Dermatologic Manifestations of Leprosy

The earliest description of leprosy comes from India around 600 BCE. Leprosy was then described in the Far East around 400 BCE. In the fourth century, leprosy was imported into Europe, where its incidence peaked in the 13th century. Leprosy has now nearly disappeared from Europe. Affected immigrants spread leprosy to North America.

Armauer Hansen discovered M leprae in Norway in 1873. M leprae was the first bacillus to be associated with human disease. Despite this discovery, leprosy was not initially thought to be an infectious disease.

In 2008, the discovery of a new cause of leprosy, Mycobacterium lepromatosis, was announced. Genetically, M leprae and M lepromatosis are very similar, but M lepromatosis causes the diffuse form of lepromatous leprosy found in Mexico and the Caribbean.[9]  

Leprosy is included among the Neglected Tropical Diseases as designated by the World Health Organization.[10] In 2016, the WHO released a 5-year global leprosy strategy, running through 2020, to "strengthen government ownership, coordination, and partnership; stop leprosy and its complications, and to stop discrimination and promote inclusion."[11]

Leprosy is not a highly infectious disease. The principal means of transmission is by aerosol spread from infected nasal secretions to exposed nasal and oral mucosa. Leprosy is not generally spread by means of direct contact through intact skin, although the most vulnerable are close contacts of patients with untreated multibacillary disease.

However, in 2011, a unique strain of M leprae was genotyped in both humans and wild armadillos infected in the southern United States, suggesting a direct means of transmission. Several people had distinct contact with armadillos, including hunting, cooking, or eating armadillos.[12]

The incubation period for leprosy is 6 months to 40 years or longer. The mean incubation period is 4 years for tuberculoid leprosy and 10 years for lepromatous leprosy.

The areas most commonly affected by leprosy are the superficial peripheral nerves, skin, mucous membranes of the upper respiratory tract, anterior chamber of the eyes, and the testes. These areas tend to be cool parts of the body. Tissue damage depends on the degree to which cell-mediated immunity is expressed, the type and extent of bacillary spread and multiplication, the appearance of tissue-damaging immunologic complications (ie, lepra reactions), and the development of nerve damage and its sequelae.

M leprae is an obligate intracellular, acid-fast, gram-positive bacillus with an affinity for macrophages and Schwann cells. For Schwann cells in particular, the mycobacteria bind to the G domain of the alpha-chain of laminin 2 (found only in peripheral nerves) in the basal lamina, causing demyelination. Their slow replication within the Schwann cells eventually stimulates a cell-mediated immune response, which creates a chronic inflammatory reaction. As a result, swelling occurs in the perineurium, leading to ischemia, fibrosis, and axonal death. In vivo, M leprae has also been demonstrated to reprogram Schwann cells to de-differentiate into mesenchymal stem cells, which may explain the spread of bacteria to other non-neural tissues.[13]

With the completion of the genomic sequence of M leprae, one important discovery is that although it depends on its host for metabolism, the microorganism retains genes for the formation of a mycobacterial cell wall. Components of the cell wall stimulate a host immunoglobulin M antibody and cell-mediated immune response, while also moderating the bactericidal abilities of macrophages.

Research showed that M leprae also induces lipid droplet accumulation in macrophages and Schwann cells, with an increase in adipophilin/adipose differentiation-related protein (ADRP). ADRP opposes the action of hormone-sensitive lipase (HSL), which degrades lipids. Infected cells from slit-skin smears in lepromatous leprosy correlate with the findings, with expression of ADRP high and HSL low or undetectable.[14] Lipid metabolism, especially ω3 and ω6 polyunsaturated fatty acids, may also play a role.[15]

The strength of the host's immune system influences the clinical form of the disease. Strong cell-mediated immunity (interferon [IFN]-gamma, interleukin [IL]–2) and a weak humoral response results in mild forms of disease, with a few well-defined nerves involved and lower bacterial loads. A strong humoral response (IFN-beta, IL-4, IL-10) but relatively absent cell-mediated immunity results in lepromatous leprosy, with widespread lesions, extensive skin and nerve involvement, and high bacterial loads. Therefore, a spectrum of disease exists such that cell-mediated immunity dominates in mild forms of leprosy and decreases with increasing clinical severity. Meanwhile, humoral immunity is relatively absent in mild disease and increases with the severity of disease. T regulatory cells also appear to suppress the normal immune response.

Toll-like receptors (TLRs) may also play a role in the pathogenesis of leprosy.[16]  M leprae activates TLR2 and TLR1, which are found on the surface of Schwann cells, especially with tuberculoid leprosy. Although this cell-mediated immune defense is most active in mild forms of leprosy, it is also likely responsible for the activation of apoptosis genes and, consequently, the hastened onset of nerve damage found in persons with mild disease. Alpha-2 laminin receptors found in the basal lamina of Schwann cells are also a target of entry for M leprae into these cells, while activation of the ErbB2 receptor tyrosine kinase signaling pathway has been identified as a mediator of demyelination in leprosy.[17]

The activation of macrophages and dendritic cells, both antigen-presenting cells, is involved in the host immune response to M leprae. IL-1beta produced by antigen-presenting cells infected by mycobacteria has been shown to impair the maturation and function of dendritic cells.[18] Because bacilli have been found in the endothelium of skin, nervous tissue, and nasal mucosa, endothelial cells are also thought to contribute to the pathogenesis of leprosy. Another pathway exploited by M leprae is the ubiquitin-proteasome pathway, by causing immune cell apoptosis and tumor necrosis factor (TNF)–alpha/IL-10 secretion.[19]

Research continues to explore the pathophysiology of leprosy, with the goal of identifying early markers of disease and new targets for treatment. The most current investigations focus on interferons,[20] the vitamin D – dependent antimicrobial pathway,[21] and NOD2-mediated signaling pathways,[22, 23] as well as the role of T regulatory cells, Th-17/IL-17a/IL-17F cytokines, CD163, and galectin-3.[14]

