INTRODUCTION — Leprosy (also known Hansen's disease) is an infectious disease caused by Mycobacterium leprae and Mycobacterium lepromatosis that involves the skin and peripheral nerves.
M. leprae and M. lepromatosis comprise "Mycobacterium leprae complex" . 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 .
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 .
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 2011, the number of registered cases fell from 5.4 million to 219,075; the prevalence rate per 10,000 fell from 21.1 to 0.37; these figures exclude Europe .
•Worldwide – The WHO reports that 202,256 new leprosy cases were registered globally in 2019, of which 14,893 were children <14 years of age. Among all new cases, 10,816 had grade 2 disabilities at diagnosis . In general, leprosy is more common among males with a ratio of approximately 1.5 to 1.
The prevalence of leprosy is variable; the overwhelming majority of cases are found in resource-limited settings. The top five countries reporting new cases are India, Brazil, Indonesia, Nepal, and Bangladesh . 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 .
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 .
•United States – According to the Registry of the National Hansen's Disease Programs, 159 new cases were detected in the United States in 2020 . 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 accounts for some cases. Contact with a known case in the United States can sometimes be established; some cases are attributable to exposure to infected armadillos [12-14]. However, in some autochthonous cases, no history of exposure can be established [15,16].
A case report in Florida in 2023 highlighted an increase in the number of new cases diagnosed in Florida over the last decade . This led to a study demonstrating the association of specific M. leprae genotypes in human and armadillo infections across the United States Gulf Coast .
●M. lepromatosis – Infection with M. lepromatosis has been reported in Canada, Asia, several Mexican provinces, South America, and Central America [18-20]. M. lepromatosis has also been identified in red squirrels in Scotland ; however, leprosy is exceedingly rare in humans in the United Kingdom and Europe . Other animal reservoirs for leprosy may exist, and persistent zoonotic transmission of organisms in the M. leprae complex may occur [22,23].
Transmission — The means of transmission 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 [24,25]. Once the upper respiratory tract of the new host is infected, widespread dissemination within the host may occur. Occasionally, the organisms may enter through broken skin . Contact with armadillos (handling, killing, or eating) has been reported in some cases .
The mechanism of M. leprae transmission and potential environmental reservoirs remain active areas of investigation . The nine-banded armadillo (Dasypus novemcinctus) remains the only well-documented zoonotic reservoir [12,14]; however molecular evidence of M. leprae and M. lepromatosis have been found in red squirrels (Sciurus vulgaris) in the United Kingdom [21,27]. Under experimental conditions, M. leprae has been shown to be ingested by amebae and survive within them [28,29] and to remain viable within amoebic cysts for as long as eight months . Preliminary evidence also suggests that ticks may be able to ingest M. leprae and transfer the organism to their eggs . It is unknown whether either of these phenomena occur in the natural environment, but the feasibility of these and other investigations of potential environmental reservoirs and vectors is greatly enhanced by the availability of molecular tools to identify M. leprae and assess its viability.
In general, most individuals do NOT develop the disease following exposure. Development of disease depends on a variety of 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. 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 . Close physical distance to the index case was associated with an increased risk of leprosy in one study .
●Type of leprosy in index patient – 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 [32,34]. (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 . 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 [12,14]. Genotyping of M. leprae from skin biopsies may aid in evaluating the likely origin of the bacilli .
●Age – Older individuals appear to be at increased risk for leprosy. In one study, the effect of age was bimodal, with an increased risk between age 5 and 15 years; the risk increased again after age 30 .
●Genetic influences – 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  as well as other genes . 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 . Such immunity is understood to be mediated through cells of monocyte/dendritic cell origin; the mechanisms of this immunity are under investigation .
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 [33,40,41].
It is difficult to discern the relative contribution of genetic factors following exposure. A prospective cohort study including 1037 patients newly diagnosed with leprosy, along with their 21,870 contacts, demonstrated that genetic relationship was a relevant risk factor, independent of physical distance for exposure .
