location for biopsy, the representative sample size of skin biopsy, and the experience of the pathologist in leprosy examination [ 49 , 63 ].

4.4. Lepromin Test

The lepromin test is an intradermal injection of the lepromin antigen (inactivated M. leprae extracted from lepromas) into the flexor surface of the forearm, and the delayed-type hypersensitivity (DTH) reaction is read at two time points. On inspection, there is an early (Fernandez) reaction and the other for a late (Mitsuda) reaction. Fernandez reaction was performed for 24 or 48 h. The Mitsuda reaction was read at 21 days and indicated resistance to Bacillus . A nodule measuring >5 mm indicates positivity [ 67 , 68 ]. While patients with TT/BT evoke a strong DTH skin reaction, those with BL/LL fail to develop any skin reaction to lepromin [ 69 ]. A previous study showed that there was no difference in the mean reaction size between household contacts and noncontact testing with two soluble antigens of M. leprae , indicating that these antigens are not useful for the diagnosis of leprosy [ 69 ]. However, lepromin tests (lepromin H and lepromin A) are useful for confirming disease classification and prognosis [ 68 ]. Lepromin antigen tends to prime the immune response and is not specific for leprosy. Earlier skin test antigens for leprosy (lepromin A, Rees antigen, and Convit antigen) have been used for nearly 40 years and have been proven safe when used in humans [ 67 ]. Recently, two new skin test antigens, Mycobacterium leprae soluble antigens (MLSA) devoid of glycolipids, particularly lipoarabinomannan (LAM), called MLSA-LAM, and MLCwA ( M. leprae cell wall-associated antigens), derived from M. leprae grown in armadillos, were produced. A clinical trial [ 68 ] showed that both antigens at low doses had a sensitivity of 20% and 25% in BT/TT leprosy patients, but specificity was 100% and 95%; at the high dose of both antigens, sensitivity was 10% and 15%, specificity was 70% and 60%, and BL/LL leprosy patients were anergic to the leprosy antigens [ 70 ].

Overall, early skin test antigens (lepromin A) for leprosy are safe when used in humans. Lepromin tests have poor accuracy for diagnosing leprosy in children. Lepromin tests have several shortcomings, including inconsistent readings due to soft rather than hard DTH reactions in some individuals, variation in potency between batches due to quality control issues, and lack of adequate sensitivity and specificity [ 68 ]. These tests are still useful for confirming classification and prognostic purposes.

4.5. PCR Tests

Active surveillance and early detection of the disease are imperative to prevent the spread of M. leprae and the burden of disability in society [ 12 , 13 ]. Polymerase chain reaction (PCR) is a molecular technique used to detect deoxyribonucleic acid (DNA) in M. leprae and M. lepromatosis . A large proportion of early cases of leprosy in children remain AFB-negative on skin smear [ 71 ]. Such cases require additional techniques to confirm the diagnosis. In situ PCR on slit-skin smears is minimally invasive and less cumbersome than skin biopsy [ 72 ]. PCR is reported to have a higher sensitivity (87–100%) in patients with a positive BI or LL type; however, PCR sensitivity can be lower (30–83%) in patients with a negative BI or TT type [ 73 ].

Over the past 30 years, PCR methods have been developed to amplify various gene targets in M. leprae . PCR techniques have been used to detect possible environmental sources for the dissemination of M. leprae as well as the aerosol route of infection by means of nasal carriage [ 74 – 77 ]. The summary sensitivity of the PCR test was 75.3% (95% CI 67.9–81.5), and the specificity was 94.5% (91.4–96.5) [ 70 ].

Quantitative polymerase chain reaction (qPCR) is at least 20 times more sensitive than microscopic detection and has become increasingly important for early diagnosis and difficult-to-diagnose cases [ 78 ]. The summary sensitivity of the qPCR test was 78.5% (95% CI 67.9–89.2), and the specificity was 89.3% (61.4–97.8) [ 78 , 79 ].

Thus, PCR is a molecular technique used to confirm the clinical diagnosis of leprosy. PCR is highly sensitive in patients with MB; however, its sensitivity is much lower in patients with PB. PCR is typically used to support the clinical diagnosis of leprosy. However, PCR is an expensive and laboratory-intensive technique, and most endemic countries cannot routinely perform it [ 74 , 75 ].

4.6. Serology Test

Phenolic glycolipid 1 (PGL-1) is the most frequently studied antigen. The chemical structure of PGL-1 is a specific antigen of M. leprae . In 1981, serological tests using PGL-1 antigen for diagnosis were performed [ 80 , 81 ]. This antigen in the cell wall is responsible for the immunological specificity of tests. PGL-1 serology, mainly using ELISA, rapid anti-PGL-1 assays, and lateral flow immunochromatographic assays, is considered surrogate marker for bacterial load and can aid in the clinical treatment of patients [ 81 – 84 ]. Anti-PGL-1 serology can identify patients early, provide early treatment, and reduce nerve damage and disability [ 84 , 85 ]. PGL-1 antibody detection is useful in MB cases but is of little use in patients with PB. A previous study showed that the positive predictive value (PPV), negative predictive value (NPV), and sensitivity of the PGL-1 test in patients with MB were 43.4%, 94.6%, and 76.8% [ 86 ].

Overall, serological tests aim to detect PGL-1 antibodies that indicate M. leprae infections. These tests can be used to monitor the effectiveness of therapy, investigate the prevalence of diseases, and explore the distribution of infections in a population. Of all available serological tests, the summary sensitivity of ELISA was 63.8% (95% CI 55.0–71.8), and the specificity was 91.0% (95% CI 86.9–93.9); the summary sensitivity of the lateral flow test was 67.9% (95% CI 58.7–75.9); the summary sensitivity of the agglutination test was 72.8% (95% CI 55.8–83.7), and the specificity was 90.1% (95% CI 61.2–98.1) [ 70 ]. Although serological tests have not proven sufficient for diagnosing leprosy, several studies have been conducted in Cuba using kits for the detection of PGL-1 antibodies [ 62 ]. In the future, this tool may become a possible strategy for actively searching for new cases of leprosy in children.

4.7. Other Diagnostic Procedures

Electrophysiological nerve tests include nerve conduction studies and needle electromyography (EMG). These tests give us to provide information on the extent of nerve involvement and distribution of lesions [ 87 ]. The sensitivity of the nerve conduction test for leprosy diagnosis is 88%, whereas EMG used in conjunction with nerve conduction tests does not have a synergistic effect [ 88 ]. A nerve biopsy specimen examination is a confirmatory test in cases of pure neural leprosy and should be performed when leprosy is suspected and skin lesions are absent [ 89 ].

Ultrasonography of the peripheral nerves in leprosy to measure the extent of peripheral nerve thickening is a low-cost, noninvasive technology [ 90 ]. This test has been used for more than 20 years to diagnose leprosy. Ultrasonography of the nerves is a useful tool for objective assessment of nerve involvement in leprosy.

Taken together, clinical evaluation is the first step in the diagnosis of leprosy and is generally sufficient in most cases. The clinical diagnosis of leprosy is dependent on the recognition of disease signs and symptoms and is therefore only possible once the disease has manifested. Leprosy diagnosis in childhood may be more difficult than that in adults and involves confusing sensory testing. Untrained health practitioners may not be effective in recognizing the early signs of the disease. Therefore, obtaining travel and family history is important for the diagnosis of leprosy. The application of auxiliary laboratory-based tools is beneficial for supporting clinical diagnosis and classification. Table 2 presents the sensitivity and specificity of different diagnostic tests.

Comparisons between the sensitivity and specificity among the various diagnostic tests for leprosy.

Because the disease presents diverse dermatologic and neurologic manifestations with a wide clinical spectrum, many such diseases should be considered in the differential diagnosis ( Figure 6 ) [ 91 ]. The differential diagnoses of leprosy are broad and varied. Loss of pinprick or light-touch sensation is helpful in distinguishing leprosy from other disorders. Loss of sensation or neuropathy may not always be present, and obtaining a skin biopsy specimen can aid in differential diagnosis.

