Hansen disease, or leprosy, is a chronic granulomatous bacterial infection that primarily affects the skin and peripheral nerves. The disease is caused by an obligate intracellular bacillus, Mycobacterium leprae, which was identified in the 19th century by the Norwegian physician Gerhard Henrik Armauer Hansen.1 The clinical presentation and histopathologic changes depend on the immune status of the patient at the time of infection and over the natural course of the disease. Diagnosis is currently based on 3 cardinal signs specified by the World Health Organization (WHO): hypopigmented or erythematous macules with sensory loss, thickened peripheral nerves, and a positive acid-alcohol-fast smear or skin biopsy.2 Modern multidrug therapy and new antibiotics of proven efficacy have made it possible to meet the WHO's targeted reduction in the incidence of Mleprae infection to a single case per 10000 inhabitants in countries where the disease is endemic. A new pathogen, Mycobacterium lepromatosis, has recently been found to cause endemic disease in Mexico and the Caribbean.3 These developments call for new medical perspectives on how to cope with a problem that is still far from resolved.

National leprosy programs implemented from 2006 through 2010 were successful in meeting the WHO's target for regions where leprosy is endemic. Reports on the situations in 141 countries were sent to the WHO in the final months of 2010. A total of 244 796 new cases were registered in 2009, with southeast Asia having the largest number (166 115 new cases); at the beginning of 2010 the worldwide prevalence was 211 903 cases.4 Currently this mycobacterial infection is endemic in more than 15 countries, but 83% of the cases are found in 3 countries: India, Brasil, and Birmania.2,4 India registered 64% of all cases. The reported prevalence of leprosy was 212 802 cases in 2008, and 2007 saw 254 252 new cases registered. The number of cases fell by 11 100 (4%) from 2006 to 2007 (Fig. 1).

Figure 1.

Number of new cases registered from 2003 to 2009 in 16 countries reporting more than 1000 cases each year. Source: Global Leprosy Situation 2010.4

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At the beginning of the 1990s, the WHO proposed their “final push strategy” for leprosy with the clear purpose of elimination, defined as a prevalence below a single case per 10 000 inhabitants in endemic regions.4 Countries like the Democratic Republic of the Congo and Mozambique reported reaching the goal, but the disease remains highly prevalent in other parts of the world. Lower prevalence rates are unrelated to the reduction in the number of new cases found. This change in prevalence does not reflect a decrease in M leprae transmission; rather, it is related to the shorter period of treatment recommended by the WHO or to the exclusion from registries of patients who have been cured or who have died.

Countries where leprosy had previously been eliminated report a rise in imported cases; one example is Spain, where most imported cases have come from South America or sub-Saharan Africa.5

Mleprae is an acid-alcohol-fast, gram-positive obligate intracellular bacillus that shows tropism for cells of the reticuloendothelial system and peripheral nervous system (notably Schwann cells); this mycobacterium is the only one with these characteristics. The taxonomic order is Actinomycetales, the family Mycobacteriaceae. Mleprae organisms are slightly curved, measure from 1 to 8μm in length and 0.3μm in diameter; like other mycobacteria, they replicate by binary fission.

The leprosy bacillus has a predilection for macrophages, collecting in intracellular groups called globi. Although never cultured in vitro, Mleprae has been grown in the foot pads of 9-banded armadillos. Replication takes from 11 to 13 days, considerably longer than the 20hours required by Mycobacterium tuberculosis. Predisposed to infect cold areas of the body such as the skin, nasal mucosa and peripheral nerves (especially superficial ones), Mleprae grows best at temperatures between 27°C and 30°C. The efficacy of this pathogen within a narrow ecological niche is primarily explained by the properties conferred by 2 structural elements: the capsule and the cell wall.6

The capsule is made up of a large number of lipids, mainly phthiocerol dimycocerosate and phenolic glucolipid-1, which is the target of an intense immunoglobulin M-mediated humoral immune response.2,6,7 Another important component of the cell wall is lipoarabinomannan, which is an antigen for the macrophage. Many of the functional genes found in other mycobacteria have been silenced or transformed into pseudogenes, thereby inactivating functions such as extracellular reproduction. Thus, a set of metabolic and reproductive functions make M leprae an obligate intracellular bacterium with a long reproductive cycle.