A sudden increase in T-cell immunity, particularly in the Th1 pattern, is responsible for type I reversal reactions. TLR2 and TLR4 have also been implicated.[14] Type II reactions (erythema nodosum leprosum, ENL) result from activation of TNF-alpha and the deposition of immune complexes in tissues with neutrophilic infiltration and from complement activation in organs. Activated memory T cells are also increased in untreated ENL.[24] One study found that cyclooxygenase 2 was expressed in microvessels, nerve bundles, and isolated nerve fibers in the dermis and subcutis during reversal reactions.[25] Another found high levels of TNF, IFN-γ, IL-1β, and IL-17A Th-17 and low levels of IL-10 and TGF-β in ENL that were reversed after a 24-week course of prednisolone.[26] Other cytokines, cortisol levels, CXC ligand 10, and matrix metalloproteinases may also have a role in both type I and II reactions.[14, 27, 28]

Leprosy is caused by M leprae, an obligate intracellular, acid-fast, gram-positive bacillus. Humans are the primary reservoir of M leprae. Animal reservoirs of leprosy have been found in three species: 9-banded armadillos, chimpanzees, and mangabey monkeys.

Most persons are immune to leprosy. Subclinical disease is common in endemic areas, and the infection progresses to clinical disease in only a select few.

Biopsies of nasal and oral mucosa of individuals who remain untreated for years have demonstrated M leprae positivity,[29, 30] suggesting respiratory secretions are the main cause of infection. However, transmission is not completely understood.

Exposure to insect vectors and infected soil has also been suspected as a possible mode of transmission.

In endemic countries, household contacts of patients are at increased risk for contracting leprosy. The relative risk is 8-10 times for lepromatous leprosy and 2-4 times for tuberculoid leprosy. In nonendemic countries, household contacts rarely acquire the disease.

HIV infection is not a risk factor for acquiring leprosy, nor does it increase the clinical symptoms or virulence of leprosy. However, latent cases of leprosy infections may emerge as part of the immune reconstitution inflammatory syndrome after starting highly active antiretroviral therapy.[31, 32]

One report describes 2 cases of leprosy developing after treatment with infliximab.[33] Both patients developed type I reversal reactions after stopping the TNF-alpha inhibitor. Another patient developed a type I reversal reaction after stopping adalimumab therapy, despite no prior diagnosis of leprosy.[34]

Several cases of tattoo inoculation leprosy have been reported, most in India.[35]

Leprosy has been reported in conjunction with visceral leishmaniasis (kala-azar).

Several reports have described leprosy developing in solid organ transplant recipients (especially kidney) and after bone marrow transplantation. It is not clear about the susceptibility of patients due to general immunosuppressive conditions (as with HIV infection); however, most affected transplant recipients developed multibacillary disease.[36, 37]

The following genes have been associated with leprosy; hence, susceptibility or resistance to leprosy may be at least partially inheritable[23] :

With the first genome-wide association study (GWAS), the following loci have markers with the strongest associations:

• HLA-DR-DQ: HLA-DR2 and HLA-DR3 (tuberculoid disease), as well as HLA-DQ1 (lepromatous leprosy); HLA-DRB1*04 is associated with resistance, and HLA-DRB1*10 is associated with susceptibility to leprosy in Brazilian and Vietnamese patients.[38] RIPK2, TNFSFIS

• LACC1, CCDC122, and NOD2

• Additionally, there are numerous studies looking into the role of other HLA, KIR, MICA and cytokine genes in contracting leprosy.[39]

• Genetic variants have been found in the shared promoter region of the PARK2 (parkin) and PACRG genes expressed on monocytes.

• Lymphotoxin-alpha (LTA) + 80 expressed on dendritic cells appears to be a risk factor for early-onset leprosy, independent of PARK2/PARCG and HLA class I and HLA-DRB1 genes.[40, 41]

• Polymorphisms in the gene promoter regions of TNF (multibacillary leprosy) and IL-10 (-819T allele) are noted in leprosy susceptibility.

• Mutations in TLR1 and TLR2 may be involved in susceptibility and/or resistance to other infectious diseases.

• Polymorphisms in the NRAMP1 gene appear on macrophages in multibacillary disease in African patients.

• TaqI polymorphism (tt genotype) at exon 9 of the vitamin D receptor gene is noted.[42]

• IFGR1 gene promoter polymorphisms found in one family demonstrated an autosomal recessive susceptibility to leprosy.[43]

• Genetic markers that may identify those more susceptible to T1R and T2R include polymorphisms in vitamin D receptor, IL-6, complement component C4b, TLR1 and TLR2, and natural resistance-associated macrophage protein 1 (NRAMP1).[44]

Frequency

United States

Approximately 6500 patients with leprosy live in the United States, about 50% of which require active medical management. Approximately 95% of these patients acquired their disease in developing countries. In the United States, 200-300 cases of leprosy are reported each year. States with large immigrant populations (eg, California, New York, Florida) have the largest number of new cases of leprosy. Small endemic foci of leprosy exist in Texas, Louisiana, and Hawaii.

International

Overall, the worldwide prevalence of leprosy (defined as the number of people on multidrug therapy at a particular point) has decreased  significantly since the introduction of short-course multidrug therapy in 1982. The WHO’s elimination goal of less than 1 case per 10,000 population was reached in the early 2000s. Approximately 95% of affected persons are found in 16 countries, most of them in the tropics and subtropics: Bangladesh, Brazil, China, Democratic Republic of the Congo, Ethiopia, India, Indonesia, Ivory Coast, Madagascar, Myanmar, Nepal, Nigeria, Philippines, South Sudan, Sri Lanka, and the United Republic of Tanzania.[45]

Despite achieving the elimination goal quickly, eradication has proved to be more elusive. Globally, annual new case detection rates for leprosy remain unchanged, and even increased slightly from 2015 to 2016. While this increase is at least partially due to active methods of case-finding and new methods of reporting and data collection, there are still gaps and inconsistent reporting, especially from countries with endemic populations.[46] Clinically, transmission remains an issue. Twenty-two countries, including most of the ones listed above, account for 94-96% of new cases and have been deemed by the WHO as "global priority countries".[11]

Race

Leprosy occurs in persons of all races. African Blacks have a high incidence of the tuberculoid form of leprosy. People with light skin and Chinese individuals tend to contract the lepromatous type of leprosy. Leprosy is endemic in Asia, Africa, the Pacific basin, and Latin America (excluding Chile). Leprosy is more a rural than urban disease.