Lepromatous leprosy: skin lesions resembling guttate psoriasis, prurigo nodularis, or hypertrophic lichen planus (photograph courtesy of Kundakci, et al.) [ 91 ].

5. Treatment

A multidrug therapy regimen has been recommended by the WHO for the treatment of children according to age and the subdivision of these cases into paucibacillary and multibacillary forms ( Table 3 ) [ 22 ]. Rifampicin, clofazimine, and dapsone (diaminodiphenyl sulfone) were used as the first-line treatments. Paucibacillary cases were treated for six months with rifampicin, dapsone, and clofazimine. Multibacillary cases were treated with rifampicin, dapsone, and clofazimine for 12 months. All patients received this drug combination monthly, under supervision.

Summarized the treatment regimen recommended from World Health Organization.

In the United States, the regimens recommended by the National Hansen's Disease Program (NHDP) have a longer treatment period because of fewer cost restrictions and exclusion of clofazimine in PB treatment ( Table 4 ) [ 92 ].

Summarization of the treatment regimen recommended by the National Hansen's Disease Program and the United States Health Resources and Services Administration.

Minocycline, ofloxacin, and clarithromycin are among the drugs used as second-line treatments. The strengths of multidrug therapy include the prevention of resistance to dapsone, rapid decline in the infectivity of infected individuals, and low rate of recurrence and reactions [ 36 ]. Nonetheless, the treatment period is long and presents logistical problems, which makes adherence difficult to achieve.

Patients with leprosy and severe nerve damage, musculoskeletal disorders, and deformities may experience discrimination at school and difficulties in the social lives of patients with leprosy. Therefore, early diagnosis and treatment can reduce the transmission and disease sequelae in children. However, it is difficult for children to take medication in the form of tablets and capsules, and it is also impossible to chew capsules, which can subsequently lead to an inappropriate dose for treatment. The lack of medicines made for children in the form of oral solutions is a limiting factor for treatment adherence.

6. Prevention

6.1. prophylactic immunization.

The aim of prophylactic immunization is to prevent infection, disease progression, or the administration of vaccines before or after exposure. Several vaccines, such as Bacille Calmette–Guérin (BCG), LepVax, and Mycobacterium indicus pranii (MIP), have proven effective [ 93 ]. However, currently, BCG is the only vaccine administered to prevent leprosy [ 94 , 95 ]. In eastern India, a study was performed on patients with leprosy up to the age of 12 years attending a tertiary care hospital [ 96 ]. The nonvaccinated group had a significantly higher proportion of MB leprosy cases than the BCG-vaccinated group ( p =0.0352). This study highlights the role of BCG vaccination in enhancing cell-mediated immunity (CMI). Overall, the protection of BCG vaccination against leprosy was estimated to range from 20% to 90% [ 97 , 98 ].

However, leprosy remains prevalent in countries with widespread BCG vaccination programs, and as is the case for tuberculosis (TB), the protection afforded by BCG vaccination against leprosy appears to wane over time [ 99 ]. In addition, a study conducted from June 1987 to December 2006 to explore the effectiveness of BCG vaccination against leprosy showed that the protection of BCG vaccination appears to be better against the MB form than against the PB form [ 100 ]. However, the efficacy of the BCG vaccination remains controversial. Therefore, the development of more effective vaccines is essential. It can be used in addition to or instead of the BCG vaccine.

6.2. Chemoprophylaxis

In the 1960s, chemoprophylaxis using dapsone for leprosy exposure was reported [ 101 ]. For chemoprophylaxis, trials were performed with dapsone/acedapsone, rifampicin, and a combination of rifampicin, ofloxacin, and minocycline (ROM). Previous studies have indicated that a single dose of rifampicin (SDR) (25 mg/kg) administered to close contacts of new leprosy patients reduces the risk of developing clinical leprosy by 57% (95% CI 33–72) [ 102 , 103 ]. Between 2015 and 2018, single-dose rifampicin postexposure prophylaxis (SDR-PEP) was conducted in the Union Territory of Dadra and Nagar Haveli (DNH) [ 104 ]. This study indicated that field-based leprosy research programs should focus on health systems.

In addition, another study conducted on results from Bangladesh who participated in this study showed that the additive protective effect of BCG and rifampicin was 80% (95% CI 50–92) [ 105 ]. This finding highlights the possibility that combined treatment strategies can reduce the incidence of leprosy. SDR postexposure prophylaxis was recommended by the WHO in 2018 and has been favored as postexposure prophylaxis for a few years; BCG vaccination may extend this [ 22 ]. However, the extent to which SDR suppresses excess leprosy cases after BCG vaccination is difficult to establish because many cases appear before SDR intervention [ 106 , 107 ]. Further studies on chemoprophylaxis for leprosy prevention are needed [ 108 ].

7. Conclusion

Leprosy is a major public health concern worldwide. All healthcare workers must have basic knowledge of this disease to diagnose it, treat patients in a timely manner, and prevent disability and/or disease spread. The development of improved diagnostic and therapeutic methods for leprosy remains a significant challenge. This review provides some knowledge on the epidemiology, clinical diagnosis, and management of leprosy and makes it possible to eliminate leprosy worldwide. Further studies on the impact of leprosy on stigma, discrimination, and mental health are required.

Data Availability

Conflicts of interest.

The authors declared no conflicts of interest.

Authors' Contributions

Kou-Huang Chen and Cheng-Yao Lin contributed equally to this work.

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Open Access

Peer-reviewed

Research Article

Presenting symptoms of leprosy at diagnosis: Clinical evidence from a cross-sectional, population-based study

Roles Conceptualization, Formal analysis, Investigation, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing

Affiliations Beijing Tropical Medicine Research Institute, Beijing Friendship Hospital, Capital Medical University, Beijing, China, Beijing Key Laboratory for Research on Prevention and Treatment of Tropical Diseases, Capital Medical University, Beijing, China

Roles Data curation, Project administration, Resources, Supervision

Affiliation Yunnan Center for Disease Control and Prevention, Yunnan, China

Roles Data curation, Funding acquisition, Project administration, Resources, Validation

* E-mail: [email protected]

• Xiaohua Chen, 
• Shun Zha, 
• Tie-Jun Shui

• Published: November 23, 2021
• https://doi.org/10.1371/journal.pntd.0009913
• Reader Comments

Leprosy is associated with different dermatologic and neurologic manifestations within a wide clinical spectrum, causing a great diagnostic challenge. Therefore, we aimed to examine associations between common presenting symptoms of leprosy and stage at diagnosis.

Methodology/Principal findings

In this cross-sectional study, we analyzed population-level data from the Leprosy Management Information System (LEPMIS) in Yunnan, China, from 2010–2020 and enrolled patients with newly detected leprosy. The data of 2125 newly detected leprosy patients, with 5000 symptoms, were analyzed. Numbness (828/5000, 16.56%), erythema (802/5000, 16.04%), Painless nor pruritic skin lesions (651/5000, 13.02%), eyebrow hair loss (467/5000, 9.34%), and tubercles (442/5000, 8.84%) were common symptoms of leprosy. The symptoms related to skin (1935/2533, 76.39%) and leprosy reaction (279/297, 93.94%) were mainly existed in MB group. While the symptoms related to disability (263/316, 83.49%), clinical feature (38/56, 69.09%), and facial features (19/23, 82.61%) were predominantly presented in delayed diagnostic group. Despite low proportions, formic sensation (99/5000, 1.98%), pain (92/5000, 1.84%), pruritus (56/5000, 1.12%), finger contracture (109/5000, 2.18%), muscle atrophy (71/5000, 1.42%), and motor dysfunction (18/5000, 0.36%) were reported during the diagnosis of leprosy. The proportions of skin, skin and nerve, and nerve symptoms as initial symptoms were 33.25%, 44.95%, and 21.80% and as only symptoms were 28.66%, 57.81%, and 13.91%, respectively. In those with physical disability, nerve symptoms were the most frequent symptoms (57.65% and 65.36% for the initial and only symptoms, respectively) compared with skin and skin and nerve symptoms. In the delayed diagnosis group, nerve symptoms were the most frequent symptoms (15.73% and 17.25%) and were associated with the longest diagnostic intervals (mean±SD: 38.88±46.02 and 40.35±49.36 months for initial and only symptoms, respectively) when compared with skin and skin and nerve symptoms.

