Leprosy

Wayne M. Meyers, Françoise Portaels, and Douglas S. Walsh

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, an acid-fast bacillus (AFB). It was first recognized by Hansen in 1873 in Bergen, Norway, while examining smears from lepromas of Norwegian patients. Notably, the organism was the first reported bacterium causing chronic disease in humans that principally affects the cooler parts of the body, especially the skin, upper respiratory tract, testes, eyes, and superficial segments of peripheral nerves.^1,2 The stigma suffered by patients with leprosy has historically been severe. For a review of the history of leprosy refer to the electronic text. Because of the stigma of leprosy, the physician must carefully consider the social implications of a diagnosis of leprosy, especially in children.

EPIDEMIOLOGY

In 1999, the World Health Organization (WHO) reported that approximately 800,000 patients were being treated for active leprosy, with 738,000 newly diagnosed cases. By 2006, the numbers had dropped to 225,000 and 259,000, respectively.³ However, many authorities consider that the total global prevalence of patients with active leprosy is much higher (1.5–2 million) and that new case rates are not necessarily rapidly declining.^4,5 The stigma of the disease and inefficiency in health care delivery systems contribute to this disparity in statistics.⁶

The highest prevalence of leprosy is in tropical Africa, South America, and Southeast Asia. Approximately 73% of all patients live in Southeast Asia (65% in India), 12% in Africa, and 8% in the Americas.¹ Approximately 6000 patients with a history of leprosy resided in the United States. Most of these patients are immigrants, but a few indigenous patients regularly come from Hawaii, Louisiana, Texas, and other southeastern states.^70,71

Geographic, ethnic, and socioeconomic factors may contribute to the spread of leprosy by affecting the number of untreated or ineffectively treated bacillary-positive patients and the opportunities for exposure. Several leprosy epidemics have occurred in nutritionally debilitated populations, although there is still no convincing evidence that the prevalence of leprosy is unusually high in chronically malnourished populations.^73,76,77 The percentage of patients who harbor large numbers of bacilli, generally those with lepromatous leprosy, is related to ethnic background. In some Asian populations, for example, 50% or more of those with leprosy have lepromatous leprosy; in Africans, this figure is 5% to 10%. In adults, leprosy occurs more commonly in men than in women (2:1–3:1); in children, the sex ratio is approximately 1:1.

Genetic factors likely influence the susceptibility of some individuals to leprosy, as well as the form of disease. Genome-wide screening in various populations has found associations with leprosy susceptibility on chromosome 10p13, near the gene for mannose receptor C, a phagocytic receptor on macrophages, on chromosome 6, within the major histocompatibility complex (MHC),⁸⁹ and on the gene for tumor necrosis factor (TNF).⁹⁰ Polymorphisms in the “promoter regions” of the IL-10 and TNF genes have also been found.^91,92 Certain human leukocyte antigens (HLADR) appear to be associated with specific forms of leprosy. For example, HLA-DR2 and HLA-DR3 alleles are associated with tuberculoid disease and HLA-DQ1 with lepromatous disease.⁹³ Growing genetic evidence supports interpopulation heterogeneity in leprosy susceptibility.

MYCOBACTERIOLOGY AND PATHOPHYSIOLOGY

M leprae is an acid-fast bacillus (AFB). As in other mycobacteria, the acid fastness is related to mycolic acids in the cell wall.¹⁶

Localization of infections to the cooler parts of the body³² suggest that the optimal temperature for growth of M leprae is below 37°C.³³ The modes of transmission of M leprae in nature have not been fully established. Skin-to-skin contact and fomites containing M leprae could be sources of infection, but it now appears that nasorespiratory transmission is more common.³⁶ The nasal mucosa of lepromatous patients harbors massive numbers of M leprae, and M leprae appears to bind to nasal mucosal cells by binding fibronectin and attaching to fibronectin receptors on mucosal cells.³⁷M leprae organisms ejected in nose blowing remain viable under ambient conditions for as long as 1 week.³⁸

In a report combining cases on file in the Leprosy Registry at the Armed Forces Institute of Pathology, cases cited in the literature, and personal observations by experienced leprologists, a total of at least 49 leprosy patients younger than 1 year were identified.³⁰ In only half of these infants did the mother have leprosy or a history of leprosy.

