Version July 2025
INTRODUCTION —
Leprosy (also known Hansen's disease) is an infection of the skin and peripheral nerves caused by Mycobacterium leprae and Mycobacterium lepromatosis.
M. leprae and M. lepromatosis comprise Mycobacterium leprae complex [1]. The deoxyribonucleic acid (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, yet is widely misunderstood. Leprosy is not highly contagious (contrary to popular belief), and effective treatment is available [3,4]. Nonetheless, leprosy carries a heavy burden of stigma [5]. Early diagnosis and treatment are necessary to minimize the likelihood of irreversible nerve damage leading to permanent disability involving the hands, feet, and eyes [6].
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 —
In the 1990s, the World Health Organization (WHO) established a goal of eliminating leprosy as a public health problem by the year 2000; "elimination" was defined as a reduction in prevalence to <1 case per 10,000 population in all endemic countries. Between 1985 and 2022, the number of registered cases fell from 5.4 million to 165,459; the prevalence rate per 10,000 fell from 21.1 to 0.21 [7]. However, new cases continue to appear, including in children, suggesting active transmission [8].
Disease burden
●M. leprae
•Worldwide – The WHO reports that 174,087 new leprosy cases were registered globally in 2022, of which 10,302 were among children <14 years of age. Among all new cases, 9,554 had Grade 2 disabilities (ie, visible deformities) at diagnosis [7]. In general, leprosy is more common among males with a ratio of approximately 1.5 to 1.
The prevalence of leprosy is variable; the majority of cases are found in resource-limited settings. The top five countries reporting new cases are India, Brazil, Indonesia, Democratic Republic of the Congo, and Bangladesh [9]. With increasing international travel, however, patients with leprosy may present anywhere.
According to the WHO, a low endemic region is one without child cases for five consecutive years; a high endemic region is one with one or more child cases within the last five years [10].
Epidemiologic data for leprosy are highly sensitive to operational factors; nearly all data are based on passive case finding. A study using active case finding by house-to-house surveys in Bangladesh recorded nearly fivefold more cases than were believed to exist in the area by passive case finding alone [11].
•United States – According to the Registry of the National Hansen's Disease Programs, 136 new cases were detected in the United States in 2022 (124 to 219 cases per year, 2013 to 2022) [12]. Approximately 75 percent of new cases detected annually in the United States are among immigrants. Among native-born United States citizens, exposure to leprosy overseas may account for some cases. However, routine travel is not a recognized risk factor for acquisition of infection. In some cases contact with a known case in the United States can be established; some cases are attributable to exposure to infected armadillos [13-15]. However, in some autochthonous cases, no history of exposure can be established [16,17]. A 2023 case report highlighted an increase in the number of new cases diagnosed in Florida over the preceding decade [15,18].
●M. lepromatosis – M. lepromatosis was identified as a second causal agent of leprosy in 2008 [19]. Infection with M. lepromatosis has been reported most commonly in patients living in or originating from Mexico; cases have also been described in a number of other countries [20].
Transmission — The means of transmission of leprosy is not fully understood. The disease is probably spread by the respiratory route; nasal discharge from untreated patients with lepromatous (multibacillary) disease frequently contains large numbers of bacilli [21,22]. Once the upper respiratory tract of the new host is infected, widespread dissemination within the host may occur. Rarely, the organisms may enter through broken skin [23]. Contact with armadillos (handling, killing, or eating) has been reported in some cases [13].
The mechanism of M. leprae transmission and potential environmental reservoirs remain active areas of investigation [24]. The nine-banded armadillo (Dasypus novemcinctus) remains the only well-documented zoonotic reservoir, supported by the association of specific M. leprae genotypes in human and armadillo infections across the United States Gulf Coast [13,15]. Molecular evidence of M. leprae and M. lepromatosis has been found in red squirrels (Sciurus vulgaris) in the United Kingdom [25-27] and chimpanzees in west Africa [28]. However, leprosy is exceedingly rare in humans in the United Kingdom and Europe [29].