Conclusions

Understanding the nature of presenting symptoms and developing symptom awareness campaigns would improve the level of leprosy awareness in the community. As nerve symptoms were related to a higher proportion of physical disability and longer diagnosis interval, we should increase awareness about nerve symptoms. Individuals with nerve symptoms should be considered the target group. Neurology outpatient visits may provide potential screening opportunities, and holding focused training for specialized neurology medical staff would enhance the capacity of the health system to recognize leprosy early.

Author summary

Early diagnosis is key in leprosy control; however, the diagnosis of leprosy is still challenging. In this study, we reviewed the common and rare symptoms of leprosy. Numbness, erythema, painless nor pruritic skin lesions, eyebrow hair loss, and tubercles were common symptoms of leprosy. Despite low proportions, formic sensation, pain, pruritus, finger contracture, muscle atrophy, and motor dysfunction were also reported by leprosy patients. As initial symptoms at symptom onset and only symptoms at diagnosis, nerve symptoms were associated with a greater degree of physical disability and a longer diagnosis interval than skin and skin and nerve symptoms. Understanding the presenting symptoms in detail would improve the level of leprosy awareness in the community. Increasing awareness of nerve symptoms, focusing on individuals with nerve symptoms at neurology outpatient visits, and holding focused training for medical staff specializing in neurology would enhance the capacity of the health system to recognize leprosy early.

Citation: Chen X, Zha S, Shui T-J (2021) Presenting symptoms of leprosy at diagnosis: Clinical evidence from a cross-sectional, population-based study. PLoS Negl Trop Dis 15(11): e0009913. https://doi.org/10.1371/journal.pntd.0009913

Editor: Carlos Franco-Paredes, Hospital Infantil de Mexico Federico Gomez, MEXICO

Received: April 30, 2021; Accepted: October 14, 2021; Published: November 23, 2021

Copyright: © 2021 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This study was funded by Health Commission of Yunnan Province (No:2017NS098) by TS. The funder played no role in study design, data collection and analysis, decision to publish, and preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Leprosy is a chronic granulomatous infectious disease caused by the bacterium Mycobacterium leprae (M . leprae) , an intracytoplasmic parasite of macrophages and Schwann cells. Depending on the immunologic status of the host, the clinical picture can range from localized to disseminated and self-limiting to progressive. The disease primarily affects the superficial peripheral nervous system and the skin, but it may also involve the upper respiratory tract mucosa, anterior chambers of the eyes, bones, and testes [ 1 ].

Although the prevalence and incidence rates for leprosy have been significantly reduced as a result of the control strategies of the World Health Organization (WHO), new cases still occur [ 1 ]. Every year, >200,000 new leprosy cases are registered globally. This number has been fairly stable over the past several years [ 2 ]. A total of 202,185 new cases were reported from 160 countries in 2019, corresponding to the global new-case detection rate of 25.9 per one million population, with 10,813 leprosy cases associated with grade 2 disability (G2D) at diagnosis globally. The proportion of G2D cases among new cases was 5.3%, corresponding to 1.7 per one million population.

Early diagnosis and prompt treatment of all new cases of leprosy with multidrug therapy (MDT) remain the key strategies for leprosy control [ 3 ]. However, as one of the great imitators, the disease exhibits different dermatologic and neurologic manifestations within a wide clinical spectrum, which causes a great diagnostic challenge [ 1 ]. Delayed diagnosis of leprosy has been reported globally [ 4 – 6 ].

As early diagnosis minimizes damage and disability, early symptoms need to be recognized to prevent long-term sequelae associated with irreversible nerve damage [ 6 ]. However, the presenting symptoms of leprosy, especially those associated with different diagnostic intervals, have not been described in detail. In this study, we therefore aimed to examine associations between common presenting symptoms of leprosy, different classifications of leprosy, and different diagnostic intervals using data from a population-based cohort of patients with incident leprosy.

Ethics statement

Ethical approval for this study was obtained by the ethics committee of the Yunnan CDC, Yunnan, China. The data extracted from LEPMIS, which is anonymous without individually identifying data. Individual identifying information was not available and therefore not used.

Study design

For this cross-sectional, population-based study, we analyzed data of patients included in the Leprosy Management Information System (LEPMIS) in Yunnan, China, from January 1, 2010, to December 31, 2020. Trained staff and/or experienced clinicians enter basic information about the disease and the medical data of patients into the database. The data were collated by Yunnan Center for Disease Control and Prevention (CDC).

Participants

Yunnan, China, bears a significant leprosy burden. The characteristics and types of included patients were representative of a leprosy cohort in contemporary China. Our study was restricted by available data for newly detected leprosy cases, including patients’ basic demographic information (sex, date of birth, and ethnicity) and clinical information (age at confirmed diagnosis, date of symptom onset, date of confirmed diagnosis, duration from symptom onset to confirmed diagnosis, chief complaint, leprosy reaction, grade of physical impairment, Ridley–Jopling classification, and WHO operational classification).

Newly detected leprosy cases were diagnosed by medical staff specializing in leprosy and verified by the Yunnan Province CDC. Leprosy diagnosis was established based on clinical signs and symptoms, skin smears, skin biopsies, and neurophysiologic examinations. The leprosy patients were classified into the following groups based on the Ridley–Jopling [ 7 ] classification: tuberculoid (TT), borderline-tuberculoid (BT), borderline-borderline (BB), borderline-lepromatous (BL), and lepromatous (LL) groups and indeterminate (I). Leprosy patients were also classified as multibacillary (MB) or paucibacillary (PB) according to the WHO operational classification [ 8 ].

For data analysis in this study, leprosy patients were divided into MB and PB groups. The study population was stratified by diagnostic intervals: early diagnosis and delayed diagnosis. The term “early detection” was used if the time between disease onset and diagnosis was within 2 years and the patient had grade 0 or grade 1 disability according to the WHO definition of leprosy-associated disability [ 8 ]. “Delayed diagnosis” was defined as a duration between disease onset and diagnosis of more than 2 years and/or grade 2 disability according to the WHO definition of leprosy-associated disability [ 8 ]. Information about presenting symptoms was extracted from chief complaint data. In terms of initial symptoms and only symptoms, the symptoms were divided into “skin symptoms”, “skin and nerve symptoms”, and “nerve symptoms”.

Statistical analysis

Statistical analysis involved comparisons of demographic data and symptoms among groups. The chi-square and Fisher’s exact tests were utilized to compare distributions of categorical variables between groups. The t test was used for continuous variables. Statistical analysis was performed using GraphPad Prism software version 5.0 (GraphPad Software Inc., San Diego, CA, USA), and statistical significance was assessed at the 0.05 level.

Characteristics of newly detected leprosy patients

During the eleven-year study period from 2010 to 2020, 2252 records of leprosy cases in Yunnan, China, were retrieved; 117 records were excluded because they were relapsed, imported, or revisited cases, and 10 records were excluded because they were missing chief complaint information ( Fig 1 ). As early diagnosis and delayed diagnosis are related to the grade of physical disability due to leprosy, 56 records were excluded due to a lack of a physical disability grade in the early and delayed diagnosis analysis.

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https://doi.org/10.1371/journal.pntd.0009913.g001

A total of 2125 new cases of leprosy were identified; 698 (32.85%) occurred in females, 1174 (55.25%) occurred in patients belonging to a ethnic minority, 1771 (83.34%) occurred in people between 15 and 59 years of age, 1830 (86.12%) occurred in farmers, 1534 (72.19%) occurred in married individuals, and 1969 (92.66%) occurred in those with an incomplete high school education ( Table 1 ).

https://doi.org/10.1371/journal.pntd.0009913.t001

Regarding operational classification, 1393 cases (65.55%) were MB, and 732 (34.45%) were PB ( Table 1 ). Regarding Ridley–Jopling classification, the predominant form was BL (n = 912, 42.92%), followed by BT (n = 503, 23.67%), LL (n = 284, 13.36%), TT (n = 201, 9.46%), BB (n = 197, 9.27%), and indeterminate (I) (n = 28, 1.32%) ( Table 1 ). A leprosy reaction was reported in 285 (13.41%) cases ( Table 1 ). With regard to physical disability, 1239 (58.78%) patients had grade 0 disability, 325 (15.29%) had grade 1 disability, and 415 (19.53%) had grade 2 disability ( Table 1 ).