Sex

In adults, the lepromatous type of leprosy is more common in men than in women after puberty, with a male-to-female ratio of 2:1. In children, the tuberculoid form of leprosy predominates and no sex preference is reported. Women tend to have a delayed presentation, which increases rates of deformity.

Age

Leprosy has a bimodal age distribution, with peaks at ages 10-14 years and 35-44 years. Leprosy is rare in infants. Children appear to be most susceptible to leprosy and tend to have the tuberculoid form.

The prognosis depends on the stage of disease. Borderline tuberculoid leprosy usually involves rapid and severe nerve damage. Reversal reactions are uncommon with lepromatous disease; therefore, lepromatous leprosy is a chronic state with long-term complications. Even with MDT, patients have long-term nerve damage and disability.

The prognosis also depends on the patient's access to therapy, the patient's compliance, and the early initiation of treatment.

Relapse (new disease after adequate MDT is completed) occurs in 0.01-0.14% of patients per year in the first 10 years. Dapsone and/or rifampin resistance should be considered.[47]

Approximately 5-10% of patients have a type I reversal reaction in the first year after completing MDT.

Because of reduced cell-mediated immunity, pregnancy can precipitate a relapse or reaction of the disease, especially type II reactions in pregnant women younger than 40 years. Dapsone is generally thought to be safe in pregnancy; the safety of clofazimine and rifampin are controversial, and thalidomide (used in type II reactions) is contraindicated during pregnancy.

Type I and type II reactions can precipitate a relapse of the disease.

Perineural granulomas have been reported to persist 18 months after MDT and clinical improvement, and they are not considered to be a relapse of the disease.[48]

Overall, children have a good prognosis because multibacillary disease and leprous reactions are uncommon.

Patients first need an explanation of the diagnosis and prognosis. Their fears should be addressed because of the cultural stigma associated with leprosy. Importantly, refute any myths that the patient may have about leprosy. Patients may need psychological counseling because they may have difficulty coming to terms with the disease or may feel rejected by society. The patient should be reassured that within a few days of starting MDT, they are not infectious and can lead a normal life.

Patients need education about how to deal with anesthesia of a hand or foot. They must learn to carefully inspect their extremities for trauma each day. Patients should also be told to wear proper footwear and protective equipment as necessary. Inexpensive canvas shoes with protective insoles are as effective as special orthopedic shoes. Inspecting limbs and eyes for the onset of anesthesia or weakness is also important. Physical therapy and occupational therapy are important tools in rehabilitation.

Patients must learn how to recognize the onset of lepra reactions, and they should be told to seek immediate medical attention if these reactions develop.

Potential deformities can be prevented by educating patients about how to deal with existing nerve damage and by treating any sequelae of this damage.

In general, leprosy affects the skin, peripheral nerves, and eyes. Systemic symptoms of leprosy are also possible. Specific symptoms vary with the severity of the disease.

Prodromal symptoms are generally so slight that leprosy is not recognized until a cutaneous eruption is present. However, 90% of patients have a history of numbness first, sometimes years before the skin lesions appear.

Temperature is the first sensation that is lost. Patients cannot sense extremes of hot or cold. The next sensation lost is light touch, then pain, and, finally, deep pressure. These losses are especially apparent in the hands and feet; therefore, the chief complaint may be a burn or ulcer in an anesthetic extremity.

Other parts of the body that might be affected by leprosy are the cool areas, which can include superficial peripheral nerves, the anterior chamber of the eyes, the testes, the chin, malar eminences, earlobes, and knees. From this stage of leprosy, most lesions evolve into the tuberculoid, borderline, or lepromatous types.

Clinical tests

Certain tests can be performed in the clinic to aid in the diagnosis of leprosy.

Tissue smear testing/slit-skin smears

An incision is made in the skin, and the scalpel blade is used to obtain fluid from a lesion. The fluid is placed on a glass slide and stained by using the Ziehl-Neelsen acid-fast method or the Fite method to look for organisms. The bacterial index (BI) is then determined as the number of organisms at 100X with oil immersion. Skin smears have high specificity but low sensitivity because 70% of all patients with leprosy have negative smear results. However, this test is useful because it detects the most infectious patients.

Histamine testing

This test is used to diagnose postganglionic nerve injury. Histamine diphosphate is dropped on healthy skin and affected skin, and a pinprick is made through each site. The site forms a wheal on healthy skin, but not on skin where nerve damage is present.

Methacholine sweat testing

An intradermal injection of methacholine demonstrates the absence of sweating in leprous lesions. This test is useful in dark-skinned patients in whom the flare with the histamine test cannot be seen.

Diagnostic criteria for leprosy

The diagnosis of leprosy is primarily a clinical one. In one Ethiopian study, the following criteria had a sensitivity of 97% with a positive predictive value of 98% in diagnosing leprosy. Diagnosis was based on 1 or more of the 3 following signs:

• Hypopigmented or reddish patches with definite loss of sensation

• Thickened peripheral nerves with some degree of sensory loss or muscle weakness corresponding to the affected nerve

• Acid-fast bacilli on skin smears or biopsy material

Classification

Leprosy disease classification is used to differentiate types of cutaneous leprosy and helps in determining the prognosis; it has evolved from the 1940s to the present. The most familiar classification systems are the Ridley-Jopling classification (1960s) and a more simplified WHO dichotomy of paucibacillary and multibacillary disease introduced in 1982. The latter system is based on the number of lesions and was intended to help field personnel to quickly triage patients for treatment. Even if the WHO allows for initial classification without testing, it is recommended that a bacillary index is determined to ensure that patients are receiving the proper treatment.[49] Thus, a general classification of disease that combines elements of both of these systems is based on the number of skin lesions present and the number of bacilli found on tissue smears. Paucibacillary disease (indeterminate leprosy and tuberculoid leprosy) has five or fewer lesions and no bacilli on smear testing. More than five lesions with or without bacilli (borderline leprosies and lepromatous leprosy) is considered multibacillary disease. Classification may be further refined by considering other criteria, such as the number of body areas affected and the size of the largest skin lesions.[50]

Indeterminate leprosy

This early form causes one to a few hypopigmented or, sometimes, erythematous macules. Sensory loss is unusual. Approximately 75% of affected persons have lesions that heal spontaneously. In some, the disease may persist in this indeterminate form. In those with weak immunity, the disease progresses to one of the other forms.