The discoveries of a naturally acquired leprosylike disease in more recently captured wild armadillos chimpanzees,^54,55 a mangabey monkey and a macaque consider that leprosy may occasionally be a zoonosis.^57-59 Reports of naturally acquired leprosy in armadillos range from 3% to 53% in the southern region of the United States.^60-63 In these species, the histopathologic features resemble that of human leprosy, and the bacilli that cause the infections cannot be distinguished from M leprae.^64-66

M leprae causes disease by its ability to survive and multiply in macrophages.⁹ If macrophages of the host digest the bacilli early, disease is not detectable, or the patient has only minimal lesions. If the macrophages are totally incapable of destroying the organisms, widely disseminated lepromatous leprosy will follow.^111-115 Survival of M leprae in macrophages depends on the immune response of the patient.

The immunopathogenesis of leprosy can be understood by examining the spectral or polar nature of the disease, whereby polar tuberculoid leprosy is characterized by one or several well-demarcated lesions; borderline leprosy disease presents with a modest number of medium size lesions; and lepromatous disease manifests widespread, poorly demarcated lesions. Each is associated with a different histopathologic features (Table 271-1) and immunologic profile, especially within lesions. Although the precise mechanisms of specific immunity remain elusive, abundant experimental evidence indicates that in a lepromatous patient, cell-mediated immunity to M leprae is markedly suppressed. Delayed hypersensitivity skin test reactions to many antigens are often depressed, but they are depressed most consistently and most severely to M leprae.¹²¹ The degree of suppression is less pronounced in clinical forms of disease that are progressively nearer on the spectrum to tuberculoid leprosy.¹²²

CLINICAL MANIFESTATIONS AND PATHOLOGY

The cardinal signs of leprosy are hypoesthetic lesions of the skin, enlarged peripheral nerve or nerves, and AFB in skin smears. In the absence of another clear explanation, any one of these signs strongly suggests leprosy.

The period from infection to clinical disease varies (usually 2–5 years), and no prodromal manifestations are well established. After an incubation period, lesions of varying description appear. The nature of the lesions depends on the immune response of the patient to M leprae. Most clinicians today follow the classification scheme outlined by Ridley and Jopling (Table 271-1).¹⁶³ Classification is important because it aids in establishing the prognosis and treatment program for the patient.

Table 271-1. Clinical and Histopathologic Classification of Leprosy

Indeterminate Leprosy

An indeterminate lesion is the first manifestation of leprosy in most patients, and may heal spontaneously, remain unchanged for months or years, or gradually progress toward tuberculoid or lepromatous disease. Patients with indeterminate leprosy have a single or a few macules in the skin (eFig. 271.1 ). The macule is poorly defined and mildly hypopigmented in deeper pigmented skin and slightly erythematous in lighter skin. Skin texture, sensation, and sweating within early macules are normal or only slightly altered. Peripheral nerves are not affected, and skin smears from lesions rarely contain bacilli. The definitive diagnosis can be made only by finding AFB in histopathologic sections. Only mild chronic inflammation is found with small infiltrations of lymphocytes or histiocytes along neurovascular channels and sometimes around appendages (eFig. 271.2A and B ).

Tuberculoid Leprosy

Patients with tuberculoid (TT) leprosy have a single or several asymmetrically distributed hypopigmented skin lesions (eFig. 271.3 ). Tuberculoid lesions arise de novo or evolve from indeterminate macules. The lesion may be macular or infiltrated, but the borders are always sharply demarcated from the surrounding normal skin and are frequently finely papulated. Lesions range from less than 1 cm to those that cover entire regions such as the thigh or buttock. Many TT lesions heal spontaneously.

In TT lesions, there is sensory loss with impaired sweating and eventually loss of hair. Involvement of peripheral nerves commonly develops in TT leprosy (eFig. 271.8 ), and cutaneous nerves can often be palpated adjacent to or within lesions. Enlarged or tender nerves anywhere should alert the clinician to the possibility of leprosy. Patients with tuberculoid (TT) leprosy have a high level of cell-mediated immunity to M leprae, which is reflected in the cellular reaction. Granulomas composed of epithelioid cells, Langhans’ giant cells, and lymphocytes are present in the dermis or subcutaneous tissue (eFig. 271.4A ). Frequently, upper dermal granulomas invade the lower layers of the epidermis (eFig. 271.4A ). Damage to nerves is a distinctive feature; in old advanced lesions, all cutaneous nerves may be damaged beyond recognition (eFig. 271.4B ).