Symptom signatures of leprosy

Among 2125 newly detected cases of leprosy disease with symptom signatures, 5000 symptoms were recorded, averaging 2.4 symptoms per case. A total of 34 distinct presenting symptoms were reported in the study population, and 76 symptoms were described in LEPMIS ( Table 2 ). The presenting symptoms were divided into symptoms related to clinical features, skin (skin appendages and skin lesions), nerves, leprosy reactions, disability, and facial and other organ features ( Table 2 ). The predominant symptoms were skin symptoms (n = 2533, 50.66%), followed by nerve symptoms (n = 1775, 35.50%), disability (n = 316, 6.32%), and leprosy reactions (n = 297, 5.94%) ( Table 3 ). Symptoms related to skin (1935/2533, 76.39%) and leprosy reactions (279/297, 93.94%) mainly occurred in the MB group. Symptoms related to disability (263/316, 83.23%), clinical features (38/56, 69.09%), and facial features (19/23, 82.61%) predominantly occurred in the delayed diagnosis group ( Table 3 ).

https://doi.org/10.1371/journal.pntd.0009913.t002

https://doi.org/10.1371/journal.pntd.0009913.t003

Skin symptoms were divided into skin lesions (n = 1877, 37.54%) and skin appendage symptoms (656, 13.12%). The common symptoms of skin lesions were erythema (n = 802, 16.04%), tubercles (n = 442, 8.84%), plaques (n = 231, 4.62%), infiltration (139, 2.78%), light-colored spots (n = 129, 2.58%), and blisters (n = 107, 2.14%). The common symptoms affecting skin appendages were eyebrow hair loss (n = 467, 9.34%) and anhidrosis and dryness (n = 189, 3.78%). Regarding nerve symptoms, the most common symptom was numbness (n = 828, 16.56%), followed by painless nor pruritic skin lesions (n = 651, 13.02%). It is worth noting that formic sensation (n = 99, 1.98%), pain (n = 92, 1.84%), and pruritus (n = 56, 1.12%) were also reported by patients with leprosy. Redness and/or swelling was the most common symptom of a leprosy reaction (n = 257, 5.14%). Finger contracture (n = 109, 2.18%), ulcers (n = 101, 2.02%), and muscle atrophy (n = 71, 1.42%) were three most common symptoms of physical disability ( Table 3 ). Injury (n = 14, 0.30%), refractory illness (n = 20, 0.22%) and weakness (n = 22, 0.26%) were related clinical features. Other involved organs included the eyes (n = 8, 0.16%), nose (n = 7, 0.14%), mouth (n = 6, 0.12%), larynx (n = 1, 0.02%), and scrotum (n = 1, 0.02%) ( Table 3 ).

Symptoms related to MB and PB leprosy

The distributions of symptoms in MB and PB patients are shown in Fig 2 . Similar proportions of clinical symptoms were found in MB and PB patients: injury [MB vs . PB, 50.00% (7/14) vs . 50.00% (7/14)], refractory illness [MB vs . PB, 55.00% (11/20) vs . 45.00% (9/20)] and weakness [MB vs . PB, 40.91% (9/22) vs . 59.09% (13/22)] ( Table 4 ). With regard to symptoms of skin appendages, no significant differences in anhidrosis and dryness (MB vs . PB, 52.38% (99/189) vs . 47.67% (90/189)] were present between MB and PB patients, while eyebrow hair loss [MB vs . PB, 95.72% (447/467) vs . 4.28% (20/467)] was predominant in MB patients ( Table 4 ). Among those reporting skin lesion-related symptoms, light-colored spots mainly occurred in PB patients [MB vs . PB, 37.21% (48/129) vs . 62.79% (81/129), while other skin lesions, including erythema (521/802, 64.69%), tubercles (438/442, 99.10%), blisters (73/107, 68.22%), papules (165/231, 71.43%), and infiltration (127/139, 91.37%) mainly occurred in MB patients ( Table 4 ). With regard to nerve symptoms, the proportions of numbness [MB vs . PB, 56.34% (464/828) vs . 43.66% (364/828)] and pain [MB vs . PB, 56.52% (52/92) vs . 43.48% (40/92)] were similar between the MB and PB patient groups ( Table 4 ). Painless nor pruritic skin lesions (408/651, 62.67%), formic sensation (77/99, 77.78%), pruritus (44/56, 78.57%) and sensory disturbance (35/49, 71.43%) were predominant in the MB group ( Table 4 ). Symptoms related to leprosy reactions, including redness and/or swelling (240/257, 93.39%), fever (26/27, 96.30%), erythema nodosum (13/13, 100.00%), and facial features (17/23, 73.91%), mainly occurred in the MB group ( Table 4 ). In contrast, some symptoms related to disability, such as finger contracture (82/109, 78.90%), muscle atrophy (56/71, 78.87%), and motor dysfunction (16/18, 88.89%), mainly occurred in the PB group, while ulcer [MB vs . PB: 54.46% (55/101) vs . 45.54% (46/101)] and shortening of the fingers and toes [MB vs . PB: 50.00% (6/12) vs . 50.00% (6/12)] occurred at similar rates in the MB and PB groups ( Table 4 ). The odds ratios of symptoms in MB and PB patients are shown in S1 Table .

https://doi.org/10.1371/journal.pntd.0009913.g002

https://doi.org/10.1371/journal.pntd.0009913.t004

Symptoms related to early and delayed diagnoses

As 56 records were missing information about the stage of leprosy, 2069 newly detected leprosy patients were included in the analysis of symptoms related to early or delayed diagnosis. In total, 1249 (58.78%) and 820 (38.59%) patients were divided into early and delayed diagnosis groups, respectively. The proportions of symptoms in the early and delayed diagnosis groups are shown in Fig 3 . Injury (10/14, 71.43%), refractory illness (11/19, 57.89%) and weakness (17/22, 77.27%), the symptoms of clinical features, were mainly present in the delayed diagnosis group. Despite the substantial proportion of patients with early diagnosis, few newly detected leprosy patients in the early diagnosis group had recorded clinical features such as injury (4/14, 28.57%), refractory illness (3/9, 33.33%), or weakness (5/22, 22.73%) ( Table 5 ). With regard to symptoms of skin appendages, no significant differences in eyebrow hair loss (59.59% vs . 41.32%) or anhidrosis and dryness [59.59% (261/438) vs . 40.41% (177/438)] was observed between the early and delayed diagnosis groups ( Table 5 ). Among those reporting skin lesion-related symptoms, erythema (555/786, 70.61%), tubercles (274/418, 65.55%), infiltration (91/132, 68.94%), and light-colored spots (80/126, 63.49%) mainly occurred in the early diagnosis group ( Table 5 ). With regard to nerve symptoms, the rates of numbness [52.40% (425/811) vs . 47.60% (386/811)] and pain [55.06% (49/89) vs . 44.94% (40/89)] were similar between the early and delayed diagnosis groups ( Table 5 ). Painless nor pruritic skin lesions (460/636, 72.33%), formic sensation (61/93, 65.59%) and pruritus (34/53, 64.15%) were predominant in the early diagnosis group ( Table 5 ). Symptoms related to leprosy reactions mainly occurred in the early diagnosis group: redness and/or swelling (151/249, 60.64%), fever (14/26, 53.85%), and erythema nodosum (10/13, 76.92%) ( Table 5 ). In contrast, symptoms related to disability, such as finger contracture (104/109, 95.41%), ulcers (74/100, 74.00%), muscle atrophy (53/71, 74.65%), motor dysfunction (16/18, 88.89%), shortening of the fingers and toes (11/12, 91.67%), claw hands and/or foot deformity (5/5, 100.00%), and facial features (19/23, 82.61%), mainly occurred in the delayed diagnosis group ( Table 5 ). The odds ratios of symptoms in the early diagnosis group are shown in S2 Table .