Other animal and/or environmental reservoirs for leprosy may exist [24,29]. Under experimental conditions, M. leprae has been shown to be ingested by amoebae and survive within them [30-32]. Ticks may be able to ingest M. leprae and transfer the organism to their eggs [33]. It is unknown whether either of these phenomena occur in the natural environment; the feasibility of investigations of potential environmental reservoirs and vectors is greatly enhanced by molecular tools to identify M. leprae and assess its viability.
In general, most individuals do NOT develop the disease following exposure; an estimated 95 percent of people are naturally resistant to infection [3]. Development of disease depends on a variety of host factors, including immune status and genetic influences, as discussed below. (See 'Risk factors' below.)
Risk factors — In many cases, it is not possible to determine the source of M. leprae infection, given the very long incubation time (up to decades). Proposed risk factors for acquisition of leprosy include:
●Close contact – Contacts of patients with leprosy have a higher risk of developing leprosy than the general population [34]. Close physical distance to the index case was associated with an increased risk of leprosy in one study [35].
Some studies have suggested that contacts of patients with lepromatous (multibacillary) leprosy have a higher risk than contacts of patients with tuberculoid (paucibacillary) leprosy or single-lesion leprosy [34,36,37]. (See 'Classification and terminology' below.)
●Armadillo exposure – In the southern United States, M. leprae infection is enzootic in the nine-banded armadillo (Dasypus novemcinctus). Human exposure to armadillos confers risk for transmission; however, the mechanism of transmission is not well understood [18]. Using molecular genotyping techniques, studies have identified the same strains of M. leprae in wild armadillos and in patients from the southern United States with no international travel [13,15]. Genotyping of M. leprae from skin biopsies may aid in evaluating the likely origin of the bacilli [38].
●Genetic factors – The immunologic response to M. leprae consists of two components: innate and acquired immunity. Innate immunity is determined by genetic factors, including alleles of the PARK2/PACRG gene [39] as well as other genes [40]. In a genome-wide association study of patients in China, variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) were found to be associated with susceptibility to leprosy [41]. Such immunity is understood to be mediated through cells of monocyte/dendritic cell origin; the mechanisms of this immunity are under investigation [42,43].
Individuals with sufficient exposure and susceptibility to M. leprae complex may develop a broad range of clinical manifestations, which vary depending upon the host's ability to mount an acquired immune response to infection. This cellular immune response appears to be controlled by a number of non-human leukocyte antigen (HLA) genes [35,44,45].
●Immunosuppression – Leprosy is rarely associated with immunosuppression (in contrast with other mycobacterial infections). There are rare published cases of leprosy in the setting of solid organ transplantation, chemotherapy, and human immunodeficiency virus (HIV) infection [46,47]. Leprosy has been described among patients receiving biologic agents for management of rheumatologic conditions [47,48]; however, autoantibodies are commonly detected among patients with leprosy, in the absence of clinical criteria for diagnosis of autoimmune disease [49].
MICROBIOLOGY —
Leprosy is caused by acid-fast bacilli of the M. leprae complex, which includes M. leprae and M. lepromatosis. M. leprae multiplies very slowly (generation time approximately 12.5 days) and is an obligate intracellular organism; it cannot be cultured in artificial media. M. leprae has less than half of the functional genes of Mycobacterium tuberculosis.
Studies in animal models indicate that M. leprae grows best at 27 to 33°C, correlating with its predilection to affect cooler areas of the body (the skin, nerve segments close to the skin, and the mucous membranes of the upper respiratory tract) [3]. M. leprae grows extensively in the nine-banded armadillo (Dasypus novemcinctus), which has a core body temperature of 34°C.
The genomes of M. leprae and M. lepromatosis have been fully sequenced [2,50]. Both genomes contain a large number of pseudogenes, and genes for key enzymes of many essential metabolic pathways are missing [29,37,50]. This accumulation of pseudogenes has allowed these mycobacteria to develop a highly adaptive niche as obligate intracellular organisms [29].