●Immunosuppression – Immunosuppression increases susceptibility to this infection, as evidenced by the development of leprosy following solid organ transplantation , chemotherapy, HIV infection , or use of biologic agents for management of rheumatologic conditions .
Drug resistance — Issues related to drug resistance are discussed separately. (See "Leprosy: Treatment and prevention", section on 'Drug resistance'.)
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 33ºC, 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) . M. leprae grows extensively in the nine-banded armadillo (Dasypus novemcinctus), which has a core body temperature of 34ºC. Leprosy is found in wild armadillos in the south central United States  and has been found in a chimpanzee, sooty mangabey monkeys, and a cynomolgus macaque .
The genomes of M. leprae and M. lepromatosis have been fully sequenced [2,47]. Both genomes contain a large number of pseudogenes, and genes for key enzymes of many essential metabolic pathways are missing [22,34,47]. This accumulation of pseudogenes has allowed these mycobacteria to develop a highly adaptive niche as obligate intracellular organisms .
M. lepromatosis was identified as the causative agent of leprosy in several patients with diffuse lepromatous leprosy [22,48]. Select M. lepromatosis gene and pseudogene sequences demonstrated 9 percent difference in nucleotides compared with the highly conserved genome of M. leprae . 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 .
Clinically, M. leprae and M. lepromatosis are indistinguishable [18,19,22,23,50]. They present with the same clinical manifestations, respond to treatment with the same antimycobacterial agents, and have comparable prognosis.
Molecular techniques are available for the identification of several mutations associated with resistance to individual agents . The rpoB gene of M. leprae and other mycobacteria is associated with rifampin resistance [51,52]. Mutations in the dihydropteroate synthase gene (folP1) predicted dapsone resistance in a survey of 38 M. leprae strains isolated from skin biopsies of patients with multibacillary leprosy . (See 'Drug resistance' above.)
Genotyping of M. leprae may be performed using a combination of single nucleotide polymorphisms (SNP) and variable number tandem repeats . The genotype of M. leprae is remarkably well conserved and the SNP frequency is significantly less than that seen in other human pathogens . Four M. leprae SNP types and 17 subtypes have been identified, and an increasing number of genotypes are being identified . Such genotyping has been used to demonstrate that in the United States, some armadillos carry M. leprae genotypes not seen elsewhere in the world and that humans and armadillos share the same genotypes [12,14]. As the technology advances, it is likely that genotyping will facilitate identification of transmission clusters, assisting control efforts and advancing epidemiologic understanding.
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 these clinical and pathologic features . The leprosy disease spectrum ranges from a form with a robust immune response and very few organisms (tuberculoid or paucibacillary) to a form with a weaker immune response and a higher burden of organisms (lepromatous or multibacillary). The classification is based on the cutaneous, neurologic, and biopsy findings, all of which correlate with immunological capability of the individual (figure 1). The categories also correlate with the number of acid-fast bacilli present in the dermis :
●Borderline tuberculoid (BT)
●Borderline lepromatous (BL)
Patients with a high degree of cell-mediated immunity and delayed hypersensitivity to M. leprae complex antigens present with one to three well-demarcated lesions with central hypopigmentation and hypoesthesia . Histologically, these demonstrate well-developed granulomatous inflammation and rare acid-fast bacilli in the tissues; this is termed polar tuberculoid (figure 1).
At the other extreme, patients with no apparent resistance to M. leprae complex bacilli present with numerous, poorly demarcated, raised or nodular lesions on all parts of the body. Histologically, these reveal sheets of foamy macrophages in the dermis containing very large numbers of bacilli. This form of infection with a high burden of disease is termed polar lepromatous. Notably, these patients are not immunosuppressed but have a selective inability to mount cellular immunity to M. leprae.
