Leprosy, first described in ancient Indian texts from the sixth century b.c., is a nonfatal, chronic infectious disease caused by Mycobacterium leprae, the clinical manifestations of which are largely confined to the skin, peripheral nervous system, upper respiratory tract, eyes, and testes. The unique tropism of M. leprae for peripheral nerves (from large nerve trunks to microscopic dermal nerves) and certain immunologically mediated reactional states are the major causes of morbidity in leprosy. The propensity of the disease, when untreated, to result in characteristic deformities and the recognition in most cultures that the disease is communicable from person to person have resulted historically in a profound social stigma. Today, with early diagnosis and the institution of appropriate and effective antimicrobial therapy, patients can lead productive lives in the community, and deformities and other visible manifestations can largely be prevented.
M. leprae is an obligate intracellular bacillus (0.3–1 μm wide and 1–8 μm long) that is confined to humans, armadillos in certain locales, and sphagnum moss. The organism is acid-fast, indistinguishable microscopically from other mycobacteria, and ideally detected in tissue sections by a modified Fite stain. Strain variability has been documented in this organism. M. leprae produces no known toxins and is well adapted to penetrate and reside within macrophages, yet it may survive outside the body for months. In untreated patients, only ~1% of M. leprae organisms are viable. The morphologic index (MI), a measure of the number of acid-fast bacilli (AFB) in skin scrapings that stain uniformly bright, correlates with viability. The bacteriologic index (BI), a logarithmic-scaled measure of the density of M. leprae in the dermis, may be as high as 4–6+ in untreated patients and falls by 1 unit per year during effective antimicrobial therapy; the rate of decrease is independent of the relative potency of therapy. A rising MI or BI suggests relapse and perhaps—if the patient is being treated—drug resistance. Drug resistance can be confirmed or excluded in the mouse model of leprosy, and resistance to dapsone and rifampin can be documented by the recognition of mutant genes. However, the availability of these technologies is extremely limited.
As a result of reductive evolution, almost half of the M. leprae genome contains nonfunctional genes; only 1605 genes encode for proteins, and 1439 genes are shared with Mycobacterium tuberculosis. In contrast, M. tuberculosis uses 91% of its genome to encode for 4000 proteins. Among the lost genes in M. leprae are those for catabolic and respiratory pathways; transport systems; purine, methionine, and glutamine synthesis; and nitrogen regulation. The genome of M. leprae provides a metabolic rationale for its obligate intracellular existence and reliance on host biochemical support, a template for targets of drug development, and ultimately a pathway to cultivation. The finding of strain variability among M. leprae isolates has provided a powerful tool with which to address anew the organism’s epidemiology and pathobiology and to determine whether relapse represents reactivation or reinfection. The bacterium’s complex cell wall contains large amounts of an M. leprae–specific phenolic glycolipid (PGL-1), which is detected in serologic tests. The unique trisaccharide of M. leprae binds to the basal lamina of Schwann cells; this interaction is probably relevant to the fact that M. leprae is the only bacterium to invade peripheral nerves.
Although it was the first bacterium to be etiologically associated with human disease, M. leprae remains one of the few bacterial species that still has not been cultivated on artificial medium or tissue culture. The multiplication of M. leprae in mouse footpads (albeit limited, with a doubling time of ~2 weeks) has provided a means to evaluate antimicrobial agents, monitor clinical trials, and screen vaccines. M. leprae grows best in cooler tissues (the skin, peripheral nerves, anterior chamber of the eye, upper respiratory tract, and testes), sparing warmer areas of the skin (the axilla, groin, scalp, and midline of the back).
Leprosy is almost exclusively a disease of the developing world, affecting areas of Asia, Africa, Latin America, and the Pacific. While Africa has the highest disease prevalence, Asia has the most cases. More than 80% of the world’s cases occur in a few countries: India, China, Myanmar, Indonesia, Brazil, Nigeria, Madagascar, and Nepal. Within endemic locales, the distribution of leprosy is quite uneven, with areas of high prevalence bordering on areas with little or no disease. In Brazil the majority of cases occur in the Amazon basin and two western states, while in Mexico leprosy is mostly confined to the Pacific coast. Except as imported cases, leprosy is largely absent from the United States, Canada, and northwestern Europe. In the United States, ~4000 persons have leprosy and 100–200 new cases are reported annually, most of them in California, Texas, New York, and Hawaii among immigrants from Mexico, Southeast Asia, the Philippines, and the Caribbean.