M. lepromatosis was identified as the causative agent of leprosy in several patients with diffuse lepromatous leprosy [19,29]. Select M. lepromatosis gene and pseudogene sequences demonstrated 9 percent difference in nucleotides compared with the highly conserved genome of M. leprae [2]. Subsequent de novo sequencing of the M. lepromatosis genome demonstrated significant differences in single-nucleotide polymorphisms, leading to the hypothesis that these two organisms evolutionarily diverged from a common ancestor approximately 13.9 million years ago [1,2]. Thus far, M. lepromatosis has not been cultured in animals and other basic biologic aspects remain unknown [51].
Clinically, infections with M. leprae and M. lepromatosis are indistinguishable [29,52-55]. They present with the same clinical manifestations, respond to treatment with the same antimycobacterial agents, and have comparable prognosis.
Genotyping of M. leprae may be performed using a combination of single nucleotide polymorphisms (SNP) and variable number tandem repeats (VNTR) [29]. The genotype of M. leprae is remarkably well conserved, and SNPs are observed less frequently than in other human pathogens [56]. Four M. leprae SNP types and 17 subtypes have been identified; an increasing number of genotypes are being identified which may be used to establish patient geographic origin [38]. Genotyping has demonstrated that in the United States, some armadillos carry M. leprae genotypes not seen elsewhere in the world [13,15]. As technology advances, it is likely that genotyping will facilitate identification of transmission clusters, assisting control efforts and advancing epidemiologic understanding [38].
CLASSIFICATION AND TERMINOLOGY —
Leprosy has a wide array of clinical and histopathologic manifestations, reflecting the broad range of cellular immune response to the M. leprae complex.
Ridley-Jopling classification — The Ridley-Jopling classification provides the optimal classification of leprosy, as it reflects the entire spectrum of clinical and pathologic features [57]. The classification is based on the cutaneous, neurologic, biopsy findings and number of acid-fast bacilli present in the dermis, all of which correlate with the immunological capability of the host (table 1) [58]:
The leprosy disease spectrum ranges from a self-limited form with very few organisms (tuberculoid or paucibacillary) and a robust cellular immune response (Th1, Th17), to higher burden of organisms (lepromatous or multibacillary) with a minimal cellular immune response (Th2, permissive macrophage phenotype, increased humoral response) [59].
●Tuberculoid (TT)
●Borderline tuberculoid (BT)
●Mid-borderline (BB)
●Borderline lepromatous (BL)
●Lepromatous (LL)
●Indeterminate (I) – Indeterminate leprosy usually manifests with hypopigmented patches with nonspecific perineural infiltrates in which rare acid-fast bacilli can be demonstrated [60]. It often occurs in children, and may heal spontaneously. The indeterminate classification should be used only if the biopsy demonstrates definitive evidence of leprosy (both nerve involvement and acid-fast bacilli).
WHO classification — The World Health Organization (WHO) classification system was designed for use in situations in which there is little or no clinical expertise or laboratory support; it is based upon the number of skin lesions present [61]. Paucibacillary (PB) leprosy is defined as five or fewer skin lesions without detectable bacilli on skin smears. Patients with only a single skin lesion are classified separately as single-lesion PB. Multibacillary (MB) leprosy is defined as six or more lesions and may be skin smear positive.
Counting skin lesions alone may lead to misclassification of many patients with PB leprosy rather than MB leprosy, leading to undertreatment in some cases [58].
CLINICAL MANIFESTATIONS AND DIAGNOSIS
Clinical suspicion — Leprosy should be suspected in the setting of chronic skin lesions that are not responding to standard treatment for more common conditions, and/or in the setting of sensory loss within lesions or in extremities [62]. Additional clues include presentation of cuts or burns in the absence of pain, and history of residence or travel in endemic settings (foreign birth, military experience, etc).
A small number of patients present with nerve involvement in the absence of skin lesions (pure neuritic or primary neural leprosy) [63].
Establishing a diagnosis — The diagnosis of leprosy is established when at least one physical finding is present (described below) (table 1) and a skin biopsy obtained from the leading edge of the skin lesion demonstrates acid-fast bacilli along with perineural inflammation, and/or M. leprae and/or M. lepromatosis DNA by polymerase chain reaction (PCR). However, patients with paucibacillary disease may have biopsy with no acid-fast bacilli and negative PCR, in which case the diagnosis is made on clinical grounds, which may be challenging in some cases.