The majority of patients fall into a broad borderline category between TT and LL. This is subdivided into borderline lepromatous, mid-borderline, and borderline tuberculoid.
Very early lesions may present as relatively nonspecific perineural infiltrates in which rare acid-fast bacilli can be demonstrated. In the absence of sufficient criteria for classification, these are called indeterminate. Indeterminate lesions are usually observed in the setting of contact investigation, often in children, and may heal spontaneously . The indeterminate classification should be used only when the biopsy sample shows definite diagnostic evidence of leprosy (both nerve involvement and acid-fast bacilli) but is not advanced enough to identify the patient's position in the leprosy spectrum. "Indeterminate" should not be used if the diagnosis of leprosy is not clearly established, since a diagnosis of leprosy may often have significant impact on a patient's family, employment, and psychological and social status.
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 . 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 .
CLINICAL MANIFESTATIONS AND DIAGNOSIS — Leprosy should be considered in the setting of skin lesions that are chronic and not responding to standard treatment for more common conditions or when sensory loss is observed within lesions or in extremities . Additional clues include presentation of cuts or burns in the absence of pain and travel history including residence in endemic countries (foreign birth, military experience, etc).
Frequently, the diagnosis is established largely on the basis of clinical manifestations, although laboratory tools can be useful for diagnostic confirmation. The diagnosis is definitively established when at least one of the physical findings below is present and a skin biopsy obtained from the leading edge of the skin lesion confirms the presence of acid-fast bacilli in a cutaneous nerve. 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, however, skin biopsy can be helpful for diagnostic confirmation and/or to rule out other causes of disease.
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 symptoms:
●Hypopigmented or reddish patch(es) on the skin
●Diminished sensation or loss of sensation within skin patch(es)
●Paresthesias (tingling or numbness in the hands or feet)
●Painless wounds or burns on the hands or feet
●Lumps or swelling on the earlobes or face
●Tender, enlarged peripheral nerves
Late findings include weakness of the hands with claw fingers, foot drop, facial paralysis or lagophthalmos, lack of eyebrows and eyelashes (picture 1), collapsed nose, or perforated nasal septum. Clinical findings correlate with the extent of nerve involvement, classification of disease, and presence of the immunologic complications known as reactions. (See 'Immunologic reactions' below.)
The examination should include evaluation of skin lesions and 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 of skin lesions, distal extremities, and motor evaluation should also be performed. Eyes should be examined by simple inspection of the conjunctiva and cornea, as well as assessment of corneal sensation.
●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 , 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 . Therefore, occasionally the organism may be observed in liver or bone marrow biopsies performed in the evaluation for fever of unknown origin . The disease can also involve other areas, such as the testicles (reduced testosterone) and larynx (hoarseness) .
●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.
Neuropathy — Nerve involvement occurs very early in the course of leprosy, as evidenced by the decrease or absence of sensation in the earliest diagnostic lesions . Preventing or minimizing injury to peripheral nerves is a major goal of treatment, and assessment of peripheral nerves is an essential component of every clinical examination for every patient. Most commonly, neuropathy manifests with loss of sensory perception, though, in some cases, patients can present with painful neuropathy, often later in the course of the disease [64,65].
In patients with tuberculoid disease, sensory and/or motor loss generally occurs in the distribution of nerves in the vicinity of the skin lesion; in patients with lepromatous disease, nerve damage may become more generalized. Commonly, nerve trunks involved include the ulnar and median nerves (claw hand), the common peroneal nerve (foot drop), the posterior tibial nerve (claw toes and plantar insensitivity), the facial nerve (lagophthalmos), the radial cutaneous nerve, and the great auricular nerve.
Subclinical neuropathy appears to be more prevalent in leprosy than was previously believed . Testing using monofilaments and other sensitive methods 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 than patients with lepromatous disease [67-69]. In a prospective study of early neuropathy diagnosis in leprosy, sensory nerve conduction, cold and warmth perception were the most frequently and earliest affected tests; in a large proportion of patients, these became abnormal ≥3 months or more before abnormalities were identified using monofilaments .