Tuberculoid leprosy

Skin lesions are few. One erythematous large plaque is usually present, with well-defined borders that are elevated and that slope down into an atrophic center. The lesions can become arciform or annular. They can be found on the face, limbs, or elsewhere, but they spare intertriginous areas and the scalp. Lesions can be dry and scaly, hypohidrotic, and hairless. Another presentation involves a large, asymmetric hypopigmented macule. Both types of lesions are anesthetic and involve alopecia.

Spontaneous resolution can occur in a few years, leaving pigmentary disturbances or scars. Progression can also occur, leading to borderline-type leprosy. In rare instances in which a patient is untreated for many years, the lepromatous type can develop.

Neural involvement is common in persons with tuberculoid leprosy; it leads to tender, thickened nerves with subsequent loss of function. The great auricular, common peroneal, ulnar, and radial cutaneous and posterior tibial nerves are often prominent. Nerve damage can happen early, resulting in wrist drop or foot drop.

Borderline leprosy

Borderline tuberculoid leprosy

Lesions in this form are similar to those in the tuberculoid form, but they are smaller and more numerous. The nerves are less enlarged and alopecia is less in borderline tuberculoid leprosy than in other forms. Disease can remain in this stage, it can convert back to the tuberculoid form, or it can progress to lepromatous leprosy.

Borderline borderline leprosy

Cutaneous lesions consist of numerous, red, irregularly shaped plaques that are less well defined than those in the tuberculoid type. Their distribution may mimic those of the lepromatous type, but they are relatively asymmetric. Anesthesia is only moderate. Regional adenopathy may be present. Disease may remain in this stage, it may improve, or it may worsen.

Borderline lepromatous leprosy

Lesions are numerous and consist of macules, papules, plaques, and nodules. Annular punched-out–appearing lesions that look like inverted saucers are common. Anesthesia is often absent. As with the other forms of borderline leprosy, the disease may remain in this stage, it may improve, or it may regress.

Lepromatous leprosy

Early cutaneous lesions consist mainly of pale macules. Late infiltrations are present with numerous bacilli. Macular lesions are small, diffuse, and symmetric. The skin may be smooth and shiny, but skin changes do not occur in lepromatous leprosy until late in the course. Therefore, early lepromatous leprosy lesions have little or no loss of sensation, nerves are not thickened, and sweating is normal. Nerve loss is slow and progressive.

Hypoesthesia occurs first over extensor surfaces of the distal extremities, followed by weakness in the same areas.

Alopecia affects the lateral aspects of the eyebrows (madarosis), spreading to the eyelashes and then the trunk. Scalp hair remains intact.

Lepromatous infiltrations can be diffuse, can occur as nodules (called lepromas), or can be plaques. The diffuse type results in the thickened skin appearance of a leonine facies. Neuritic lesions are symmetric and slow to develop.

Eye involvement occurs, causing pain, photophobia, decreased visual acuity, glaucoma, and blindness.

Nasal infiltration can cause a saddle-nose deformity and impaired olfaction. Hoarseness ("leprous huskiness") and stridor are a result of laryngeal involvement.[51]

Oral lepromas, usually located on the hard and soft palate, uvula, tongue ("cobblestoning"), lips, and gums, can progress to necrosis and ulceration. Tissue destruction may result.[52]

Infiltration of the helix or megalobule (elongation and wrinkling of the earlobe) may occur.

Lymphadenopathy and hepatomegaly can result from organ infiltration.

Aseptic necrosis and osteomyelitis can occur with repeated trauma after joint invasion.

Brawny edema of the lower extremities is a late finding.

Unlike the other types of leprosy, lepromatous leprosy cannot convert back to the less severe borderline or tuberculoid types of disease.

Histoid leprosy

This is a recognized clinical variant of lepromatous leprosy.[53] It can occur as a result of M leprae resistance to monotherapy of MDT. Reports of de novo histoid leprosy suggest that it may also possibly evolve from borderline or indeterminate leprosy. Paucibacillary and multibacillary forms also exist. They may present as firm plaques or nodules. The lesions may occur on the thighs/buttocks, back, face, and extremities, especially bony areas like the elbows and knees. Eyebrows and nasal cartilage are usually spared.

Pure neural leprosy

This occurs in the absence of skin lesions, presenting with mononeuritis (isolated peripheral nerve involvement, including cranial nerves), mononeuritis multiplex, and polyneuritis.[54] Nerve abscesses have been reported.[55] Slit-skin smears are negative. However, cutaneous lesions may follow, which would require reclassification into one of the traditional categories listed above.[6]

Lepra reactions

Lepra reactions, including erythema nodosum leprosum (ENL), are complications that occur in 20-50% of patients after the start of therapy or occasionally before therapy (see Complications).

Reactional states occur in approximately 20-50% of patients and are acute inflammations of the disease. They may be induced by MDT, physical or mental stress, puberty, childbirth, trauma, pregnancy, or surgical procedures. A leprous reaction should be considered a medical emergency and mandates immediate care. These states can result in permanent neurologic sequelae and are the leading causes of grade 2 disability. Patients at the highest risk are those with multibacillary leprosy, those with preexisting/persistent nerve impairment, those with positive anti-PGL-I, and those with positive bacillary indexes in skin smears.[56] MDT should be continued through the reactional episode.