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https://doi.org/10.1371/journal.pntd.0009913.t005

Initial symptoms at symptom onset and only symptoms at diagnosis

A total of 2069 and 2125 newly detected leprosy patients were included in the analyses of initial symptoms and only symptoms related to physical disability and diagnosis interval, respectively. The initial symptoms at symptom onset and the only symptoms at diagnosis were divided into skin, skin and nerve, and nerve symptoms ( Table 6 ). The proportions of skin, skin and nerve, and nerve symptoms as initial symptoms were 33.25%, 44.95%, and 21.80% and as only symptoms were 28.66%, 57.81%, and 13.53%, respectively. Regarding initial symptoms, the proportions of patients with physical disability (G1D + G2D) were 28.92%, 30.32% and 57.65% for skin, skin and nerve, and nerve symptoms, respectively. Regarding only symptoms, the proportions were 25.97%, 33.78% and 65.36%, respectively. Similarly, regarding skin, skin and nerve, and nerve symptoms as initial symptoms, the proportions of patients with a diagnosis interval of more than 5 years were 8.72%, 5.70%, and 15.97%, respectively. For these symptoms as the only symptoms, the proportions were 7.25%, 7.78%, and 17.50%, respectively ( Table 6 ). In addition, for skin, skin and nerve, and nerve symptoms as the initial symptoms, the means±standard deviations (SDs) of the diagnosis intervals were 28.77±31.55, 25.60±26.20, and 38.88±46.02, respectively. For these symptoms as the only symptoms, the means±SDs of the diagnosis intervals were 27.52±28.89, 28.07±30.66, and 40.35±49.36, respectively ( Table 6 ).

https://doi.org/10.1371/journal.pntd.0009913.t006

Understanding the symptoms associated with leprosy, the subtypes of leprosy, and the diagnostic interval will help guide early diagnosis initiatives. In this retrospective analysis, we described the main complaints in newly detected leprosy patients over the past decade in Yunnan, China, a region with a high burden of leprosy, and revealed the common symptoms of leprosy and the symptoms associated with different subtypes of leprosy and different diagnostic intervals using data from a population-based cohort of patients with incident leprosy.

Information about presenting symptoms in the patient population was obtained via symptom self-reports and record-based symptom information extraction. To collect data on self-reported symptoms, information about presenting symptoms can be directly elicited from patients through semistructured interviews or questionnaires [ 9 ]. Alternatively, for record-based symptom information collection, information on presenting symptoms can be recorded during healthcare encounters (e.g., with a primary care physician) and captured as part of the patient’s health record [ 9 ]. In this study, we used the latter approach, as self-reported symptoms captured retrospectively (after diagnosis) would have a high risk of bias [ 9 ].

Presenting symptoms have been reported in numerous studies and included weakness [ 10 ], anhidrosis and dryness [ 10 ], eyebrow hair loss [ 11 ], eye closure weakness [ 12 ], a collapsed nose [ 13 ], edema [ 14 ], erythema nodosum [ 15 ], numbness [ 16 ], loss of sensation [ 10 ], pain [ 17 ], pruritus [ 18 ], muscle atrophy [ 19 ], and claw hand deformity [ 20 , 21 ]. Initially, the small sensory and autonomic nerve fibers in the skin are damaged, causing local loss of hair, an inability to sweat and difficulty detecting temperature and touch sensations. Damage to peripheral nerves can lead to widespread skin dryness, loss of sensation, and weakness or paralysis of the muscles in areas of the body supplied by the affected nerve. Eyes, hands, and feet with loss of sensation, paralysis or dryness have an increased risk of injury. Dry skin can lead to cracks. If cracks, injuries, and ulcerations are not cared for and healed, they can become infected, leading to further injury and destruction, resulting in visible damage and destruction of the eyes, hands, and feet. These are easily observed impairments; these injuries, along with paralysis, are obvious and considered grade 2 disability in leprosy [ 10 ].

A symptom signature denotes the nature and relative frequency of symptoms (or symptom combinations) at presentation to the medical facility by patients later diagnosed with leprosy or with a particular subtype or stage of leprosy. As leprosy mainly affects the skin and peripheral nervous system, skin symptoms and nerve symptoms were predominant. Numbness (nerve symptoms), erythema (skin lesions), painless nor pruritic skin lesions (nerve symptoms), eyebrow hair loss (skin appendage), and tubercles (skin lesion) were common symptoms of leprosy. Despite the low proportions, nerve (formic sensation, pain, and pruritus) and disability (finger contracture, muscle atrophy, and motor dysfunction) symptoms, which have been seldom mentioned as physical symptoms of leprosy previously, were obvious in this study.

Among the newly detected cases of leprosy with symptom signatures in this study, the majority of cases were MB cases, while minority were PB cases. Describing only the symptoms related to leprosy would lead to bias in the presenting symptoms; thus, we analyzed the symptoms related to the subtypes of leprosy in detail. Light-colored spots and pale-white spots mainly occurred in PB cases, while other skin symptoms, including erythema, eyebrows hair loss, tubercles, blisters, plaques, infiltration, and papules, mainly occurred in MB cases. Symptoms related to leprosy reactions and facial features mainly occurred in MB cases, while symptoms related to physical disability, such as finger contracture, muscle atrophy, and motor dysfunction, mainly occurred in the PB group. In addition, painless nor pruritic skin lesions, formic sensation, pruritus, and sensory disturbance were predominant in the MB group. The diverse clinical manifestations are strongly correlated with the host’s immune response to M . leprae [ 22 ]. Symptom signatures can be described as “narrow”, when most patients present with a particular symptom, or “broad”, when patients present with a wide range of symptoms [ 9 ]; eyebrow hair loss, tubercles, papules, and symptoms related to leprosy reactions, such as redness and/or swelling, fever, and erythema nodosum, which all had proportions higher than 90% in MB cases, were considered narrow signatures of MB leprosy. In this study, we also found that finger contracture, muscle atrophy, and motor dysfunction were potential symptoms of PB leprosy.

Early diagnosis is an important aspect of leprosy control strategies, as early case detection, regular and complete MDT, and early detection of impairment and disability have played a pivotal role in reducing the disease and disability burdens in the community [ 2 ]. Awareness of presenting symptoms will improve the level of leprosy awareness in the community and the capacity of the health system to recognize leprosy early, thus influencing the length of the interval from symptom onset to presentation (the patient interval) and from initial presentation to specialist referral (the primary care interval) [ 5 ]. We described the symptoms related to the different stages of diagnosis. All the skin and leprosy reactions symptoms and some of the nerve symptoms, including painless nor pruritic skin lesions, formic sensation, and pruritus, mainly existed in the early diagnosis group, while all symptoms related to clinical features, facial features and physical disability mainly occurred in the delayed diagnosis group. Finger contracture, shortening of the fingers and toes, and claw hand and/or foot deformity were regarded as narrow signatures and associated with delayed diagnosis of leprosy. It is worth noting that painless nor pruritic skin lesions, formic sensation and pruritus occurred in not only the MB group but also the early diagnosis group, while symptoms related to physical disability, such as finger contracture, muscle atrophy, and motor dysfunction, were associated with not only PB but also delayed diagnosis, which implies that diagnosis of PB leprosy, which usually presents as physical disability even in the early stage of disease onset, is a critical problem that needs further research.

Leprosy neuropathy is considered the most common peripheral neuropathy with an infectious etiology worldwide and a public health problem [ 23 ]. Diagnosing leprosy in the absence of typical dermatological features is challenging, and a lack of features frequently causes a delay in diagnosis [ 24 ]. Primary neural leprosy (PNL), also known as pure neural or neuritic leprosy, was initially described in the Indian classification in 1955 [ 25 ]. Since then, it has been a challenge to clinically diagnose, as no skin lesions occur and slit skin smear bacilloscopy is negative. In a previous study, 4–8% (up to 18% in some Indian case series) of patients with leprosy may present with PNL, characterized by evidence of nerve deficit or thickening, with or without tenderness in the absence of skin involvement [ 26 ]. According to another Indian study, on average, PNL accounts for 5–17.7% of all leprosy cases [ 27 ]. In this study, 21.80% and 13.53% of the newly detected leprosy patients presented with nerve symptoms as the first symptoms and the only symptoms, respectively, consistent with previous studies. Despite having the lowest patient proportion, the nerve symptom group had the highest proportion of physical disability and the longest diagnosis interval compared with the skin and skin and nerve groups. These results imply that we should increase awareness of nerve symptoms. Individuals with nerve symptoms should be considered the new target population, neurology outpatients should undergo leprosy screening, and focused training should be provided for specialized neurology medical staff to enhance the capacity of health systems to recognize leprosy early.