Segmental demyelination appears to be the final common pathway of nerve injury in leprosy; the mechanisms leading to this are poorly understood [4,66,71]. 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 . M. leprae antigens may provoke a humoral response inducing nerve damage. The lipoarabinomannan (LAM) molecule of M. leprae has been observed to colocalize with the membrane attack complex (MAC) in nerves of biopsies from leprosy patients . Another M. leprae antigen, PGL-1, has been shown to induce macrophages to produce nitric oxide (NO) that damages the mitochondria of axons in a zebrafish model .
Ophthalmic injury — Impairment of nerves innervating of the musculature of the eyelids and providing sensory innervation to the cornea may lead to lagophthalmos, drying of the cornea, corneal abrasion, and corneal ulceration . Careful inspection of the cornea and conjunctiva is an essential part of the examination of every leprosy patient. The ability to close the eyelids fully should also be assessed.
Immunologic reactions — Immunologic reactions are systemic inflammatory complications that may occur before 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 may affect 30 to 50 percent of all leprosy patients .
There are two types of leprosy reactions: type 1 (may be referred to as T1R, reversal reaction, or RR) and type 2 (may be referred to as T2R, erythema nodosum leprosum, or ENL). T1R typically occurs in patients with borderline disease (BT-BL), while T2R occurs in patients with lepromatous disease (BL-LL) (figure 1); distinguishing between the types can be difficult. The two types of reactions appear to have different underlying immunologic mechanisms, but both are poorly understood and the factors that initiate them are unknown [4,77].
A general feeling of fatigue, malaise, and fever may be present with both reaction types. Other manifestations include neuritis, arthritis, iritis, and nasopharyngeal symptoms. The inflammation associated with reactions can lead to severe nerve injury with subsequent paralysis and deformity. The reaction may simulate drug allergy, worsening of disease, new-onset neuropathy, or, in severe cases, septic shock.
The development of new lesions during or after completion of treatment is usually attributable to an immunologic reaction. Less common considerations include disease relapse and drug resistance. (See "Leprosy: Treatment and prevention", section on 'New skin lesions during or after treatment'.)
Type 1 reaction (T1R, reversal reaction) — Type 1 reaction typically occurs in patients with BT, BB, or BL disease. Clinical manifestations include:
●A red, swollen patch in preexisting skin lesion on the face or overlying a major nerve trunk
●Erythema and induration of preexisting skin lesions (picture 10)
●The inflammation associated with reactions can lead to severe nerve injury with subsequent paralysis and deformity
●Significant edema of the hands or feet, sometimes associated with small joint pain
●Ulcerated skin lesions
●Pain or tenderness in one or more nerves (eg, painful elbow, due to ulnar nerve involvement)
●Loss of nerve function with muscle weakness or loss of sensation (eg, new wound on the hand from coffee-mug burn) (picture 11)
In the absence of treatment, the natural course of T1R is several months. T1R appears to result from spontaneous enhancement of cellular immunity and delayed-type hypersensitivity to M. leprae antigens . Skin biopsies may reveal edema, increased granulomatous organization, or increased numbers of multinucleated giant cells, although these findings are seen in only about half of the cases . As a result, often the diagnosis must be made on clinical grounds alone. No routine laboratory tests are available to assist in the diagnosis. Elevated serum levels of chemokine CXCL10 have been strongly associated with the occurrence of T1R, although CXCL10 is not elevated in advance of the reaction and therefore does not appear to be predictive [79,80].
Risk factors and triggering events are not well understood [81,82]. 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 avoid a reaction.
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, erythema nodosum leprosum, ENL) — Type 2 reaction occurs in patients with BL and LL disease. A clinical severity scale for ENL has been developed that can assist clinicians in characterizing ENL and following response to treatment [83,84].