Borderline Leprosy

Borderline (BT) leprosy has features of both the LL and the TT forms and represents a continuous spectrum of disease ranging from near-tuberculoid to near-lepromatous. It is an unstable form of leprosy and may evolve gradually toward TT leprosy by undergoing reversal reactions or be downgraded toward LL leprosy. Table 271-1 describes the three major subgroups of borderline leprosy. In BT leprosy, the number of lesions is usually greater than in TT leprosy, and the borders of each lesion, macule, or plaque are defined less sharply than in TT leprosy. Small satellite lesions may develop around larger macules or plaques. BL leprosy often presents with widespread nodular infiltrations or plaques of varying size (eFig. 271.5 ). Damage to nerves and the resulting deformity develop early and are often widespread. Pain in nerves or neuropathic changes (eg, sensory changes that lead to damaged hands or feet or muscular weakness such as footdrop) frequently bring the patient to the physician.

Lepromatous Leprosy

In LL leprosy, the bacilli multiply freely and the disease disseminates widely, often before striking cutaneous manifestations develop. LL leprosy may evolve from indeterminate or BB leprosy or may be the first recognizable form. In its earliest form, LL leprosy manifests as “juvenile leprosy,” which is difficult to detect and frequently goes unrecognized until a more advanced stage develops.¹⁷³ Skin texture may be altered slightly, but the vague macules with indistinct borders are detected only under appropriate lighting, preferably daylight. No changes occur in sensation or sweating in the macules, and frequently AFB are not detectable in smears from skin. Histopathologic sections may reveal a few bacilli to confirm the diagnosis. The hypopigmented or slightly erythematous macules of early LL leprosy are missed easily because they are vague and have slight, if any, sensory changes. These macules may coalesce and cover large areas of skin, even nearly the entire body before being recognized as advanced LL. If skin smears or biopsy specimens are taken in the macular stage, diagnosis is almost assured. If the disease is not diagnosed and treated in the macular stage, infiltration of the skin will increase gradually, and nodules may develop. The skin is infiltrated most heavily in the cooler portions of the body, notably the ears (pinnae) and face. By this time, nerves are usually enlarged, with early signs of sensory loss in the hands and feet. Eyebrows are thinned and eventually lost, beginning at the lateral edges. These advanced changes of LL leprosy are not common findings in young children but are well known (eFig. 271.6 ). Patients of Latin American ancestry, especially those from Mexico and Costa Rica, may contract the highly anergic diffuse form of LL leprosy called Lucio leprosy. The disease may be so diffuse that it is not recognized until sensory changes in the hands and feet appear, and the eyebrows and other body hair begin to disappear. In advanced forms of Lucio leprosy, there is a marked obstructive vasculitis in the skin, with the production of dermal infarcts and irregular ulcers (Lucio phenomenon).^174,175 Lucio leprosy has been reported in children as young as 7 years.¹⁷⁶

In advanced lepromatous disease, the skin is usually markedly thickened with replacement of the dermis by inflammatory cells (eFigs. 271.6 and 271.7A ). Anergy to M leprae becomes apparent early in the lepromatous lesion, with the bacilli-laden macrophage (Virchow cell or lepra cell) being the predominant inflammatory cell (eFig. 271.7B ). In early lesions, they tend to accumulate around vessels, nerves, and appendages, but they may eventually replace the entire dermis (eFig. 271.7A ). In advanced lesions, dense masses of bacilli called globi may replace nearly the entire cytoplasm of the macrophage (eFig. 271.7B ).

Reactions

The course of leprosy, treated or nontreated, is often interrupted by acute episodes called reactions, and fall into two general categories: reversal reactions (or type 1) and erythema nodosum leprosum (ENL) (or type 2). Reversal reactions complicate borderline leprosy and represent delayed hypersensitivity reactions with an upgrading of cell-mediated immunity toward TT leprosy. Lesions become erythematous and edematous, and neuritis is common (eFig. 271.9 ). Differentiating reversal reactions from relapsing lesions is frequently difficult and requires careful correlation of clinical and histopathologic findings. This correlation is becoming increasingly important in endemic areas where shorter-term chemotherapeutic regimens of fixed duration are used.^184,185 The following criteria for differentiating relapses and reversal reactions are suggested: a relapse involves an increased number of lesions, positive skin smears for AFB (for BB and BL patients), tissue reaction inconsistent with a reversal reaction, and a favorable response to chemotherapy; a reversal reaction, on the other hand, involves an exacerbation of existing lesions, skin smears negative for AFB, tissue reaction consistent with a reversal reaction, and a rapid response to anti-inflammatory drugs (see below).