Lepra type I (reversal) reactions usually affect patients with borderline disease. Reversal reactions are a shift toward the tuberculoid pole after the start of therapy, and they are type IV cell-mediated allergic hypersensitivities, with CD4+ lymphocytes infiltrate lesions with high levels of IFN-gamma and TNF-alpha, indicating an improvement in cell-mediated immunity. These reactions are characterized by increased inflammation of preexisting lesions and edema of the face and extremities, with edema and tenderness of peripheral nerves. New skin lesions are common, and the patient may have an acute febrile illness. The peak time for type I reactions is during the first 6 months of therapy and for up to 12 months. Corticosteroid treatment is aimed at controlling acute inflammation, relieving pain, and reversing nerve and eye damage. With treatment, approximately 60-70% of the patient's nerve function is recovered.[57] If neuritis is absent, NSAIDs may be helpful. Skin lesions have been successfully treated with the addition of topical tacrolimus.[58]

Lepra type II reactions, or erythema nodosum leprosum (ENL), occur in approximately 10% of patients with borderline lepromatous leprosy and in 20% of patients with lepromatous leprosy. These reactions are type III humoral (antibody-antigen) hypersensitivities, with a systemic inflammatory response to immune complex deposition. The most common presenting symptoms are crops of painful erythematous nodules of the skin and subcutaneous tissue. Sweet syndrome –like lesions have also occurred.[59] Bullae, ulcers, and necrosis also may occur.[60] Nerve damage is slower than in reversal reactions. The reaction usually manifests after a few years of therapy, and, although a single acute episode is possible, relapses occur intermittently over several years. Associated fever, malaise, arthralgias, neuralgia, iridocyclitis, dactylitis, orchitis, and proteinuria may be present. The use of clofazimine in MDT substantially reduces the incidence of ENL to 5%. Clofazimine has also been used to treat ENL. Mild cases can be treated with NSAIDs. Thalidomide is effective except in the case of neuritis or iritis, in which case corticosteroids should be used. Thromboembolic events are reported with thalidomide use.[61]  Other treatment therapies reported to be effective include colchicine, pentoxifylline, cyclosporine A, azathioprine,[62] methotrexate,[63] intravenous immunoglobulin, infliximab,[64] and etanercept.[65]

Lowering the dose of dapsone may decrease the severity of bullae and ulcers.

Lucio phenomenon[66] is a cutaneous necrotizing vasculitis that is sometimes designated a type II reaction. It is common in Mexico and Central America and is characterized by erythematous, geometric, irregular-shaped macules that rapidly progress to ulceration and necrosis on acral areas or extremities of patients with diffuse lepromatous leprosy. Systemic symptoms such as hepatosplenomegaly, fever, arthritis, and nephritis are usually present. Thalidomide is ineffective in treating this type of reaction; however, no consensus on treatment had been determined.[67] Most patients with Lucio phenomenon have not received MDT or were treated irregularly; therefore, MDT is recommended. Azathioprine or cyclophosphamide with corticosteroids with or without plasmapheresis has also been used.

The real challenge in managing leprosy is the treatment of reactional states.

If the course of MDT is not complete, continue taking those medications as directed.

Systemic steroids are effective in reducing inflammation and edema in reversal reactions; therefore, they are the most helpful medications in preventing nerve damage.

Prednisone at 1-2 mg/kg/d should be given until clinical improvement is seen, then tapered slowly over 3-6 months (and possibly longer).[68] One study suggests a course of at least 8 months.[69] This long course is necessary to decrease the severity of disabilities and deformities.

Clofazimine can also be used as a steroid-sparing agent for reversal reactions, alone or with corticosteroids.

Although the World Health Organization (WHO) does not support its use for ENL, thalidomide is highly effective with ENL. It is ineffective for the treatment of reversal reactions.

It is not unusual for an immunosuppressive therapy for a reactional state to cause a re-activation of a latent comorbid infection. Consider screening for chronic hepatitis B, chronic strongyloidiasis, latent tuberculosis, Chagas disease, and human immunodeficiency virus (HIV) infections before starting MDT, in patients who come from geographic areas where any of these conditions are endemic.[70]

Neuropathy induced by leprosy can result in trauma, pressure necrosis, or secondary infection that goes unnoticed, leading to amputation of digits or limbs. Wrist and foot drop are also common. Silent neuropathy can occur in the absence of overt signs of nerve or skin inflammation. Even with corticosteroid treatment, only approximately 60% of nerve function is recovered. Cyclosporine A may be useful in controlling nerve impairment and pain.[71] Intraneural corticosteroid injection in one case resulted in nerve regeneration and improved sensory and motor function.[72] Tibialis posterior transfer by the interosseus route with early postoperative mobilization can correct foot drop in leprosy.[73, 74]

Injuries can result in ulcerations, cellulitis, scarring, and bony destruction. Foot ulcers discovered early should be treated with rest because they heal if they are not subject to weight bearing.

Osteoporosis and fractures can result from bony changes due to leprosy. Risedronate and other bisphosphates may help improve lumbar bone mineral density.[75]

Contractures can develop and may result in fixation. Common sequelae include clawing of hands and feet.

Arthritis/arthralgias may occur in approximately 10% of patients with leprosy and joint symptoms, and in conjunction with reactional states. Most have polyarticular symmetric arthritis. The arthritis is generally not responsive to conventional therapy, but 50% become asymptomatic within 24 months of diagnosis.[76]

Eye damage, especially in the anterior portion of the eye, can result in loss of the corneal reflex, lagophthalmos, ectropion, entropion, and blindness. One study found the risk of ocular complications in patients with multibacillary disease, after completion of MDT, to be 5.6%, with eye-threatening complications at 3.9%.

Skin drying and fissures can be caused by autonomic disruption.

Hypogonadism and testicular atrophy can lead to sterility and gynecomastia. Testosterone replacement is the treatment of choice.

Renal involvement in leprosy, particularly lepromatous leprosy and ENL, have been described. Findings may range from hematuria and proteinuria to acute and chronic glomerulonephritis, interstitial nephritis, and pyelonephritis.[77]

Lepromin testing

This test indicates host resistance to Mycobacterium leprae. Its results do not confirm the diagnosis, but they are useful in determining the type of leprosy.

A positive finding indicates cell-mediated immunity, which is observed in tuberculoid leprosy. A negative finding suggests a lack of resistance to disease and is observed in patients with lepromatous leprosy. A negative result also indicates a worsened prognosis.