M leprae has a predilection for Schwann cells, explained by specific binding to the G domain of the laminin-α2 chain, which is expressed specifically in the basal lamina of peripheral nerves. Once the pathogen penetrates a cell, replication proceeds slowly until T cells recognize the mycobacterial antigens and a chronic inflammatory reaction begins.7

Development of the disease, with clinical manifestations, depends on the patient's immune status. A role for genetics, associated with a susceptibility locus at chromosome 10p13 near the mannose receptor 1 gene, has now been suggested; mannose receptors on the surface of macrophages are important in phagocytosis.8 In addition, class II HLA/major histocompatibility complex genes at chromosome 6 have also been implicated in the type of leprosy a patient develops. The HLA-DR2 and HLA-DR3 genes have been linked to tuberculoid leprosy whereas HLA-DQ1 is most often found in patients with the lepromatous form. Many other immune system components have been associated with clinical phenotype and course of disease. An intense, organized, specific cellular response is seen in cases at the tuberculoid pole, whereas an absence of a specific immune response is seen at the opposite pole, in lepromatous leprosy. The lepromatous form affects the skin and peripheral nerves, causing well-defined infiltrated plaques that are annular or ovoid. These lesions are usually anesthetic and may affect any area of the body. Biopsy of the skin and region surrounding nerves reveals granulomas with an abundance of epithelioid histiocytes, multinucleated giant cells, and CD4+ T cells that secrete interferon-γ. One of the most important findings is the scarcity or absence of acid-alcohol-fast bacilli (Figs. 2 and 3), although a few may sometimes be observed. The immunologic and clinical situation is different in lepromatous leprosy as there is no specific immune response. Bacilli proliferate in the tissues and foamy macrophages can be observed; few CD4+ and CD8+ T cells are present, and granulomas do not usually form (Figs. 4 and 5). Immunohistochemical findings in skin biopsies show mainly interleukins 4 and 10.2

Figure 2.

Tuberculoid leprosy. Granulomatous inflammation in the dermis is composed of epithelioid cells surrounded by T cells. Hematoxylin-eosin, original magnification ×100.

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Figure 3.

Granuloma in tuberculoid leprosy, showing foamy histiocytes arranged in a concentric pattern. Hematoxylin-eosin, original magnification ×400.

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Figure 4.

Lepromatous leprosy. Epidermal atrophy with a Grenz zone. Macrophages and foamy areas around blood vessels can be seen. Hematoxylin-eosin, original magnification ×100.

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Figure 5.

Abundance of acid-alcohol-fast bacilli in lepromatous leprosy. Fite-Faraco, original magnification ×400.

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The immune response to Mleprae is variable and gives rise to spontaneously changing clinical manifestations, which may present as type 1 or 2 leprosy reactions. Reactions are related to immune system changes, such as those caused by antileprosy medication, stress, or pregnancy. A type 1 reversal reaction involves type IV hypersensitivity.9 Blood levels of cytokines—such as interferon-γ and tumor necrosis factor—rise and CD4+ T cells are activated. A type 2 (or erythema nodosum leprosum) reaction corresponds to a type III hypersensitivity reaction due to immune complex deposition associated with systemic toxicity, elevated tumor necrosis factor levels, and increased neutrophilic infiltration and complement deposition in the skin. This type develops mainly in cases of dimorphous (borderline) leprosy and lepromatous leprosy.

Although the mechanism by which the pathogen is transmitted is poorly understood, we do know that the transmissibility of M leprae is low. Overcrowding and prolonged contact are known risk factors.10 The possibility that the respiratory tract plays a significant role in transmission has recently been studied. The bacterial load is high in patients with lepromatous leprosy, who have been reported to harbor as many as 7000 million bacilli in a gram of tissue, whereas in other forms of the disease, the load is known to be much lower, on the order of a million bacilli in total. M leprae has been found in high numbers (100 million viable bacilli per day) in nasal mucosa.11 Although the skin has been suggested to be a possible route of transmission, this hypothesis has never been proven. As the viability of bacilli outside the body extends over a period ranging from 36hours to 9 days, fomites can play a role in transmission. The respiratory tract may provide a point of entry for the bacillus, and aerosol inoculation has been shown to be possible in immunodeficient mice.

No relationship between the bacillus and a vector has been established, but the possibility cannot be ruled out. As leprosy is not a highly contagious disease, certain conditions must be met before a host can be infected. Cases of tuberculoid leprosy transmitted through tattooing have been reported, mainly in India.12 As vertical transmission has been reported, mother-child dyads should be followed.13

The Ridley-Jopling clinical classification system (Fig. 6), based on the patient's clinical state and immune status, is the most widely used.14 The disease is organized in 2 poles and an intermediate state, referring to lepromatous, tuberculoid and dimorphous (borderline) leprosy, respectively. Dimorphous cases are classified according to which pole (lepromatous or tuberculoid) they tend toward, preceded by the word borderline (thus, cases are borderline lepromatous, borderline tuberculoid, or borderline borderline). Indeterminate cases are considered to represent the initial stage of the disease. These unstable cases eventually move toward one of the poles but progression can be halted with treatment and a cure is possible. In fact, a cure is easy in this stage, although clinical diagnosis is difficult. All dimorphous or indeterminate cases progress toward a pole, usually becoming lepromatous. In 1998, the WHO's Expert Committee on Leprosy determined that treatment could be started before smear tests were done; thus, a practical, rapid means of classification was established for worldwide application without need for diagnostic equipment and without putting health care workers at risk.2,4,10 Paucibacillary cases are those in which skin lesions number no more than 5; cases with 6 or more skin lesions are classified as multibacillary.15 This system is imperfect, however, as a large number of multibacillary cases are misclassified as paucibacillary, with repercussions on treatment.