Clinically, T2R characterized by sudden eruption of numerous painful nodules (picture 12), which may be superficial or deep in the dermis. These can form pustules and may ulcerate, discharging yellow pus that contains polymorphs and degenerating acid-fast bacilli but is sterile on culture. Lesions are commonly found on the extensor surfaces of the limbs and on the face. They may last for a few days and may be succeeded by crops of new ones. As lesions fade, they may appear as brawny induration on the forearms and thighs. Biopsy of a new lesion within 24 hours demonstrates an infiltrate of polymorphs superimposed upon the chronic inflammation and heavy bacterial load of M. leprae. This is a very useful diagnostic test, since polymorphs are extremely rare in all other types of leprosy lesions.
Other clinical manifestations include high fever, headache, insomnia, and/or depression due to generalized pain, tender lymphadenopathy, orchitis, iridocyclitis, muscle tenderness, and painful and/or swollen joints. In the absence of treatment, the natural course of T2R is one to two weeks, but, frequently, the reaction is recurrent, sometimes over many months. Laboratory tests frequently demonstrate an elevated leukocyte count, low hemoglobin, and hematocrit. Elevation of liver function tests and serum C-reactive protein may be observed .
The Lucio phenomenon is a very rare complication presenting as sudden necrotizing vasculopathy in patients with longstanding, untreated lepromatous leprosy . It occurs primarily in patients whose ancestry is from Mexico, particularly the Sinaloa area. It presents with necrotizing, punched-out ulcerations that may be extensive in distribution and may be life threatening.
Risk factors for T2R include puberty, pregnancy, and lactation .
The mechanism of T2R is poorly understood. It is widely regarded as an immune complex disorder, although the evidence for this is not compelling . 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  and B cells  are altered during ENL, and neutrophils have been observed in the tissue lesions .
Management of T2R is discussed separately. (See "Leprosy: Treatment and prevention", section on 'Type 2 reaction (T2R, erythema nodosum leprosum [ENL])'.)
Laboratory tools — Laboratory tools include histopathologic examination of skin biopsies and polymerase chain reaction (PCR). No reliable blood or skin tests are available for diagnosis of leprosy.
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) . The NHDP Laboratory also offers histopathology services and molecular assays for detection of M. leprae and M. lepromatosis in tissues .
Skin biopsy — To assess the extent and type of infiltrate and involvement of dermal nerves, a full-thickness skin biopsy should be taken from the most active margin of the most active lesion, entirely within a lesion (picture 13). Routine hematoxylin and eosin sections demonstrate the range of findings across the spectrum discussed above. Examination of hematoxylin and eosin sections and Fite stains can aid in the early diagnosis and management of leprosy across the spectrum of disease.
Polymorphonuclear leukocytes are a hallmark of T2R, and fibrin thrombi are characteristic of Lucio lesions. No reliable histologic criteria have been identified for T1R, so this remains a clinical diagnosis. Mycobacterial culture should be performed on biopsies from skin lesions to exclude cutaneous infections due to M. tuberculosis and nontuberculous mycobacteria. To demonstrate M. leprae and/or M. lepromatosis, the Fite stain is superior to the standard Ziehl Neelsen stain.
Skin smears, in which a small incision is made (on the ears, elbows, and/or knees) to collect a dermal fluid sample, are no longer widely used.
Polymerase chain reaction — PCR is available for detection of M. leprae and M. lepromatosis DNA in tissue [2,92]. PCR is more useful as an identification tool (eg, when clinical or histologic features are inconclusive) than as a detection tool. In one study, PCR on biopsies from patients with lepromatous disease had sensitivity and specificity of >90 percent and 100 percent; PCR on biopsies from patients with tuberculoid disease had sensitivity and specificity of 34 and 80 percent, respectively . The NHDP laboratory performs PCR on biopsies submitted for pathologic review.