The comparative genomics of single-nucleotide polymorphisms support the likelihood that four distinct strains exist, having originated in East Africa or Central Asia. A mutation spread to Europe and subsequently underwent two separate mutations that were then followed by spread to West Africa and the Americas.
The global prevalence of leprosy is difficult to assess, given that many of the locales with high prevalence lack a significant medical or public health infrastructure. Estimates range from 0.6 to 8 million affected individuals. The lower estimate includes only persons who have not completed chemotherapy, excluding those who may be physically or psychologically damaged from leprosy and who may yet relapse or develop immune-mediated reactions. The higher figure includes patients whose infections probably are already cured and many who have no leprosy-related deformity or disability. Although the figures on the worldwide prevalence of leprosy are debatable, incidence is not falling; there are still an estimated 500,000 new cases annually.
Leprosy is associated with poverty and rural residence. It appears not to be associated with AIDS, perhaps because of leprosy’s long incubation period. Most individuals appear to be naturally immune to leprosy and do not develop disease manifestations after exposure. The time of peak onset is in the second and third decades of life.
The most severe lepromatous form of leprosy is twice as common among men as among women and is rarely encountered in children. The frequency of the polar forms of leprosy in different countries varies widely and may in part be genetically determined; certain human leukocyte antigen (HLA) associations are known for both polar forms of leprosy (see below). Furthermore, variations in immunoregulatory genes are associated with an increased susceptibility to leprosy, particularly the multibacillary form. In India and Africa, 90% of cases are tuberculoid; in Southeast Asia, 50% are tuberculoid and 50% lepromatous; and in Mexico, 90% are lepromatous. (For definitions of disease types, see Table 203-1 and “Clinical, Histologic, and Immunologic Spectrum,” below.)
TABLE 203-1Clinical, Bacteriologic, Pathologic, and Immunologic Spectrum of Leprosy ||Download (.pdf) TABLE 203-1Clinical, Bacteriologic, Pathologic, and Immunologic Spectrum of Leprosy
|Feature ||Tuberculoid (TT, BT) Leprosy ||Borderline (BB, BL) Leprosy ||Lepromatous (LL) Leprosy |
|Skin lesions ||One or a few sharply defined annular asymmetric macules or plaques with a tendency toward central clearing, elevated borders ||Intermediate between BT- and LL-type lesions; ill-defined plaques with an occasional sharp margin; few or many in number ||Symmetric, poorly marginated, multiple infiltrated nodules and plaques or diffuse infiltration; xanthoma-like or dermatofibroma papules; leonine facies and eyebrow alopecia |
|Nerve lesions ||Skin lesions anesthetic early; nerve near lesions sometimes enlarged; nerve abscesses most common in BT ||Hypesthetic or anesthetic skin lesions; nerve trunk palsies, at times symmetric ||Hypesthesia a late sign; nerve palsies variable; acral, distal, symmetric anesthesia common |
|Acid-fast bacilli (BIa) ||0–1+ ||3–5+ ||4–6+ |
|Lymphocytes ||2+ ||1+ ||0–1+ |
|Macrophage differentiation ||Epithelioid ||Epithelioid in BB; usually undifferentiated but may have foamy changes in BL ||Foamy change the rule; may be undifferentiated in early lesions |
|Langerhans giant cells ||1–3+ ||— ||— |
|Lepromin skin test ||+++ ||— ||— |
|Lymphocyte transformation test ||Generally positive ||1–10% ||1–2% |
|CD4+/CD8+ T cell ratio in lesions ||1.2 ||BB: NT; BL: 0.48 ||0.50 |
|M. leprae PGL-1 antibodies ||60% ||85% ||95% |
The route of transmission of leprosy remains uncertain, and transmission routes may in fact be multiple. Nasal droplet infection, contact with infected soil, and even insect vectors have been considered the prime candidates. Aerosolized M. leprae can cause infection in immunosuppressed mice, and a sneeze from an untreated lepromatous patient may contain >1010 AFB. Furthermore, both IgA antibody to M. leprae and genes of M. leprae—demonstrable by polymerase chain reaction (PCR)—have been found in the nose of individuals from endemic areas who have no signs of leprosy and in 19% of occupational contacts of lepromatous patients. Several lines of evidence implicate soil transmission. (1) In endemic countries such as India, leprosy is primarily a rural and not an urban disease. (2) M. leprae products reside in soil in endemic locales. (3) Direct dermal inoculation (e.g., during tattooing) may transmit M. leprae, and common sites of leprosy in children are the buttocks and thighs, suggesting that microinoculation of infected soil may transmit the disease. Evidence for insect vectors of leprosy includes the demonstration that bedbugs and mosquitoes in the vicinity of leprosaria regularly harbor M. leprae and that experimentally infected mosquitoes can transmit the infection to mice. Skin-to-skin contact generally is not considered an important route of transmission.