In summary, this study provides a detailed description of the symptom signatures of leprosy, including MB/PB leprosy, leprosy with an early/delayed diagnosis, leprosy for which the first/only symptoms are physical disability and leprosy diagnosed at different intervals, among newly detected leprosy patients. Numbness, erythema, painless nor pruritic skin lesions, eyebrow hair loss, and tubercles were common symptoms of leprosy. Despite their low proportions, formic sensation, pain, pruritus, finger contracture, muscle atrophy, and motor dysfunction were reported during the diagnosis of leprosy. In detail, finger contracture, muscle atrophy, and motor dysfunction mainly occurred in the PB group. These symptoms, along with other symptoms related to disability, were predominantly in the delayed diagnosis group. This implies that leprosy diagnosis, especially PB leprosy diagnosis, is still a challenge. As nerve symptoms were related to physical disability and a longer diagnosis interval, increasing awareness of nerve symptoms would be helpful for preventing physical disability and promoting the early detection of leprosy cases.

To our knowledge, this is the largest study to date to examine the symptoms of newly detected leprosy cases before diagnosis. Our findings are based on a large cohort of newly detected leprosy patients and self-reported data on symptoms, WHO classification, diagnosis interval and physical disability. The study participants were largely representative of leprosy patients nationwide, with some underrepresentation of reversal reaction and erythema nodosum leprosum.

This study has some limitations. First, as there is no standard assessment tool for risk of bias in observational nonrandomized studies, we could not evaluate the risk of bias. Second, because the disease exhibits different dermatologic and neurologic manifestations within a wide clinical spectrum, many diseases should be considered in the differential diagnosis [ 1 ]. We described only the symptoms relevant to leprosy and did not describe the symptoms used to form the differential diagnosis. Despite suspected symptoms, a leprosy diagnosis still needs to be confirmed with a special medical examination performed by trained medical staff according to the criteria of leprosy diagnosis. Third, the clinical features of the disease depend on bacterial proliferation, the immunologic response of the host to M . leprae , and peripheral neural involvement. According to the clinical features, leprosy can be divided into indeterminate leprosy, TT, BT, BB, BL, LL, type I leprosy reaction (reversal reaction), type II leprosy reaction, and some rare clinical forms, such as pure neural-type leprosy, histoid leprosy, localized lepromatous or borderline disease, and Lucio leprosy (lepra bonita) (erythema nodosum leprosum reaction) [ 1 ]. The number of leprosy patients enrolled in this study was limited; therefore, it was difficult to cover every subtype of leprosy. Further investigations in larger populations will increase confidence in the diagnostic and discriminatory value of the suspected symptoms.

In conclusion, the diagnosis of leprosy is still challenging because leprosy is one of “the great imitators” and a disease with “many faces” [ 1 ]. Expanding knowledge about the presenting symptoms will be helpful in the detection new leprosy cases. Elucidating suspected symptoms of leprosy would improve the clinical diagnosis rate and promote early diagnosis, thereby preventing physical disability in leprosy patients.

Supporting information

S1 table. odds ratios of mb of leprosy disease by presenting symptoms..

https://doi.org/10.1371/journal.pntd.0009913.s001

S2 Table. Odds ratios of early diagnosis of leprosy disease by presenting symptoms.

https://doi.org/10.1371/journal.pntd.0009913.s002

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• 8. WHO. World health organization expert committee on leprosy: Seventh report. Technical Report Series 847. Geneva: WHO; 1998.

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• Published: 12 November 2020

A comprehensive research agenda for zero leprosy

• Peter Steinmann   ORCID: orcid.org/0000-0003-4800-3019 1 , 2 ,
• Courtenay Dusenbury 3 ,
• David Addiss 4 ,
• Fareed Mirza 5 &
• W. Cairns S. Smith 6  

Infectious Diseases of Poverty volume  9 , Article number:  156 ( 2020 ) Cite this article

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Leprosy control achieved dramatic success in the 1980s–1990s with the implementation of short course multidrug therapy, which reduced the global prevalence of leprosy to less than 1 in 10 000 population. However, a period of relative stagnation in leprosy control followed this achievement, and only limited further declines in the global number of new cases reported have been achieved over the past decade.

In 2016, major stakeholders called for the development of an innovative and comprehensive leprosy strategy aimed at reducing the incidence of leprosy, lowering the burden of disability and discrimination, and interrupting transmission. This led to the establishment of the Global Partnership for Zero Leprosy (GPZL) in 2018, with partners aligned around a shared Action Framework committed to achieving the WHO targets by 2030 through national leprosy program capacity-building, resource mobilisation and an enabling research agenda. GPZL convened over 140 experts from more than 20 countries to develop a research agenda to achieve zero leprosy. The result is a detailed research agenda focusing on diagnostics, mapping, digital technology and innovation, disability, epidemiological modelling and investment case, implementation research, stigma, post exposure prophylaxis and transmission, and vaccines. This research agenda is aligned with the research priorities identified by other stakeholders.

Conclusions

Developing and achieving consensus on the research agenda for zero leprosy is a significant step forward for the leprosy community. In a next step, research programmes must be developed, with individual components of the research agenda requiring distinct expertise, varying in resource needs, and operating over different timescales. Moving toward zero leprosy now requires partner alignment and new investments at all stages of the research process, from discovery to implementation.

Following dramatic progress between 1980 and 2000, the control of leprosy (also known as Hansen’s disease), and reduction of the deep-rooted stigma and discrimination against people affected by the disease, have slowed considerably over recent years [ 1 , 2 ]. In 2019, 202 185 new leprosy diagnoses were reported to the World Health Organization (WHO) [ 3 ]. The global implementation of multidrug therapy (MDT) for leprosy was a game-changer in the 1980s and 1990s [ 4 ]. The 1991 World Health Assembly (WHA) approval of a resolution to eliminate leprosy as a public health problem triggered the donation of MDT drugs to the WHO and innovations in leprosy case management and documentation, which led to a sharp reduction in the registered global prevalence of leprosy to less than 1 in 10 000 population [ 5 ]. Unfortunately, this strategy did not have a sustained impact on disease incidence; success and the perception that leprosy was no longer a problem led to a loss of political commitment to leprosy control, resulting in reduced resource allocation [ 4 ].

In September 2016, during the 19th International Leprosy Congress in Beijing, leading stakeholders called for the creation of a partnership to advance zero leprosy to achieve true elimination. Following extensive consultations, the Global Partnership for Zero Leprosy (GPZL) ( https://zeroleprosy.org/ ) was formally established in 2018. It has over 700 members with a broad range of experience and expertise, and is managed by a leadership team and secretariat. GPZL’s vision of “no disease, no disability, and no discrimination/stigma” is in line with the targets and objectives of the WHO Global Leprosy Programme ( https://www.searo.who.int/entity/global_leprosy_programme/en/ ), the International Federation of Anti-Leprosy Associations (ILEP; https://www.ilepfederation.org/ ), the Sasakawa Health Foundation, Novartis International and other key stakeholders. Members of the partnership have aligned around a shared Action Framework to achieve WHO’s 2030 global leprosy targets [ 6 ] through collaboration on country-led planning and capacity building, resource mobilization, and an enabling GPZL research agenda.

This Policy Platform describes the development, content and conclusions of the GPZL research agenda as well as the next steps in resourcing and implementing it. The leprosy community has diverse expertise and strong national and international dimensions, including in research, where the International Leprosy Association facilitates an International Leprosy Congress every three years. There are also national and regional leprosy associations, with a geographically-defined focus and often strong anchoring in local academic bodies. Global and local associations of people affected by leprosy, and non-governmental organisations working in leprosy, play an important role. Leprosy research is funded through grants from public and private bodies while national leprosy program directors and ministries of health are at the front line of defining implementation research needs. Consensus on any leprosy research agenda therefore has to involve all these stakeholders in order to be successful.