The lepromin test is not a useful diagnostic tool; it consists of injecting a calibrated number of autoclaved M. leprae injected into the skin; the results are assessed after three to four weeks. The test does not measure exposure or infection . A positive test reflects the ability to develop a granuloma following exposure to M. leprae antigens; a positive test does NOT indicate exposure to leprosy . Tuberculin skin tests (TSTs) do not significantly cross-react with M. leprae infection; in one study of a population in which tuberculosis was highly endemic, 70 percent of controls had positive TST, but only 15 to 50 percent of leprosy patients had positive TST .
Serologic tests — Serologic tests for M. leprae phenolic glycolipid-1 (PGL-1) are described but are not available in the United States because they are not sufficiently sensitive to provide a reliable measure of infection without other clinical or histologic evidence [97-99]. Patients with lepromatous disease develop a strong polyclonal antibody response to M. leprae that is not beneficial for fighting infection (but produces many false-positive serologic tests); these individuals have positive serologic responses to PGL-1. Patients with tuberculoid disease seldom produce antibody to PGL-1, and therefore the test is not helpful for diagnosis in these patients (for whom the diagnosis is usually most difficult). Many contacts have been found to have antibodies to PGL-1 also, but only a small percentage of them go on to develop the infection [100-102]. Thus, PGL-1 alone is not a reliable diagnostic test nor is it satisfactorily predictive of the development of infection.
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 14A-D). 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".)
●Fungal infection – Tinea typically begins as a pruritic, ring-shaped, erythematous, scaling patch or plaque that spreads centrifugally, followed by central clearing; the advancing border is erythematous and slightly raised (picture 15A-C). The diagnosis is established by potassium hydroxide preparation. (See "Dermatophyte (tinea) infections".)
●Annular psoriasis – Annular lesions are not a classic feature of psoriasis but occasionally occur. The diagnosis is facilitated by concomitant detection of features that are more typical of psoriasis such as classic plaques or signs of nail disease. The diagnosis is based on clinical manifestations and biopsy if needed. (See "Approach to the patient with annular skin lesions".)
●Keloid – Keloids are raised dermal lesions that form at a wound site and extend beyond the boundaries of the original wound to invade the surrounding skin. Keloids may also develop in the absence of a clear inciting stimulus. The diagnosis is based on clinical manifestations and biopsy if needed. (See "Keloids and hypertrophic scars".)
●Systemic lupus erythematosus – 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. (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 16). The diagnosis is established by skin biopsy. (See "Cutaneous leishmaniasis: Clinical manifestations and diagnosis".)
●Mycosis fungoides – Mycosis fungoides is characterized by heterogenous cutaneous manifestations including patches, plaques, tumors, generalized erythroderma, alopecia, or, rarely, papules. The diagnosis is established by skin biopsy. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)
●Neurofibromatosis – Cutaneous manifestations of neurofibromatosis include café-au-lait macules, axillary and/or inguinal freckling, and neurofibromas. The diagnosis is based on characteristic clinical features. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)
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".)
●General principles – Leprosy (also known Hansen's disease) is an infectious disease caused by mycobacteria of the Mycobacterium leprae complex that involve the skin and peripheral nerves. 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, Indonesia, Bangladesh, and Nigeria. 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, older age, genetic predisposition, and immunosuppression. (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 'Physical examination' 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 in a cutaneous nerve, or M. leprae and/or M. lepromatosis DNA by polymerase chain reaction. (See 'Laboratory tools' above.)
●Classification – Leprosy is classified using the following categories: tuberculoid (TT), borderline tuberculoid (BT), mid-borderline (BB), borderline lepromatous (BL), lepromatous (LL), and indeterminate (I) (figure 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 resistance 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 treatment has been completed. There are two types of leprosy reactions: type 1 (typically occurs in patients with borderline disease) and type 2 (occurs in patients with lepromatous disease) but distinguishing between the types can be difficult. (See 'Immunologic reactions' above.)
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