In areas where leprosy is endemic and frequently recognized clinically, a diagnosis based on clinical manifestations alone may be sufficient. In areas where leprosy is relatively uncommon, skin biopsy may provide diagnostic confirmation and help rule out other causes of disease.
Clinical evaluation
Physical examination — The diagnosis of leprosy should be considered in patients with skin lesions and/or enlarged nerve(s) accompanied by sensory loss. Leprosy should be suspected in the setting of the following clinical manifestations:
●Diminished sensation or loss of sensation within skin lesions
●Paresthesias (tingling or numbness in the hands or feet)
●Painless wounds or burns on the hands or feet
●Tender, enlarged peripheral nerves
Late findings include weakness of the hands with claw hand (ulnar and median nerves), foot drop (common peroneal nerve), claw toes and plantar insensitivity (posterior tibial nerve), facial paralysis or lagophthalmos (inability to fully close the eyelids), madarosis (lack of eyebrows and eyelashes) (picture 1), saddle-nose deformity, or perforated nasal septum.
Assessment of peripheral nerves is an essential component of every clinical examination for every patient; preventing or minimizing injury to peripheral nerves is a major goal of treatment. This should include palpation of peripheral nerves for enlargement and/or tenderness, including the ulnar nerve at the elbow, median and superficial radial cutaneous nerve at the wrist, great auricular nerve in the neck (picture 2), and common peroneal nerve at the popliteal fossa. A sensory examination (using a monofilament or cotton tip) of skin lesions and distal extremities should be performed, as should motor evaluation. (See 'Nerve involvement' below.)
Eyes should be examined by inspection of the conjunctiva and cornea, as well as assessment of corneal sensation. (See 'Ocular involvement' below.)
In lepromatous disease, intermittent bacteremia may lead to development of focal lesions in various organs [64]. Therefore, occasionally the organism may be observed in liver or bone marrow biopsies performed in the evaluation for fever of unknown origin [65]. The disease can also involve the larynx (hoarseness) and testicles (reduced testosterone leading to hypogonadism) [66,67]. (See 'Testicular involvement' below.)
Skin lesions
●Tuberculoid leprosy (TT) (picture 3) generally has one or two larger macular hypopigmented or erythematous anesthetic lesions, which have a well-defined, often raised margin; occasionally, they are scaly plaques.
●Borderline tuberculoid (BT) (picture 4) lesions are sharply defined macules, sometimes appearing as "target" lesions with central clearing. In BT disease, lesions are more numerous than in TT disease and are usually on one side of the body. TT and BT lesions are considered "paucibacillary" (PB) in the World Health Organization (WHO) classification.
●Lesions in the mid-borderline (BB) and lepromatous portion of the spectrum are considered "multibacillary" (MB) in the WHO classification. Mid-borderline (picture 5) clinically may resemble borderline tuberculoid leprosy or borderline lepromatous leprosy with few to several "punched out" lesions; central areas are often anesthetic.
●Borderline lepromatous leprosy (BL) (picture 6) lesions may consist of erythematous macules, papules, and/or nodules and are distributed symmetrically on the body. There are areas of normal skin found between lesions, but the margins of the lesions are often diffuse rather than sharply defined. Larger lesions, either macules or plaques, are in asymmetrical distribution.
●Lepromatous leprosy (LL) (picture 7 and picture 8) is usually generalized at diagnosis and may consist of erythematous macules, papules, and/or nodules. Characteristic features of advanced disease include body hair loss, especially of eyebrows and lashes [68], and nodular thickening of earlobes (picture 7). In some instances, lepromatous leprosy presents with diffuse infiltration and palpable thickening of the skin rather than with discrete lesions. Invasion of the mucosa of the nose may imitate nasal stuffiness, as with a common cold. Septal perforation and/or collapse (saddle nose) may follow unless the condition is treated. Asymptomatic, intermittent bacteremia occurs during lepromatous disease, during which M. leprae may develop focal lesions in various organs [64]. Therefore, occasionally the organism may be observed in liver or bone marrow biopsies performed in the evaluation for fever of unknown origin [65]. The disease can also involve other areas, such as the testicles (reduced testosterone) and larynx (hoarseness) [66].