To perform this test, bacillary suspension is injected into the forearm. An assessment of the reaction at 48 hours is called the Fernandez reaction, and a positive result indicates delayed hypersensitivity to antigens of M leprae or mycobacteria that cross-react with M leprae. When the reaction is read at 3-4 weeks, it is called the Mitsuda reaction, and a positive result indicates that the immune system is capable of mounting an efficient cell-mediated response.

Serology and polymerase chain reaction (PCR) testing

These are most useful in detecting multibacillary disease. However, serological tests to detect early or subclinical leprosy as a supplement or alternative to histopathology has become more important in the quest to reduce the number of new cases.

The most common serologic test detects antibodies to M leprae–specific phenolic glycolipid-I (PGL-I). This test is useful primarily in patients with untreated lepromatous leprosy, because 90% of patients have antibodies. However, antibodies are present in only 40-50% of patients with paucibacillary disease. PGL-I antibody levels decline significantly during MDT; therefore, these levels may be monitored for chemotherapy effectiveness.[79]

Lateral flow assays can detect PGL-I antibodies within 10 minutes with a sensitivity of 90-97.4% in multibacillary leprosy patients. It has the added advantages of using whole blood (versus serum), the technique is easily taught, the results are easily interpreted, and it requires no special equipment.[80] The immunogold OnSite Leprosy Ab Rapid test [Gold-LFA] and the luminescent up-converting phosphor anti-PGL-I test [UCPLFA] may be especially useful in detecting multibacillary patients with low bacillary indices.[81]

The use of the anti–45-kd and modified anti-PGL-I antibody assays in combination may be more sensitive in detecting cases of paucibacillary leprosy than either assay individually.[82]

A combination of the MDO-LID test and the Smart-Reader system (a cellphone-based test reader platform) has demonstrated 87% sensitivity on multibacillary patients and 32.3% on paucibacillary patients, with a specificity of 97.4%.[83]

PCR analysis targeting 16s ribosomal RNA can be used to detect and identify M leprae. The technique is used most often when acid-fast bacilli are detected but clinical or histopathologic features are atypical. Specimens for PCR should be fixed in alcohol or should be rapidly processed because prolonged formalin fixation decreases the sensitivity.[84]

In-situ PCR directed against the 36-kd antigen of M leprae has shown promise in detecting 60% of suspect and 70% of early leprosy.[85]

The development of a one-step reverse transcriptase PCR assay may be more sensitive in detecting bacilli in slit smears and skin biopsy specimens. This RNA-based assay is also effective for monitoring bacteria clearance during therapy.[86]

Rapid diagnostic tests and enzyme-linked immunosorbent assay (ELISA) systems continue to evolve and be highly sensitive and specific.[87]  One study in Brazil found an increase of IgM and IgG (specifically IgG1 and IgG) antibodies against NDO-HSA, LID-1, and NDO-LID detected by ELISA in multibacillary patients.[88]

Cytology

Fine-needle aspirate (FNA) cytology with Ziehl-Neelsen staining and multiplex PCR was successful in diagnosing pure neural leprosy in the field.[89]

Diagnosis of erythema nodosum leprosum has been made using H&E staining with modified Ziehl-Neelsen stain on FNA material.[90]

Radiographs

Plain radiographs may be useful to detect and monitor leprosy-induced bone changes.[91]

Resorption, fragmentation, and maligned fractures are common signs of leprosy-induced bone changes. Medullary sclerosis or wavy diaphyseal borders indicate diaphyseal whittling.

Ultrasound

Sonographic measurement of peripheral nerves to calculate cross-sectional areas to determine nerve enlargement and entrapment is increasingly useful in the diagnosis of pure neural leprosy.[92] Well-established as a method of nerve evaluation, it also offers the advantages of being low-cost, widely available, and noninvasive.[93]

Color Doppler can also be applied to evaluate for normal hypovascularization and increased vascularity with inflammation.[4]

Nerve conduction studies (NCS), either at the muscle or at the nerve itself, are most useful in diagnosing nerve impairment, especially in pure neural leprosy, in which the neuropathy may be silent. At the least, NCS can help in determining the nerve from which to obtain a biopsy specimen from for histology studies.[6]

In the indeterminate form, findings are nonspecific. Histiocytes and lymphocytes are scattered, with some concentration around dermal appendages and nerves. At times, an acid-fast bacillus can be observed in a nerve bundle. The number of dermal mast cells may be increased.

In the tuberculoid form of leprosy, well-developed epithelioid granulomas are observed in the papillary dermis, often around neurovascular structures. The granulomas are surrounded by lymphocytes, which extend into the epidermis. Langhans giant cells are common. Dermal nerves are destroyed or swollen because of the granulomas. Acid-fast bacilli are not observed. S-100 is useful in identifying nerve fragmentation and differentiating it from other granulomatous disease.[94] Fite-Faraco staining combined with PCR was shown to be more sensitive than H&E and Ziehl-Neelsen staining.[95]

In the borderline tuberculoid form, well-developed epithelioid cell granulomas are apparent and diffuse, but few or no Langhans giant cells are observed. Few lymphocytes are present in the epidermis in this form, compared with tuberculoid leprosy. Bacilli are absent or rare, but they can be found in dermal nerves and in the arrector pilorum. Nerves are moderately swollen.

In the borderline borderline form of leprosy, diffuse epithelioid granulomas that lack giant cells are observed in the dermis below the subepidermal zone of uninvolved papillary dermis (ie, grenz zone). Nerves are slightly swollen, and acid-fast bacilli are present in moderate numbers.

In the borderline lepromatous form, smaller granulomas with some foamy changes and numerous lymphocytes are observed. Nerves often have an onionskin appearance as a result of invasion of the perineurium. A few epithelioid cells may be observed.

In the lepromatous form of leprosy, a diffuse infiltrate of foamy macrophages is present in the dermis below a subepidermal grenz zone. An enormous number of acid-fast bacilli develop within the foamy macrophages, singly or in clumps, called globi. Lymphocytes are scant, and giant cells are typically absent. Numerous bacilli invade the nerves, but these are fairly well preserved with little infiltrate. Nodular, or dermatofibroma-like lesions in lepromatous leprosy, referred to as histoid leprosy, result in a diffuse fascicular arrangement of spindled cells in the dermis admixed with foamy macrophages that contain numerous bacilli.