In endemic countries, ~50% of leprosy patients have a history of intimate contact with an infected person (often a household member), while, for unknown reasons, leprosy patients in nonendemic locales can identify such contact only 10% of the time. Moreover, household contact with an infected lepromatous case carries an eventual risk of disease acquisition of ~10% in endemic areas as opposed to only 1% in nonendemic locales. Contact with a tuberculoid case carries a very low risk. Physicians and nurses caring for leprosy patients and the co-workers of these patients are not at risk for leprosy.
Although multilocus variable-number short-nucleotide tandem-repeat (VNTR) analyses have generally demonstrated considerable variability among isolates, highly similar and even identical VNTR results have been obtained with isolates from a limited number of families with multiple cases. Moreover, VNTR results have been similar for isolates within certain geographic locales and divergent for isolates within others. These findings suggest that genomic analyses may prove useful in the future for defining M. leprae transmission patterns.
M. leprae causes disease primarily in humans. However, in Texas and Louisiana, 15% of nine-banded armadillos are infected, and armadillo contact occasionally results in human disease. Armadillos develop disseminated infection after IV inoculation of live M. leprae.
CLINICAL, HISTOLOGIC, AND IMMUNOLOGIC SPECTRUM
The incubation period prior to manifestation of clinical disease can vary between 2 and 40 years, although it is generally 5–7 years in duration. This long incubation period is probably, at least in part, a consequence of the extremely long doubling time for M. leprae (14 days in mice versus in vitro doubling times of 1 day and 20 min for M. tuberculosis and Escherichia coli, respectively). Leprosy pre-sents as a spectrum of clinical manifestations that have bacteriologic, pathologic, and immunologic counterparts. The spectrum from polar tuberculoid (TT) to borderline tuberculoid (BT) to mid-borderline (BB, which is rarely encountered) to borderline lepromatous (BL) to polar lepromatous (LL) disease is associated with an evolution from asymmetric localized macules and plaques to nodular and indurated symmetric generalized skin manifestations, an increasing bacterial load, and loss of M. leprae–specific cellular immunity (Table 203-1). Distinguishing dermatopathologic characteristics include the number of lymphocytes, giant cells, and AFB as well as the nature of epithelioid cell differentiation. Where a patient presents on the clinical spectrum largely determines prognosis, complications, reactional states, and the intensity of antimicrobial therapy required.
At the less severe end of the spectrum is tuberculoid leprosy, which encompasses TT and BT disease. In general, these forms of leprosy result in symptoms confined to the skin and peripheral nerves. TT leprosy is the most common form of the disease encountered in India and Africa but is virtually absent in Southeast Asia, where BT leprosy is frequent.
The skin lesions of tuberculoid leprosy consist of one or a few hypopigmented macules or plaques (Fig. 203-1) that are sharply demarcated and hypesthetic, often have erythematous or raised borders, and are devoid of the normal skin organs (sweat glands and hair follicles) and thus are dry, scaly, and anhidrotic. AFB are generally absent or few in number. Tuberculoid leprosy patients may have asymmetric enlargement of one or a few peripheral nerves. Indeed, leprosy and certain rare hereditary neuropathies are the only human diseases associated with peripheral-nerve enlargement. Although any peripheral nerve may be enlarged (including small digital and supraclavicular nerves), those most commonly affected are the ulnar, posterior auricular, peroneal, and posterior tibial nerves, with associated hypesthesia and myopathy.