●Indeterminate disease (picture 9) usually presents as a small hypopigmented or erythematous macule with diminished sensation. In some cases, these infections do not progress. Bacilli are rarely found in the biopsy. If the lesion does not fully resolve, it will develop into one of the established types in the leprosy spectrum.
Nerve involvement — The peripheral nerves are affected very early in the course of leprosy, as evidenced by the decrease or absence of sensation in the earliest skin lesions [3]. Commonly involved nerve trunks are described above. (See 'Physical examination' above.)
Most commonly, neuropathy manifests with loss of sensory perception, though patients can present with acute pain (acute neuritis) or chronic pain (neuropathic pain) later in the course of the disease [69,70].
Subclinical neuropathy appears to be more prevalent in leprosy than was previously believed [71]. Testing with a monofilament has demonstrated that functional nerve impairment occurs earlier in the course of lepromatous disease than in tuberculoid disease, even though patients with tuberculoid disease may be aware of numbness or weakness earlier in the course of their illness [72-74]. In a prospective study of early neuropathy diagnosis in leprosy, the most frequently and earliest abnormal tests were sensory nerve conduction and temperature perception; in a large proportion of patients, these became abnormal ≥3 months before abnormalities were identified using monofilaments [75].
Segmental demyelination appears to be the final common pathway of nerve injury in leprosy; the mechanisms leading to this are poorly understood [3,71,76]. Traditional approaches to study pathogenesis, such as biopsy of the affected tissue, are not feasible with the major peripheral nerve trunks involved in leprosy. The experimentally infected armadillo serves a model for some aspects of nerve injury pathogenesis in leprosy [77].
Ocular involvement — Impairment of nerves innervating the musculature of the eyelids and providing sensory innervation to the cornea may lead to lagophthalmos (inability to fully close the eyelids), drying of the cornea, corneal abrasion, and corneal ulceration [78]. Careful inspection of the cornea and conjunctiva is an essential part of the examination of every patient with leprosy.
Testicular involvement — Testicular atrophy leading to gynecomastia, loss of libido and secondary infertility occurs in 10 to 50 percent of men with leprosy. Routine management should include assessment of testicular function, with administration of testosterone if needed [79]. (See "Clinical features and diagnosis of male hypogonadism".)
Immunologic reactions — Immunologic reactions are systemic inflammatory complications that may occur before leprosy treatment (some patients initially present for medical attention in the setting of a reaction), during treatment, or months to years after treatment has been completed. These reactions are estimated to affect 30 to 50 percent of patients with leprosy [80].
There are two main types of leprosy reactions:
●Type 1 (may be referred to as T1R, reversal reaction, or RR) – typically occurs in patients with borderline disease (BT-BL)
●Type 2 (may be referred to as T2R, erythema nodosum leprosum, or ENL) – occurs in patients with lepromatous disease (BL-LL)
With both reaction types, a general feeling of fatigue, malaise, and fever may be present. The inflammation associated with reactions can lead to severe nerve injury with subsequent paralysis and deformity. The reactions may be confused with drug allergy, worsening of disease and new-onset neuropathy.
Distinguishing between these reactions can be difficult. The two reactions appear to have different underlying immunologic mechanisms; both are poorly understood and the factors that initiate them are not known [3,81]. Polymorphonuclear leukocytes are a hallmark of type 2 reactions (T2Rs); no reliable histologic criteria have been identified for type 1 reactions (T1Rs), so this remains a clinical diagnosis.
The development of new skin lesions during or after completion of treatment is usually attributable to an immunologic reaction. Other considerations are discussed separately. (See "Leprosy: Treatment and prevention", section on 'Progression of signs or symptoms'.)
Type 1 reaction (T1R, reversal reaction) — Type 1 reaction typically occurs in patients with BT, BB, or BL disease. Clinical manifestations include:
●Erythema and induration of preexisting skin lesions (picture 10)
●Significant edema of the hands or feet, sometimes associated with small joint pain
●Pain or tenderness in one or more nerves (eg, painful elbow, due to ulnar nerve involvement)
●Loss of nerve function (acute neuritis) with muscle weakness (such as foot drop)
No routine laboratory tests are available to assist in the diagnosis. Skin biopsies may demonstrate edema, increased granulomatous organization, or increased numbers of multinucleated giant cells, reflecting spontaneous enhancement of cellular immunity and delayed-type hypersensitivity to M. leprae antigens [3]. However, these findings are observed in only about half of the cases [82]. As a result, often the diagnosis must be made on clinical grounds alone.