Research agenda development

The GPZL Leadership Team appointed a chair in early 2018 to coordinate the development of the research agenda, with support from a senior expert advisor and the GPZL Secretariat. A working group was established with subgroup facilitators who led discussions across eight topic areas that had been selected by the Leadership Team members as priorities: (i) diagnostics; (ii) mapping, digital technology and innovation; (iii) disability; (iv) epidemiological modelling and investment case; (v) implementation research; (vi) stigma; (vii) post-exposure prophylaxis (PEP) and transmission; and (viii) vaccines. An open call for participants was issued to recruit experts and persons who had experienced leprosy. The research agenda process strived to engage the diversity of the leprosy community as well as the broader neglected tropical diseases (NTD) community to ensure agreement and ownership of the research priorities. Overall, more than 144 persons from over 20 countries signed up to participate.

A mapping of past initiatives to define leprosy research priorities, including those conducted by the Leprosy Research Initiative (LRI; https://www.leprosyresearch.org/ ) and the Research to Stop Neglected Tropical Diseases Transmission Initiative (R2STOP; https://r2stop.org/ ) provided a starting point. It was considered important that the research agenda be built on previous work and followed established principles for qualitative research (COREQ) [ 7 ]. The team also engaged with the NTD community through a panel discussion at the 2018 Coalition for Operational Research on NTDs (COR-NTD; https://www.ntdsupport.org/cor-ntd ) meeting in New Orleans, USA. The detailed research priorities for each of the 8 priority themes was published in Leprosy Review [ 8 ] along with a commentary [ 9 ]. The current article focuses on the context of the research priority identification and their significance.

Research areas and priorities

Similar to many other NTDs, leprosy is a complex condition in terms of its clinical and epidemiological characteristics, long-term medical and biological consequences (or effects), and intersections with socio-economic and cultural factors [ 10 , 11 ]. Several cross-cutting themes emerged during the working group and subgroup deliberations, including the need for integration between research efforts. To achieve breakthroughs, research projects may need to integrate multiple disciplines and collaborate across traditionally separated fields. For example, research to understand the successful implementation of post-exposure prophylaxis (PEP) would necessarily need a complementary component on acceptability and the impact of stigma and discrimination on care-seeking behaviours.

Research should be prioritized based upon its potential impact and likelihood of leading to transformative, effective, and efficient innovations. At the same time, operational research that leads to stronger programmatic capacity and informs integration with, and strengthening of, national public health and health systems is needed to ensure that these new technical innovations are accessible and scalable at the national and sub-national levels. The need for high-quality leprosy research studies meeting the standards required for inclusion in WHO Guidelines has been noted [ 12 ].

A major partner in developing the research agenda was LRI, which was launched in 2013. The LRI conducted a similar priority-setting process in 2018 to inform its investment priorities. LRI adopted an elegant mixed-methods approach to defining and evaluating research priorities [ 13 ]. A recent editorial [ 9 ] compared the outcomes of the GPZL and LRI approaches and showed that, while the outcomes were not identical they were well aligned, offering welcome validation of the findings and reassuring the GPZL that its process has produced a robust research agenda.

The eight finalized research areas, and the priorities identified for each research area, are summarised in the panel.

As with other NTDs, COVID-19 poses significant challenges to leprosy control. WHO has issued interim guidance for community-based programs in the context of the COVID-19 pandemic [ 14 ], and national programs are restarting program interventions while relevant research gradually resumes, as the situation allows. Of particular concern are delays in diagnosis and interruption of treatment that might translate into increased morbidity, incomplete cure and the spread of drug resistance.

Panel: the research priorities to achieve zero leprosy

Diagnostics.

The development, standardization, and deployment of accurate diagnostic tests for the early detection of infection and disease is a top priority. This may include molecular-based [ 15 , 16 ] and immunological tools [ 17 ] that require digital support. Because a diagnosis of leprosy is usually made on clinical signs and symptoms and there is no “gold standard” nor easy method to correlate infection to disease progression, patients are often diagnosed and treated late, increasing the likelihood of further transmission and disease-related disability. Contact screening may offer opportunities for early diagnosis [ 18 , 19 ] and targeted interventions. Another priority is harmonization, i.e., validation and quality assurance programmes to ensure standard procedures, correct interpretation, and thus high confidence in test results [ 20 ].

Digital technology and innovation

Governments, policymakers, and other stakeholders are seeking scalable and sustainable digital health solutions that can be integrated into national health systems and, ideally, expanded to include other conditions [ 21 ]. Digital interventions such as eLearning, digital diagnostics, and geolocation of leprosy patients are priorities. A number of applications are under development, including digital registries; a leprosy referral and surveillance network among healthcare providers; tele-dermatology to support health workers with access to medical specialists [ 22 ]; and, smartphone apps to facilitate diagnosis and treatment for peripheral health workers [ 23 ]. Policy to support the practical implementation of these developments will also be needed.

The early detection and treatment of leprosy is critical to preventing disabilities [ 24 ]. Effective strategies for preventing and stopping disability exist and rehabilitation techniques are available [ 25 ], but more knowledge to inform the accessibility, effectiveness, and cost-effectiveness of services is needed, as are new tools to improve practice. Better understanding of the causes of disability and ways to optimize disease management, is required for marginalised and economically and socially poor communities. Evidence on the significance of early detection [ 24 ], including the impact of case-finding and contact-tracing strategies on the prevalence of leprosy-related disabilities among new cases, will support morbidity prevention, as will work to better understand the pathophysiology, detection, and management of reactions. Minimizing the impact of living with impairments due to leprosy is another priority and requires studies on the prevention and treatment of disability and on the efficacy, accessibility, and effectiveness of rehabilitation services, assistive devices, and community-based rehabilitation programs [ 26 ]. Better estimates on the number of people disabled from leprosy (and their needs) and estimates of the burden of leprosy disability are necessary to understand and quantify the need and to allocate resources [ 27 ].

Epidemiological modelling and investment case

Decisions on the selection and implementation of leprosy interventions [ 28 , 29 ] should be based on a robust analysis of the benefits, risks, and costs [ 30 , 31 ]. These include a financial and cost analysis of leprosy and an estimate of its socioeconomic burden. Currently, such evidence is scarce. Transmission models should be improved, as epidemiologic modelling is a powerful tool to prioritize alternative tools and interventions and evaluate endgame strategies as donors commit to zero leprosy [ 32 ]. An Elimination Investment Case (EIC) provides a framework for a systematic assessment of what is needed to achieve zero leprosy and the challenges, risk, and sustainability of various initiatives [ 33 , 34 ].

Implementation research

Implementation research is required to improve the functioning of national leprosy programs and to increase the effectiveness of collaborations with their long-term partners [ 35 ]. It is equally relevant to increasing the quality of leprosy data within countries and globally [ 36 ]. Priority operational issues include case mapping, data management, monitoring and surveillance, health systems strengthening, genetic and clinical drug resistance surveillance, and active case finding. Advances in mapping technologies such as global positioning systems and geographic information systems that combine discrete location data with mobile or static services [ 37 , 38 ] have not yet been fully integrated by the leprosy community into routine operations to target interventions [ 39 ]. Better data are needed for decision-making [ 40 ]. The AIM Initiative ( https://aiminitiative.org/ ) promotes integrated mapping of routine NTD data for evidence-based intervention planning. These operational research priorities can be pursued as individual topics or integrated into program evaluation targets, larger proposals and global health systems strengthening initiatives.