Tuberculoid (TT) leprosy: a well-defined, hypopigmented, anesthetic macule with anhidrosis and a raised granular margin (arrowhead).
In tuberculoid leprosy, T cells breach the perineurium, and destruction of Schwann cells and axons may be evident, resulting in fibrosis of the epineurium, replacement of the endoneurium with epithelial granulomas, and occasionally caseous necrosis. Such invasion and destruction of nerves in the dermis by T cells are pathognomonic for leprosy.
Circulating lymphocytes from patients with tuberculoid leprosy readily recognize M. leprae and its constituent proteins, patients have positive lepromin skin tests (see “Diagnosis,” below), and—owing to a type 1 cytokine pattern in tuberculoid tissues—strong T cell and macrophage activation results in a localized infection. In tuberculoid leprosy tissue, there is a 2:1 predominance of helper CD4+ over CD8+ T lymphocytes. Tuberculoid tissues are rich in the mRNAs of the proinflammatory TH1 family of cytokines: interleukin (IL) 2, interferon γ (IFN-γ), and IL-12; in contrast, IL-4, IL-5, and IL-10 mRNAs are scarce.
Lepromatous leprosy patients present with symmetrically distributed skin nodules (Fig. 203-2), raised plaques, or diffuse dermal infiltration, which, when on the face, results in leonine facies. Late manifestations include loss of eyebrows (initially the lateral margins only) and eyelashes, pendulous earlobes, and dry scaling skin, particularly on the feet. In LL leprosy, bacilli are numerous in the skin (as many as 109/g), where they are often found in large clumps (globi), and in peripheral nerves, where they initially invade Schwann cells, resulting in foamy degenerative myelination and axonal degeneration and later in Wallerian degeneration. In addition, bacilli are plentiful in circulating blood and in all organ systems except the lungs and the central nervous system. Nevertheless, patients are afebrile, and there is no evidence of major organ system dysfunction.
Lepromatous (LL) leprosy: advanced nodular lesions.
Found almost exclusively in western Mexico and the Caribbean is a form of lepromatous leprosy without visible skin lesions but with diffuse dermal infiltration and a demonstrably thickened dermis, termed diffuse lepromatosis.
In lepromatous leprosy, nerve enlargement and damage tend to be symmetric, result from actual bacillary invasion, and are more insidious but ultimately more extensive than in tuberculoid leprosy. Patients with LL leprosy have acral, distal, symmetric peripheral neuropathy and a tendency toward symmetric nerve-trunk enlargement. They may also have signs and symptoms related to involvement of the upper respiratory tract, the anterior chamber of the eye, and the testes.
In untreated LL patients, lymphocytes regularly fail to recognize either M. leprae or its protein constituents, and lepromin skin tests are negative (see “Diagnosis,” below). This loss of protective cellular immunity appears to be antigen-specific, as patients are not unusually susceptible to opportunistic infections, cancer, or AIDS and maintain delayed-type hypersensitivity to Candida, Trichophyton, mumps virus, tetanus toxoid, and even purified protein derivative of tuberculin. At times, M. leprae–specific anergy is reversible with effective chemotherapy. In LL tissues, there is a 2:1 ratio of CD8+ to CD4+ T lymphocytes. LL patients have a predominant TH2 response and hyperglobulinemia, and LL tissues demonstrate a TH2 cytokine profile, being rich in mRNAs for IL-4, IL-5, and IL-10 and poor in those for IL-2, IFN-γ, and IL-12. It appears that cytokines mediate a protective tissue response in leprosy, as injection of IFN-γ or IL-2 into lepromatous lesions causes a loss of AFB and histopathologic conversion toward a tuberculoid pattern. Macrophages of lepromatous leprosy patients appear to be functionally intact; circulating monocytes exhibit normal microbicidal function and responsiveness to IFN-γ.
Lepra reactions comprise several common immunologically mediated inflammatory states that cause considerable morbidity. Some of these reactions precede diagnosis and the institution of effective antimicrobial therapy; indeed, these reactions may precipitate presentation for medical attention and diagnosis. Other reactions follow the initiation of appropriate chemotherapy; these reactions may cause patients to perceive that their leprosy is worsening and to lose confidence in conventional therapy. Only by warning patients of the potential for these reactions and describing their manifestations can physicians treating leprosy patients ensure continued credibility.