Risk factors and triggering events are not well understood [83,84]. Therefore, it is not possible to predict which patients may experience this reaction; no changes should be made to the basic treatment regimen in an attempt to prevent a reaction.
In the absence of treatment, the inflammation can lead to severe nerve injury with subsequent paralysis and deformity. The natural course of T1R is several months.
Treatment of type 1 reactions is discussed separately. (See "Leprosy: Treatment and prevention", section on 'Type 1 reaction (T1R, reversal reaction)'.)
Type 2 reaction (T2R, ENL) — Type 2 reaction occurs in patients with BL and LL disease [85,86]. Clinically, T2R is characterized by the sudden eruption of numerous painful papules and nodules (picture 11), which may be superficial or deep in the dermis. These can form pustules (sterile on culture) and may ulcerate. Lesions are commonly found on the extensor surfaces of the limbs and on the face. As lesions fade, they may appear as brawny induration on the forearms and thighs. Other clinical manifestations of T2R include high fever, headache, generalized pain, muscle tenderness, arthritis, tender lymphadenopathy, orchitis, and iridocyclitis. A clinical severity scale for erythema nodosum leprosum (ENL) has been developed that can assist clinicians in characterizing ENL and following response to treatment [85,86].
Biopsy of an early T2R skin lesion demonstrates an infiltrate of neutrophils superimposed upon the chronic inflammation and heavy bacterial load of M. leprae. This is a very useful diagnostic test, since neutrophils are extremely rare in all other types of leprosy lesions. Serum inflammatory markers (eg, C-reactive protein) are often elevated [87].
The main risk factor for T2R is presence of a high bacterial load. Additional risk factors may include hormonal changes such as puberty, pregnancy, and lactation [88].
The mechanism of T2R is poorly understood. It is widely regarded as an immune complex disorder, although the evidence for this is not compelling [3]. Elevated circulating levels of tumor necrosis factor-alpha and other proinflammatory cytokines have been observed, but their roles in pathogenesis remain unclear. Subsets of T cells [89] and B cells [90] are altered during ENL, and neutrophils have been observed in the tissue lesions [91].
In the absence of treatment, T2R is recurrent, sometimes over many months.
Management of T2R is discussed separately. (See "Leprosy: Treatment and prevention", section on 'Type 2 reaction (T2R, erythema nodosum leprosum [ENL])'.)
Lucio phenomenon — The Lucio phenomenon is a rare complication presenting as sudden necrotizing vasculopathy in patients with longstanding, untreated lepromatous leprosy [92,93]. It presents with necrotizing ulcerations that may be extensive in distribution and can lead to potentially life-threatening sepsis and multiorgan dysfunction.
It occurs more commonly in Central Mexico (particularly the Sinaloa area) and South America.
Both M. leprae and M. lepromatosis may be associated with Lucio reactions.
Management of is discussed separately (See "Leprosy: Treatment and prevention", section on 'Lucio phenomenon'.)
Diagnostic approach
Biopsy — For diagnosis and classification of leprosy, a full-thickness skin biopsy (ie, 4 mm punch biopsy) should be taken from the leading edge of the most active lesion. We send the tissue for histopathology and PCR.
For patients with clinical manifestations suggestive of an immunologic reaction, biopsy may be useful for diagnosis of T2R.
In rare cases with isolated nerve involvement in the absence of skin lesions (pure neuritic or primary neural leprosy), nerve biopsy may be useful for diagnosis [63].
The National Hansen's Disease Programs (NHDP) Clinical Center in Baton Rouge, Louisiana, and its clinics around the United States, offer consultations and evaluations for leprosy (1-800-642-2477) [94]. The NHDP Laboratory also offers histopathology services and molecular assays for detection of M. leprae and M. lepromatosis in tissues [95].