Figure 6.

Clinical and immunologic classification system for leprosy. IFN-γ refers to interferón gamma; IL, interleukin.

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Leprosy affects primarily the skin, superficial peripheral nerves, the eyes, and certain organs (e.g., the testicles). A disseminated skin condition is often the reason patients seek care, although they may also complain of numbness and other types of paresthesia or systemic signs such as fever and weight loss. Lepromatous leprosy (Fig. 7) is considered to be at the dynamic, progressive, systemic, and infectious end of the spectrum. Bacteriology will be positive and the Mitsuda reaction (intradermal lepromin test) will be negative due to the absence of specific cell-mediated immunity. Tuberculoid leprosy (Fig. 8) is stable, rarely contagious, and may even be self-limiting. The bacillus is not detectable on bacteriology, but the Mitsuda reaction will be positive and granulomas are typically found on biopsy.

Figure 7.

Typical leonine facies in lepromatous leprosy.

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Figure 8.

Tuberculoid leprosy: a single, hairless plaque with well-defined borders.

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Dimorphous Cases

The clinical presentation of dimorphous leprosy (Fig. 9) may be acute or subacute and cases are initially indeterminate. Considered an unstable, transient clinical state, dimorphous leprosy requires appropriate treatment. Nearly all cases progress to lepromatous disease. Patients with dimorphous leprosy present with scaly, erythematous plaques that may be circular or annular, with borders that are diffuse externally and well defined internally. With time the lesion atrophies and there is loss of adnexa. On occasion, it has been suggested that when the external borders of annular lesions are well defined, the disease progresses to tuberculoid leprosy, whereas well-defined internal borders predict progression to lepromatous disease.

Figure 9.

Dimorphous leprosy characterized by infiltrated, erythematous, scaly plaques that are annular in shape and have well-defined internal borders and atrophic centers.

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Leprosy is diagnosed clinically on the basis of 3 cardinal signs set out by the WHO's Expert Committee on Leprosy in 1997.2,15 The diagnosis is made when an individual who has not completed a course of treatment has 1 or more of the following signs:

• 1.

  A hypopigmented (or erythematous) anesthetic skin lesion

• 2.

  A thickened peripheral nerve

• 3.

  A positive skin smear or bacilli observed in a biopsy

When all 3 signs are present diagnostic sensitivity has been reported to be as high as 97% (Table 1).15 Although 90% of paucibacillary cases are diagnosed based on lesion count, up to 30% of multibacillary patients are underdiagnosed.

Peripheral nerve thickening normally occurs after anesthetic macules have appeared. Nerve involvement follows a characteristic pattern of distribution and is more marked in multibacillary cases.

The elimination of leprosy as a world health problem is feasible, as this infectious disease is one of the few that meet certain strict requirements for eradication. Among the requirements leprosy meets are its spread by a single means of transmission (from untreated infected individuals) and the possibility of diagnosis by means of simple, practical tools. Furthermore, effective therapy is available and once prevalence falls below a certain level in a population, the likelihood of resurgence is very remote. Finally, unlike the situation with tuberculosis, leprosy infection does not seem to be unfavorably influenced by human immunodeficiency virus infection. By 2003 leprosy had been eliminated from 117 countries, but the disease continues to present a public health problem in 17 countries.2 In 1981 the WHO introduced multidrug therapy with rifampicin, clofazimine, and dapsone (diaminodiphenyl sulfone) for first-line treatment.31 All patients should receive this drug combination monthly under supervision (Table 2).

Minocycline, ofloxacin, and clarithromycin are among the drugs used as second-line treatments. The strengths of multidrug therapy are the prevention of resistance to dapsone, the rapid decline of infectivity of infected individuals, and the low rate of recurrence and reactions.32 Nonetheless, this treatment period is long and presents logistical problems; adherence is difficult to achieve.

Hansen disease remains a concern today. All physicians must have a basic understanding of this disease in order to diagnose it and prevent disability and/or contagion. Knowledge of immunopathologic mechanisms reveals the complexity of certain diseases and provides the basis for understanding and treating them. Our current level of knowledge makes it possible to eliminate leprosy, a goal that calls for the concerted efforts of medical, social, political, and scientific resources to prevent the spread of an infection that should no longer exist.

The authors declare that they have no conflicts of interest.