Among the targets in ILEP’s Triple Zero Campaign—Zero Transmission, Zero Disability, and Zero Discrimination—the third (which includes stigma and mental well-being) has received the least attention. This is despite stigma and attitudinal barriers being cited as major challenges by persons affected by leprosy [ 41 ]. Stigma is a barrier to zero leprosy in terms of missed prevention opportunities and access to treatment and appropriate case management, and improved mental well-being is central to reducing the burden of leprosy [ 42 ]. Interventions to reduce stigma such as support groups offering peer counselling, peer-to-peer networks led by local experts, socioeconomic development, and the involvement of persons affected in leprosy services have been studied but little standardization has been achieved [ 43 ]. Such interventions need to be validated in different settings [ 44 , 45 ] and scale up must be explored in order to define standardized approaches.

Post exposure prophylaxis (PEP) and transmission

Evidence for the efficacy of PEP with single dose rifampicin (SDR) has been established through multiple studies [ 46 , 47 , 48 , 49 ]. Among current research, the Leprosy Post-Exposure Prophylaxis (LPEP) program focuses on feasibility and impact [ 50 , 51 , 52 ]. Issues related to acceptability, perception [ 53 ], drug resistance [ 54 ] and impact of the treatment among those at highest risk of disease remain to be studied. The PEOPLE trial evaluates different PEP regimens and delivery modalities; the PEP4LEP trial assesses multiple contact tracing and screening platforms; the MALTALEP trial [ 55 ] examined the benefits of immunization with Bacille Calmette-Guerin (BCG) alone or in combination with SDR; and the PEP++ study [ 56 ] aims to establish an enhanced chemoprophylaxis regimen for close contacts of persons with leprosy. Another unmet research question pertains to the effect of chemoprophylaxis on transmission.

Priorities for understanding M. leprae transmission are related to understanding human-to-human transmission [ 57 ]. One of the main challenges to interrupting transmission is the long incubation period, during which transmission to contacts is assumed to occur. Other transmission-related research priorities are transmission networks, the extent and epidemiological significance of non-human reservoirs, and host–pathogen interactions. A better understanding of these might facilitate the development of diagnostic tests for both infection as well as pre-clinical and clinical disease [ 58 ].

Until recently, immunotherapy options for leprosy were limited to the live vaccine BCG [ 59 , 60 , 61 ]. Renewed efforts to develop partially effective vaccines, such as different BCG strains, into improved leprosy vaccines [ 62 , 63 ] have resulted in Mycobacterium indicus pranii (MIP), a whole cell vaccine of heat-killed mycobacteria [ 64 ]. The ideal vaccine against leprosy would need to induce strong, long-lasting T cell responses directed against M. leprae antigens, thereby limiting infection, preventing disease, and reducing bacterial transmission to others [ 65 , 66 ]. Only recently has it been practical to contemplate the development and delivery of a new generation of leprosy vaccines. Of critical relevance for such vaccines is the recent availability of adjuvants that enable a new generation of T cell vaccines. LepVax is a multivalent recombinant protein formulated in a modern adjuvant that is used in more than a dozen vaccine candidates and is a safe and effective inducer of durable T cell responses [ 67 ]. It has been suggested that LepVax might first be used as a curative rather than a prophylactic vaccine [ 67 ]. For both MIP and LepVax, however, full clinical trials and registration in multiple countries have yet to be achieved and safety monitoring must be established. In the case of curative vaccines, sensitive diagnostic tests are critical.

Despite the impact of MDT on leprosy, particularly in the 1990s, the number of reported cases remained stagnant over the last decade and concerns are growing that a significant number of cases may go unreported and undiagnosed [ 2 , 68 ]. In addition to traditional public health approaches such as active case finding [ 69 ], new techniques and innovations are needed: these require innovative, high-quality research and an engaged scientific community that is aligned and committed to addressing key research priorities [ 70 ].

The recent WHO Leprosy Guidelines highlighted the insufficient quality of leprosy research in many areas [ 71 ]. The establishment of the GPZL, a coalition of all key actors, in 2018 has already revitalized thinking towards leprosy control through extensive engagement with leprosy stakeholders and the NTD community as a whole. Experience with elimination efforts for other NTDs has highlighted the importance of this type of commitment and alignment [ 72 , 73 ]. For example, a comprehensive research agenda for the elimination of lymphatic filariasis (LF), commissioned by the Bill & Melinda Gates Foundation in 2004 under the auspices of the Global Alliance to Eliminate Lymphatic Filariasis (GAELF), catalysed key scientific research, resulted in the development of new tools and strategies, and focused funding for LF elimination around priority strategies [ 74 ].

For LF and a few other NTDs, including schistosomiasis, a research agenda development process and research priorities were commissioned and funded almost in their entirety by a single donor, namely the Bill & Melinda Gates Foundation. This has not been the case for leprosy. Thus, the challenge now is to mobilise resources to implement this research agenda, which will require further priority-setting and coordination on protocol development, the cooperation of experts and institutions with a wide range of expertise, availability of field sites, and very considerable financial investment.

The individual components of the research agenda vary in resource needs, will require distinct expertise, and will operate over different timescales. The stigma, disability, and PEP research plans are well advanced, with many activities in progress or even near implementation and scaling up. Epidemiologic modelling is being funded by the GPZL as part of its advocacy and resource mobilisation strategy in 2020. The operational research and digital health plans can be tackled and progress made in the short term, while innovations in the fields of diagnostics and vaccines will require much longer timescales.

The research agenda needs to be imaginatively yet loosely managed as there are considerable synergies between the different elements, such as PEP, vaccines, and diagnostics, yet research is notoriously unpredictable and progress cannot be fully controlled. Of particular importance is early input from stigma and disability experts in the development of tools and approaches that might touch on socially sensitive areas including concerns over disclosure and surveillance.

Developing and achieving consensus on the research agenda for zero leprosy is an important step forward for the leprosy community. The next step—further prioritization, partner alignment, resource mobilisation, planning, and coordination of the realisation of that research agenda—is equally critical. Moving towards zero leprosy requires investments from existing and new partners at all stages of the process, from discovery to implementation. Technical innovation is required to create the necessary tools for intervention and diagnosis. High-quality implementation research is needed to standardize those tools and bring them into national programs, supported by a strong evidence base. The G-FINDER report on research and development funding for NTDs including leprosy presents the scale of the current investment and the sources of funding [ 75 ]. However coordination is needed to ensure that resources are directed, in an impactful and measurable way, to the sustained, effective programs required to achieve zero leprosy. Ideally, coordination and control will increasingly be by the countries and communities most in need of innovations.

Availability of data and materials

From the GPZL.

Abbreviations

Bacille Calmette-Guerin

Global partnership for zero leprosy

Leprosy research initiative

Multi-drug therapy

Mycobacterium indicus pranii

Neglected tropical diseases

Post-exposure prophylaxis

World Health Organization

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Acknowledgements

We thank all members and contributors to the working group. Robin Moseley provided editorial assistance.

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Peter Steinmann

University of Basel, Basel, Switzerland

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Courtenay Dusenbury

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Novartis Foundation, Basel, Switzerland

Fareed Mirza

University of Aberdeen, Aberdeen, UK

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CD is the secretariat director of the GPZL. FM was a staff of the Novartis Foundation at the time of the data collection. The authors declare that they have no competing interests.

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Steinmann, P., Dusenbury, C., Addiss, D. et al. A comprehensive research agenda for zero leprosy. Infect Dis Poverty 9 , 156 (2020). https://doi.org/10.1186/s40249-020-00774-4

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Received : 12 August 2020

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DOI : https://doi.org/10.1186/s40249-020-00774-4

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INTRODUCTION

M. leprae and M. lepromatosis comprise " Mycobacterium leprae complex" [ 1 ]. The DNA sequences of M. leprae and M. lepromatosis differ enough to distinguish them as separate species, but they share many similarities (both are obligate intracellular parasites with a tropism for nerves) and cause the same clinical disease [ 2 ].

Leprosy is an important global health concern. Contrary to popular folklore, leprosy is not highly contagious, and very effective treatment is available [ 3,4 ]. Early diagnosis and treatment are necessary to minimize the likelihood of disability involving the eyes, hands, and feet due to neuropathy as these are often not reversible and may require lifelong care [ 5 ].

The epidemiology, microbiology, clinical manifestations, and diagnosis of leprosy are reviewed here. Issues related to treatment are discussed separately. (See "Leprosy: Treatment and prevention" .)

EPIDEMIOLOGY