If histopathology evaluation of skin biopsy is not available, slit-skin smear may be performed; this tool is used mainly in resource-limited settings. The approach consists of a small incision (on the ears, elbows, and/or knees); the samples are smeared on a slide and Fite stained, and a trained technician makes a semiquantitative assessment of the bacterial index (BI) on a scale of 0 to 6+ [96].
●Histopathology – Routine hematoxylin and eosin sections demonstrate the type of infiltrate and involvement of dermal nerves (picture 12). Histopathology findings are described further in the table (table 1).
In the setting of a suspected immunologic reaction, polymorphonuclear leukocytes are a hallmark of type 2 reactions (T2Rs); no reliable histologic criteria have been identified for type 1 reactions (T1Rs).
●AFB staining – M. leprae and M. lepromatosis are observed on histology as acid-fast bacilli but cannot be grown in culture. To demonstrate M. leprae and/or M. lepromatosis in tissue, the Fite stain is superior to the standard Ziehl-Neelsen stain.
Patients with paucibacillary disease may have no visible acid-fast bacilli (table 1).
The bacterial load in a biopsy or skin smear may be expressed as a bacteriologic index (BI), which is the number of bacilli per 100x field, expressed as a logarithmic scale (over 1000 bacilli per average field = 6+; 100 to 1000 bacilli = 5+, etc) [97].
During treatment, the tissue bacterial load in skin smears or biopsies slowly falls to zero (over a period of years). The response to treatment is determined primarily by clinical assessment, rather than histology. (See "Leprosy: Treatment and prevention", section on 'Clinical response and follow-up'.)
●Polymerase chain reaction (PCR) — PCR is available for detection of M. leprae and M. lepromatosis DNA in tissue [2,95].
For patients with lepromatous disease, PCR on biopsies have high sensitivity and specificity (in one study, >90 percent and 100 percent, respectively) [98,99]. For patients with paucibacillary disease, the sensitivity of the PCR on biopsies is low (in one study, sensitivity and specificity of 34 and 80 percent, respectively) [98].
In the setting of suspected drug resistance, PCR may be performed for detection of mutations associated with drug resistance. Resistance testing is not performed routinely in most countries; it may be obtained upon request for specimens sent to the United States National Hansen Disease Program (NHDP).
No role for other tests
●Lepromin test – The lepromin skin test is not a useful tool for diagnosis of leprosy; it does not measure exposure or infection [100]. A positive test reflects the ability to develop a granuloma following exposure to M. leprae antigens, but does NOT indicate exposure to leprosy [101]. Tuberculin skin tests (TSTs) do not have significant cross-reactivity with M. leprae [102].
●Serology – Serologic tests are not routinely used in making the diagnosis of leprosy. Serologic tests for M. leprae phenolic glycolipid-1 (PGL-1) are not sufficiently sensitive to provide a reliable measure of infection in the absence of other clinical or histologic evidence [103-105].
DIFFERENTIAL DIAGNOSIS —
Lack of sensory perception to light touch or pinprick distinguishes leprosy lesions from other conditions, although it is not invariably present. The diagnosis of leprosy can generally be established via skin biopsy. The differential diagnosis includes:
●Granuloma annulare – Localized granuloma annulare classically presents as an asymptomatic, non-scaly, erythematous annular plaque with peripheral papules, a firm, rope-like border, and central clearing (picture 13). The most frequent sites are the wrists, ankles, dorsal hands, and dorsal feet. The diagnosis is based on clinical manifestations and biopsy if needed. (See "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis" and "Approach to the patient with annular skin lesions".)
●Fungal infection – Tinea typically begins as a ring-shaped, erythematous, scaling patch or plaque that spreads centrifugally, followed by central clearing; the advancing border is erythematous and slightly raised (picture 14). The diagnosis can be confirmed by potassium hydroxide preparation or histology (biopsy is not required to be performed). (See "Dermatophyte (tinea) infections".)