The histoid form has spindle-shaped clusters of histiocytes in a whorled or parallel pattern. In paucibacillary histoid leprosy, these clusters are in the papillary and mid dermis. Multibacillary histoid leprosy has a grenz zone with the histiocytes located in the mid and deep dermis.[96] Globus formation is usually absent. They also tend to grow in an expansive, rather than infiltrative, manner. Bacilli are notably longer than ordinary lepra bacilli.

Compared to primary leprosy, the histology of reversal reactions are more edematous, with a greater number of lymphocytes and macrophages with epithelioid characteristics. Foci of necrosis and epidermal involvement are also seen.[68]

In pure neural leprosy, biopsies of the nerve may show similar histology to that of an affected cutaneous lesion. If unaffected skin near an affected nerve was taken, a clue may be an inflammatory infiltrate around cutaneous nerve filaments.[6]

Paucibacillary disease can be treated with a combination of 2 drugs, whereas multibacillary disease requires triple-drug therapy. Single skin lesions (paucibacillary) can be treated with a single dose of 3 drugs. The length of treatment depends on the type of disease and on the access to drugs.

WHO and US treatment regimens for paucibacillary and multibacillary disease are listed below. Therapy for single skin lesions is not universal, because 80% of single skin lesions heal spontaneously. Therefore, only the WHO has a recommended treatment.

Current WHO recommendations for treatment of leprosy are as follows[97] :

• Paucibacillary disease - Dapsone at 100 mg/d plus rifampin at 600 mg once a month for 6 months; children aged 10-14 years – Dapsone at 50 mg/d plus rifampin at 450 mg once a month for 6 months

• Multibacillary disease - Dapsone at 100 mg/d plus rifampin at 600 mg once a month plus clofazimine at 300 mg once a month and 50 mg/d for 1 year; children aged 10-14 years - Dapsone at 50 mg/d plus rifampin at 450 mg once a month plus clofazimine at 150 mg once a month and 50 mg/d for 1 year

• Single skin lesion - A single dose of rifampin at 600 mg, ofloxacin at 400 mg, and minocycline at 100 mg; children aged 10-14 years - Single dose of rifampin at 300 mg, ofloxacin at 200 mg, and minocycline at 50 mg; treatment of single skin lesions not recommended for pregnant women and children younger than 5 years

Current US recommendations for the treatment of leprosy are as follows (regimens for children are general guidelines)[98] :

• Paucibacillary disease - Dapsone at 100 mg/d plus rifampin at 600 mg/d for 1 year; for children, dapsone at 1 mg/kg/d plus rifampin 10-20 mg/kg/d for 1 year

• Multibacillary disease - Dapsone at 100 mg/d plus rifampin at 600 mg/d plus clofazimine at 50 mg/d for 2 years; for children, dapsone at 1 mg/kg/d plus rifampin 10-20 mg/kg/d plus clofazimine at 1 mg/kg/d for 2 years (In the United States, clofazimine can only be obtained as an Investigational New Drug (IND) through the National Hansen's Disease Program [1-800-642-2477].)

Resistance to rifampin and dapsone has been reported.[99] WHO treatment recommendations are as follows[97] :

• Rifampin resistance: 24-month treatment broken down as 6 months of 50-mg/d clofazimine, 400-mg/d ofloxacin, and 100-mg/d minocycline, followed by 18 mo of 50-mg/d clofazimine plus 400-mg/d ofloxacin or 100-mg/d minocycline

• Dapsone resistance in paucibacillary disease - Clofazimine is substituted for dapsone; clofazimine at 300 mg once a month and 50 mg/d plus rifampin at 600 mg once a month for 6 months

• Dapsone resistance in multibacillary disease: Treat as described above with only clofazimine and rifampin, omitting the dapsone

• Other drugs that have been proposed as alternatives include moxifloxacin and rifapentine, but no specific regimens have been validated as effective.

Recommended monitoring guidelines for medications are found at the Hansen's Disease Recommended Treatment Regimens.

A modified course of multidrug therapy (MDT) using rifampin and clofazimine was used effectively in patients with dapsone hypersensitivity syndrome.[100]

A small study also demonstrated the efficacy of a 4-week regimen of 600 mg of rifampin and 400 mg ofloxacin for paucibacillary disease.[101]

Treatment of pure neural leprosy often follows that of multibacillary disease.

Skin lesions usually resolve within the first year of treatment, although some may persist for up to 5 years in multibacillary disease.

Lack of improvement despite MDT may be due to anergy. This may be proven by a negative Mantoux test prior to administering the BCG injection. When given with MDT, BCG stimulates the suppressed cell-mediated immunity to produce a delayed hypersensitivity reaction, and induces clearance of bacilli.[102]

One promising avenue to measure treatment efficacy may be to follow immunoglobulin G levels of LID-1 fusion protein, and ML0405 and ML2331, both recombinant proteins. One study of Brazilian and Venezuelan patients demonstrated a decrease in reactivity across the clinical spectrum (highest levels in lepromatous leprosy → lowest levels in paucibacillary leprosy) and with MDT.[103]

Potential deformities can be prevented by educating patients about how to minimize existing nerve damage and by treating any sequelae of this damage. Close follow-up is important to ensure patient compliance (see Complications).

Methotrexate may be useful in the management of inflammatory response leprosy reactions, particularly when corticosteroids are contraindicated.[104]

Further inpatient care

Patients with leprosy may need hospitalization for acute complications. Sanatoria, which were widely used in the past, are no longer necessary. Most patients can be treated in an outpatient setting.

Community-based rehabilitation programs are important to integrate and support people with leprosy and their families.

Emergency surgery may be necessary if a patient with profound nerve inflammation presents with a nerve abscess or loss of nerve function secondary to compression. Prompt recognition and surgical drainage of the abscess can often restore nerve function.

Elective surgery may be required for correction of lagophthalmos (ie, inability to close the eye).