Erythma nodosum leprosum developed in approximately 50% of LL patients after they had undergone a few months of chemotherapy; however, with the addition of clofazimine to the standard therapeutic regimen, frequency is much reduced.¹⁸⁶ Tender erythematous subcutaneous nodules develop rapidly (eFig. 271.10 ); the nodules are often accompanied by fever and occasionally by synovitis and iridocyclitis.^187,188

DIAGNOSIS

An experienced observer can make a clinical diagnosis of leprosy in most patients, except those with very early leprosy, with a high degree of accuracy. However, in areas of low prevalence, diagnosis is often delayed (in the United States, the usual delay in diagnosis after the patient’s first visit to a physician for symptoms related to leprosy is approximately 1.5 to 2 years). Historical features that suggest leprosy in a patient with chronic skin lesions include contact with patients with leprosy or residence in an endemic area. Sensory loss or unexplained damage to hands or feet suggests damage to nerve trunks. Clinicians must evaluate sensory changes in a lesion by testing light touch with the use of a few fibers of cotton or calibrated nylon filaments and heat-cold discrimination with the use of warm and cold water in test tubes. Spontaneous sweating can be observed directly, or induced sweating can be evaluated. The main nerve trunks must be palpated for tenderness and enlargement. Skin in the area of discrete lesions must also be palpated gently to detect enlargement of cutaneous nerves. In the world population, leprosy is the most common cause of peripheral neuropathy and must be considered in any patient with peripheral neuropathy.¹⁶⁸ However, as leprosy is considered one of the “great imitators,”¹⁹⁴ histopathologic evaluation is strongly recommended to supplement and confirm the clinical diagnosis.

Unfortunately, currently available skin tests with soluble M leprae antigens are unreliable for diagnosis.¹⁹⁶ Enzyme-linked immunosorbent assays and gelatin particle agglutination tests for antibodies to the PGL-1 of M leprae are available.^197-199 Although specificity for M leprae is high, these tests detect antibodies to PGL-1 in only approximately 50% of paucibacillary patients. Other serologic tests for antibodies to M leprae–specific epitopes on protein moieties of the bacillus are being evaluated.²⁰⁰ PGL-1 antigen is detectable in the serum and urine of most multibacillary patients.^201,202 Biopsy specimens from well-defined lesions of leprosy should be taken from the active border and fixed in buffered 10% formalin or other suitable fixative. The Fite-Faraco staining method is used because the Ziehl-Neelsen stain does not demonstrate M leprae optimally in tissue sections. A histopathologic diagnosis of leprosy must not be made unless the evidence is convincing. DNA probes specific for M leprae are available and are useful in identifying leprosy bacilli in tissue or nasal secretions.^24,36 Specimens for DNA evaluation or PCR amplification should be preserved in 70% ethyl alcohol.^154-156

TREATMENT

Once a diagnosis of leprosy is established, chemotherapy must be initiated and appropriate measures begun for preventing or correcting deformity in patients with neuropathic changes.^211-213

Neuropathic changes involve primarily nerves and other structures in the cooler parts of the body, and are most profound in the eyes, face, hands, and feet. Damage to the hand, for example, is related to loss of normal autonomic, sensory, and motor function. These impairments are illustrated in eFigures 271.11, 271.12, and 271.13 . Early appropriate surgical intervention can often restore motor function (eFig. 271.14 ), and physiotherapy will maintain useful hands.²¹²

Because of drug-resistant M leprae, combined drug regimens are mandatory for the treatment of all forms of leprosy.^{209,215,218,227} Specific agents are reviewed in the electronic text.

The three chemotherapeutic agents most commonly used are dapsone, clofazimine, and rifampin.²¹⁴

In 1982, a WHO study group recommended the multidrug therapy regimens described hereafter.²³⁰ For field programs, paucibacillary patients are classified only as those who have five or fewer lesions, without reference to skin smear evaluation. All other patients are multibacillary.