●Systemic lupus erythematosus and other autoimmune connective tissue diseases – Cutaneous manifestations of lupus may be localized ("butterfly rash") or generalized, with an erythematous macular-papular eruption involving sun-exposed skin. The diagnosis is based on clinical diagnostic criteria. Autoantibodies (including antinuclear antibody) are commonly observed among patients with leprosy, in the absence of clinical criteria for diagnosis of autoimmune disease [106]. (See "Overview of cutaneous lupus erythematosus".)
●Cutaneous leishmaniasis – Lesions of cutaneous leishmaniasis tend to occur on exposed areas of the skin; localized disease begins as a pink papule that enlarges and develops into a nodule, leading to painless ulceration with an indurated border (picture 15). The diagnosis is established by skin biopsy. (See "Cutaneous leishmaniasis: Clinical manifestations and diagnosis".)
●Mycosis fungoides – Mycosis fungoides (the most common type of cutaneous T-cell lymphoma) is characterized by heterogenous cutaneous manifestations including patches, plaques, tumors, generalized erythroderma, and alopecia. The diagnosis is established by skin biopsy. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)
●Cutaneous sarcoidosis – Lesions of cutaneous sarcoidosis may present as indurated red-brown papules and plaques of the skin, including the face. The diagnosis is one of exclusion, established by skin biopsy showing noncaseating granulomatous inflammation, negative infectious workup, and investigation of other organ systems for involvement. (See "Cutaneous manifestations of sarcoidosis".)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Leprosy".)
SUMMARY AND RECOMMENDATIONS
●General principles – Leprosy (also known Hansen's disease) is an infection of the skin and peripheral nerves caused by Mycobacterium leprae and M. lepromatosis. Leprosy is an important global health concern; early diagnosis and a full course of treatment are critical for preventing lifelong neuropathy and disability. (See 'Introduction' above.)
●Epidemiology – The majority of leprosy cases occur in resource-limited settings; countries with high numbers of cases include India, Brazil, and Indonesia. With increasing international travel, however, patients with leprosy may present anywhere. In the United States, a few hundred new cases are detected per year; approximately 75 percent of cases are among immigrants. (See 'Epidemiology' above.)
●Transmission and risk factors – Leprosy is probably spread by the respiratory route, though the means of transmission is not fully understood. In the United States, it is also a zoonosis; contact with armadillos has been documented in some cases. Other risk factors include close contact with known cases and genetic predisposition. (See 'Transmission' above and 'Risk factors' above.)
●Clinical manifestations and diagnosis
•Physical examination – Early physical exam findings include hypopigmented or reddish skin patches, diminished sensation or loss of sensation in involved areas, paresthesias, painless wounds or burns, and tender, enlarged peripheral nerves. Neuropathy and ophthalmic injury can also occur. (See 'Clinical evaluation' above.)
•Diagnosis – The diagnosis is established when at least one of these physical findings is present and a skin biopsy obtained from the leading edge of the skin lesion confirms the presence of acid-fast bacilli along with perineural inflammation, or M. leprae and/or M. lepromatosis DNA by PCR. Patients with paucibacillary disease may have biopsy with no acid-fast bacilli and negative PCR, requiring a clinical diagnosis. (See 'Diagnostic approach' above.)
●Classification – Leprosy is classified along a spectrum from tuberculoid to lepromatous forms (table 1). Patients with a high degree of cell-mediated immunity and delayed hypersensitivity present on the tuberculoid end of the spectrum, with relatively few well-demarcated lesions. Patients with no apparent immunity to M. leprae present on the lepromatous end of the spectrum with numerous, poorly demarcated lesions. (See 'Classification and terminology' above.)
●Immunologic reactions – Immunologic reactions are systemic inflammatory complications that occur either before treatment (some patients initially present for medical attention in the setting of a reaction), during treatment, or months to years after completion of treatment. There are two main types of reactions: type 1 (reversal reaction; typically occurs in patients with borderline disease) and type 2 (erythema nodosum leprosum; occurs in patients with lepromatous disease) but distinguishing between the types can be difficult. (See 'Immunologic reactions' above.)
ACKNOWLEDGMENTS —
The UpToDate editorial staff acknowledges Barbara Stryjewska, MD, and David Scollard, MD, PhD, who contributed to earlier versions of this topic review.