Reconstructive surgery can be used to repair nasal collapse in patients with lepromatous leprosy, but it is not recommended until the disease has been inactive for a minimum of 1 year.

Other surgery may be needed to improve function or for cosmesis.

Contractures can be surgically repaired.

Consultations with an ophthalmologist, a plastic surgeon, an orthopedic surgeon, an otolaryngologist, a neurosurgeon, and/or a neurologist may be necessary.

Reasons for a consultation with an ophthalmologist include the following:

• Lagophthalmos

• Erythema nodosum leprosum (ENL)–induced iritis

• Direct invasion of the anterior chamber of the eye by Mycobacterium leprae

• Corneal and conjunctival insensitivity

• Infection or scarring from involvement of CN V and CN VII

• Cataracts

Specialists in rehabilitation medicine, including physical and occupational therapists, can help in reducing morbidity.

Consultation with a prosthetics specialist also may be appropriate.

Restrictions on activity depend on the extent of nerve damage.

In patients with bone or joint destruction, weight bearing should be minimized.

Patients with anesthesia of the limbs must be educated about their condition, and they should wear appropriate protection (especially footwear).

Plantar ulceration requires rest and avoidance of weight bearing.

Weakness or paralysis requires physical therapy to prevent contractures.

No skin or serologic tests are available to identify a carrier of leprosy.

In the southern United States, close contact with armadillos should be avoided.[12]

Household contacts of patients with lepromatous disease should be monitored annually for 5 years after diagnosis. There are no universal recommendations for chemoprophylaxis. Children especially should be observed for the development of disease. In endemic countries, chemoprophylaxis may be useful in controlling leprosy. The Prospective (sero-)Epidemiological Study on Contact Transmission and Chemoprophylaxis in Leprosy (COLEP) found that a single dose of rifampin was 57% effective in preventing leprosy in contacts for the first 2 years after diagnosis of a new index case.[105] A 6-year follow-up reported sustained lack of additional prevention beyond 2 years. However, this remained statistically significant. It also found that the most effective groups affected were in the contact groups of female index cases and in those who were in the contact groups of 2 or more leprosy patients.[106] In the United Kingdom, close contacts of lepromatous leprosy patients younger than 12 years are given rifampin at 15 mg/kg once a month for 6 months as prophylaxis.[107]

Attempts have been made to develop a vaccine against leprosy. Although not widely used, antileprosy vaccination can be immunoprophylactic and therapeutic. Current vaccines with various degrees of use are the BCG vaccine; the Mycobacterium w vaccine; the Mycobacterium avium-intracellulare complex (Mycobacterium ICRC) vaccine; and the BCG plus heat-killed Mycobacterium leprae, Mycobacterium tufu, and Mycobacterium habana vaccine.

The BCG vaccine has variable results in protecting certain populations; therefore, it is not widely prescribed. However, repeat immunization with the BCG vaccine may result in further protection. In the United Kingdom, the BCG vaccine is given to household contacts younger than 12 years.

In India, the Mycobacterium w and Mycobacterium ICRC vaccines are given. Mycobacterium w has a synergistic effect with chemotherapy, with accelerated clearing of the infection and shortening of treatment.

Follow-up to monitor post-MDT reactions is no longer necessary because these reactions are rare. Nonetheless, prevention of disability and rehabilitation is important; therefore, suggested follow-up is 5-10 years after treatment is completed. Patients should be educated about the clinical signs of reoccurrence and should be instructed to return for an evaluation if they have any skin, eye, or nerve changes. Periodic assessments for neural impairment are recommended, and prompt treatment of reactions substantially reduces and prevents further damage and disability. Previous nerve involvement is predictive of further nerve function impairment.

Sensation and muscle strength in the hands, feet, and eyes should be checked on a regular basis. The eyes, nerves, and nose should be examined at follow-up to ensure timely recognition of reactivated disease.

Class Summary

Antimicrobials are used to eliminate organisms. The first-line drugs are dapsone, rifampin, and clofazimine. Clofazimine can also be used alone to treat type II (ENL) reactions. Second-line agents include minocycline, ofloxacin, and clarithromycin, which can be used to treat a single skin lesion or to treat patients with dapsone allergy.

Dapsone (Avlosulfon)

Dapsone blocks folic acid synthesis. It is bacteriostatic and weakly bactericidal. It was widely used as monotherapy for leprosy until resistance developed. Now it is part of MDT for leprosy.

Rifampin (Rifadin, Rimactane)

Rifampin is bactericidal for M leprae. It inhibits DNA-dependent RNA polymerase, interfering with bacterial RNA synthesis. It is part of MDT for leprosy.

Clofazimine (Lamprene)

Clofazimine is a red, fat-soluble, crystalline dye. It inhibits mycobacterial growth and binds preferentially to mycobacterial DNA. It has antimicrobial properties. One mechanism of action may be to modulate M leprae-mediated effects on ADRP and HSL, subsequently affecting lipid metabolism in macrophages. It is slowly bactericidal against M leprae. Clofazimine has anti-inflammatory properties.

Minocycline (Minocin)

Minocycline is bacteriostatic. It inhibits bacterial protein synthesis by reversibly binding at the 30S unit.

Ofloxacin (Floxin)

Ofloxacin is a pyridine carboxylic acid derivative with broad-spectrum bactericidal effects. It inhibits DNA gyrase, interfering with bacterial DNA synthesis.

Class Summary

These anti-inflammatory agents are used primarily in the treatment of type I (reversal) reactions and silent neuropathy (see Complications). These drugs can be used to treat leprosy reactions when a risk of neurologic deficits is present or when moderately inflamed lesions occur in cosmetically important places. Systemic corticosteroids may also be used to treat type II reactions.

Prednisone (Deltasone)

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. It stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Class Summary

These agents are especially useful in treating type II (ENL) reactions. Thromboembolic events are reported with thalidomide use.

Thalidomide (Thalomid)

Thalidomide is an immunomodulatory agent that may suppress excessive production of TNF-alpha and down-regulate selected cell-surface adhesion molecules involved in leukocyte migration. It can be used to treat recurrent or refractory ENL.