TYPE 1 LEPRA REACTIONS (DOWNGRADING AND REVERSAL REACTIONS)
Type 1 lepra reactions occur in almost half of patients with borderline forms of leprosy but not in patients with pure lepromatous disease. Manifestations include classic signs of inflammation within previously involved macules, papules, and plaques and, on occasion, the appearance of new skin lesions, neuritis, and (less commonly) fever—generally low-grade. The nerve trunk most frequently involved in this process is the ulnar nerve at the elbow, which may be painful and exquisitely tender. If patients with affected nerves are not treated promptly with glucocorticoids (see below), irreversible nerve damage may result in as little as 24 h. The most dramatic manifestation is footdrop, which occurs when the peroneal nerve is involved.
When type 1 lepra reactions precede the initiation of appropriate antimicrobial therapy, they are termed downgrading reactions, and the case becomes histologically more lepromatous; when they occur after the initiation of therapy, they are termed reversal reactions, and the case becomes more tuberculoid. Reversal reactions often occur in the first months or years after the initiation of therapy but may also develop several years thereafter.
Edema is the most characteristic microscopic feature of type 1 lepra lesions, whose diagnosis is primarily clinical. Reversal reactions are typified by a TH1 cytokine profile, with an influx of CD4+ T helper cells and increased levels of IFN-γ and IL-2. In addition, type 1 reactions are associated with large numbers of T cells bearing γ/δ receptors—a unique feature of leprosy.
TYPE 2 LEPRA REACTIONS: ERYTHEMA NODOSUM LEPROSUM
Erythema nodosum leprosum (ENL) (Fig. 203-3) occurs exclusively in patients near the lepromatous end of the leprosy spectrum (BL/LL), affecting nearly 50% of this group. Although ENL may precede leprosy diagnosis and the initiation of therapy (sometimes, in fact, prompting the diagnosis), in 90% of cases it follows the institution of chemotherapy, generally within 2 years. The most common features of ENL are crops of painful erythematous papules that resolve spontaneously in a few days to a week but may recur; malaise; and fever that can be profound. However, patients may also experience symptoms of neuritis, lymphadenitis, uveitis, orchitis, and glomerulonephritis and may develop anemia, leukocytosis, and abnormal liver function tests (particularly increased aminotransferase levels). Individual patients may have either a single bout of ENL or chronic recurrent manifestations. Bouts may be either mild or severe and generalized; in rare instances, ENL results in death. Skin biopsy of ENL papules reveals vasculitis or panniculitis, sometimes with many lymphocytes but characteristically with polymorphonuclear leukocytes as well.
Moderately severe skin lesions of erythema nodosum leprosum, some with pustulation and ulceration.
Elevated levels of circulating tumor necrosis factor (TNF) have been demonstrated in ENL; thus, TNF may play a central role in the pathobiology of this syndrome. ENL is thought to be a consequence of immune complex deposition, given its TH2 cytokine profile and its high levels of IL-6 and IL-8. However, in ENL tissue, the presence of HLA-DR framework antigen of epidermal cells—considered a marker for a delayed-type hypersensitivity response—and evidence of higher levels of IL-2 and IFN-γ than are usually seen in polar lepromatous disease suggest an alternative mechanism.
Lucio’s phenomenon is an unusual reaction seen exclusively in patients from the Caribbean and Mexico who have the diffuse lepromatosis form of lepromatous leprosy, most often those who are untreated. Patients with this reaction develop recurrent crops of large, sharply marginated, ulcerative lesions—particularly on the lower extremities—that may be generalized and, when so, are frequently fatal as a result of secondary infection and consequent septic bacteremia. Histologically, the lesions are characterized by ischemic necrosis of the epidermis and superficial dermis, heavy parasitism of endothelial cells with AFB, and endothelial proliferation and thrombus formation in the larger vessels of the deeper dermis. Like ENL, Lucio’s phenomenon is probably mediated by immune complexes.
Complications of the extremities in leprosy patients are primarily a consequence of neuropathy leading to insensitivity and myopathy. Insensitivity affects fine touch, pain, and heat receptors but generally spares position and vibration appreciation. The most commonly affected nerve trunk is the ulnar nerve at the elbow, whose involvement results in clawing of the fourth and fifth fingers, loss of dorsal interosseous musculature in the affected hand, and loss of sensation in these distributions. Median nerve involvement in leprosy impairs thumb opposition and grasp; radial nerve dysfunction, although rare in leprosy, leads to wristdrop. Tendon transfers can restore hand function but should not be performed until 6 months after the initiation of antimicrobial therapy and the conclusion of episodes of acute neuritis.