In the United States, recommendations of the National Hansen’s Disease Program differ somewhat from the WHO recommendations. Since these recommendations may change, it is advisable to contact the center before treating any patient (1-800-862-7326).

The WHO guidelines recommend MDT treatment of adults with paucibacillary disease (indeterminate, tuberculoid, and borderline tuberculoid) with rifampin, 600 mg once a month, plus dapsone, 100 mg daily, is given for 6 months, and treatment is then stopped. After the conclusion of multidrug therapy, the patient should be seen every 3 to 6 months. All apparent relapses require histopathologic examination for establishing whether the lesions represent relapses or reversal reactions. Relapsing patients must be treated again. The aforementioned multidrug therapy is not used alone in patients with concurrent tuberculosis.

The Hansen’s Disease Center in Baton Rouge, Louisiana, recommends treatment of paucibacillary disease in the United States with dapsone, 100 mg daily, plus rifampin, 600 mg daily, for 1 year.

The WHO guidelines recommend MDT treatment of adults with multibacillary disease (lepromatous, borderline lepromatous, and borderline) with rifampin, 600 mg monthly; dapsone, 100 mg daily; and clofazimine, 50 mg daily, are given. If patient compliance is questionable, the rifampin and 300 mg of clofazimine should be given monthly under supervision, in addition to the 50 mg daily.

These drugs must be given for 2 years. For patients in whom the hyperpigmentation caused by clofazimine is unacceptable, daily doses of 250 to 375 mg of prothionamide or ethionamide may be substituted for clofazimine. Another alternate therapy suggested by WHO, for those unwilling to accept the hyperpigmentation of clofazimine or for those are noncompliant with other regimens, consists of rifampin (600 mg), ofloxacin (400 mg), and minocycline (100 mg), coined “ROM”, all of which are administered on a single day, once monthly, for at least 2 years.²⁴⁰

The Hansen’s Disease Center in Baton Rouge, Louisiana, recommends treatment of multibacillary disease in the United States with dapsone, 100 mg daily, plus rifampin, 600 mg daily, for 1 year, and clofazimine, 50 mg daily, for 2 years. Minocycline, 100 mg daily, is substituted for clofazimine in patients who will not take clofazimine.

Pediatric dosages of multidrug therapy are given as follows in percentage of adult dose: less than 15 kg body weight, 25% of adult dose; 15 to 30 kg, 50%; 30 to 45 kg, 75%; and greater than 45 kg, 100% of adult dose.²⁴¹

Patients undergoing a reversal (type 1) reaction or erythema nodosum leprosum (type 2) reaction should be observed daily in the early stages and hospitalized if the symptoms are severe. Formerly, specific therapy was stopped or the dosage reduced during reactions, but these measures are no longer recommended.²³⁰ Damage to eyes and neuropathic changes may ensue rapidly without immediate attention. Nerve tenderness and function must be assessed frequently during reactions. Acute inflammation of isolated lesions without damage to nerves is likely to be of little consequence except for cosmetic considerations.

For reversal reactions, analgesics are given, and the affected area is put at rest. Large daily doses of corticosteroids are started and tapered to a minimal effective dose.

Mild erythema nodosum leprosum reactions are treated with analgesics; more severe ENL is treated with thalidomide or corticosteroids.²⁴⁷ Pediatric doses of thalidomide in ENL have not been established, but the initial adult dose is 100 mg four times daily followed by a minimal effective dose, usually 100 mg daily. Clofazimine is effective in most patients with ENL and does not have the disadvantages of thalidomide or corticosteroids. The anti-inflammatory action of clofazimine is not manifested until after 4 to 6 weeks of continuous use. The dosage must be adjusted to the minimal effective level.

PREVENTION

Control programs today are based on the general principles that (1) the number of contagious patients is reduced by chemotherapy and (2) the surveillance of contacts will detect early leprosy. In endemic areas, improved housing is probably a highly important preventive measure by reducing close contact of patients with healthy individuals. The most important obstacles to improving control of leprosy include persistence of M leprae in treated patients, cost and toxicity of antileprotic medications, long duration of therapeutic regimens, patient compliance, and social stigma of leprosy.²⁵⁰ WHO does not recommend BCG vaccination for the prevention of leprosy.²⁶⁰ Although intensive studies on vaccines for leprosy based on specific antigens of M leprae are in progress, no definitive reports on efficacy have been published.

REFERENCES

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