Plantar ulceration, particularly at the metatarsal heads, is probably the most common complication of leprous neuropathy. Therapy requires careful debridement; administration of appropriate antibiotics; avoidance of weight-bearing until ulcerations are healed, with slowly progressive ambulation thereafter; and wearing of special shoes to prevent recurrence.
Footdrop as a result of peroneal nerve palsy should be treated with a simple nonmetallic brace in the shoe or with surgical correction attained by tendon transfers. Although uncommon, Charcot’s joints, particularly of the foot and ankle, may result from leprosy.
The loss of distal digits in leprosy is a consequence of insensitivity, trauma, secondary infection, and—in lepromatous disease—a poorly understood and sometimes profound osteolytic process. Conscientious protection of the extremities during cooking and work and the early institution of therapy have substantially reduced the frequency and severity of distal digit loss in recent times.
In lepromatous leprosy, bacillary invasion of the nasal mucosa can result in chronic nasal congestion and epistaxis. Saline nose drops may relieve these symptoms. Long-untreated LL leprosy may further result in destruction of the nasal cartilage, with consequent saddle-nose deformity or anosmia (more common in the preantibiotic era than at present). Nasal reconstructive procedures can ameliorate significant cosmetic defects.
Owing to cranial nerve palsies, lagophthalmos and corneal insensitivity may complicate leprosy, resulting in trauma, secondary infection, and (without treatment) corneal ulcerations and opacities. For patients with these conditions, eyedrops during the day and ointments at night provide some protection from such consequences. Furthermore, in LL leprosy, the anterior chamber of the eye is invaded by bacilli, and ENL may result in uveitis, with consequent cataracts and glaucoma. Thus leprosy is a major cause of blindness in the developing world. Slit-lamp evaluation of LL patients often reveals “corneal beading,” representing globi of M. leprae.
M. leprae invades the testes, while ENL may cause orchitis. Thus males with lepromatous leprosy often manifest mild to severe testicular dysfunction, with an elevation of luteinizing and follicle-stimulating hormones, decreased testosterone, and aspermia or hypospermia in 85% of LL patients but in only 25% of BL patients. LL patients may become impotent and infertile. Impotence is sometimes responsive to testosterone replacement.
Secondary amyloidosis is a complication of LL leprosy and ENL that is encountered infrequently in the antibiotic era. This complication may result in abnormalities of hepatic and particularly renal function.
Patients with various forms of leprosy, but particularly those with the BT form, may develop abscesses of nerves (most commonly the ulnar), with a cellulitic appearance of adjacent skin. In such conditions, the affected nerve is swollen and exquisitely tender. Although glucocorticoids may reduce signs of inflammation, rapid surgical decompression is necessary to prevent irreversible sequelae.
Leprosy most commonly presents with both characteristic skin lesions and skin histopathology. Thus the disease should be suspected when a patient from an endemic area has suggestive skin lesions or peripheral neuropathy. The diagnosis should be confirmed by histopathology. In tuberculoid leprosy, lesional areas—preferably the advancing edge—must be biopsied because normal-appearing skin does not have pathologic features. In lepromatous leprosy, nodules, plaques, and indurated areas are optimal biopsy sites, but biopsies of normal-appearing skin also are generally diagnostic. Lepromatous leprosy is associated with diffuse hyperglobulinemia, which may result in false-positive serologic tests (e.g., Venereal Disease Research Laboratory, rheumatoid arthritis, and antinuclear antibody tests) and therefore may cause diagnostic confusion. On occasion, tuberculoid lesions may not (1) appear typical, (2) be hypesthetic, and (3) contain granulomas (instead containing only nonspecific lymphocytic infiltrates). In such instances, two of these three characteristics are considered sufficient for a diagnosis. It is preferable to overdiagnose leprosy rather than to allow a patient to remain untreated.
IgM antibodies to PGL-1 are found in 95% of patients with untreated lepromatous leprosy; the titer decreases with effective therapy. However, in tuberculoid leprosy—the form of disease most often associated with diagnostic uncertainty owing to the absence or paucity of AFB—patients have significant antibodies to PGL-1 only 60% of the time; moreover, in endemic locales, exposed individuals without clinical leprosy may harbor antibodies to PGL-1. Thus PGL-1 serology is of little diagnostic utility in tuberculoid leprosy. Heat-killed M. leprae (lepromin) has been used as a skin test reagent. It generally elicits a reaction in tuberculoid leprosy patients, may do so in individuals without leprosy, and gives negative results in lepromatous leprosy patients; consequently, it is likewise of little diagnostic value. Unfortunately, PCR of the skin for M. leprae, although positive in LL and BL disease, yields negative results in 50% of tuberculoid cases, again offering little diagnostic assistance.
Included in the differential diagnosis of lesions that resemble leprosy are sarcoidosis, leishmaniasis, lupus vulgaris, dermatofibroma, histiocytoma, lymphoma, syphilis, yaws, granuloma annulare, and various other disorders causing hypopigmentation (notably pityriasis alba, tinea, and vitiligo). Sarcoidosis may result in perineural inflammation, but actual granuloma formation within dermal nerves is pathognomonic for leprosy. In lepromatous leprosy, sputum specimens may be loaded with AFB—a finding that can be incorrectly interpreted as representing pulmonary tuberculosis.
TREATMENT Leprosy ANTIMICROBIAL THERAPY Active Agents
Established agents used to treat leprosy include dapsone (50–100 mg/d), clofazimine (50–100 mg/d, 100 mg three times weekly, or 300 mg monthly), and rifampin (600 mg daily or monthly; see “Choice of Regimens,” below). Of these drugs, only rifampin is bactericidal. The sulfones (folate antagonists), the foremost of which is dapsone, were the first antimicrobial agents found to be effective for the treatment of leprosy and are still the mainstays of therapy. With sulfone treatment, skin lesions resolve and numbers of viable bacilli in the skin are reduced. Although primarily bacteriostatic, dapsone monotherapy results in a resistance-related relapse rate of only 2.5%; after ≥18 years of therapy and subsequent discontinuation, only another 10% of patients relapse, developing new, usually asymptomatic, shiny, “histoid” nodules. Dapsone is generally safe and inexpensive. Individuals with glucose-6-phosphate dehydrogenase deficiency who are treated with dapsone may develop severe hemolysis; those without this deficiency also have reduced red cell survival and a hemoglobin decrease averaging 1 g/dL. Dapsone’s usefulness is limited occasionally by allergic dermatitis and rarely by the sulfone syndrome (including high fever, anemia, exfoliative dermatitis, and a mononucleosis-type blood picture). It must be remembered that rifampin induces microsomal enzymes, necessitating increased doses of medications such as glucocorticoids and oral birth control regimens. Clofazimine is often cosmetically unacceptable to light-skinned leprosy patients because it causes a red-black skin discoloration that accumulates, particularly in lesional areas, and makes the patient’s diagnosis obvious to members of the community.
Other antimicrobial agents active against M. leprae in animal models and at the usual daily doses used in clinical trials include ethionamide/prothionamide; the aminoglycosides streptomycin, kanamycin, and amikacin (but not gentamicin or tobramycin); minocycline; clarithromycin; and several fluoroquinolones, particularly ofloxacin. Next to rifampin, minocycline, clarithromycin, and ofloxacin appear to be most bactericidal for M. leprae, but these drugs have not been used extensively in leprosy control programs. Most recently, rifapentine and moxifloxacin have been found to be especially potent against M. leprae in mice. In a clinical trial in lepromatous leprosy, moxifloxacin was profoundly bactericidal, matched in potency only by rifampin. Choice of Regimens
Antimicrobial therapy for leprosy must be individualized, depending on the clinical/pathologic form of the disease encountered. Tuberculoid leprosy, which is associated with a low bacterial burden and a protective cellular immune response, is the easiest form to treat and can be cured reliably with a finite course of chemotherapy. In contrast, lepromatous leprosy may have a higher bacillary load than any other human bacterial disease, and the absence of a salutary T cell repertoire requires prolonged or even lifelong chemotherapy. Hence, careful classification of disease prior to therapy is important.
In developed countries, clinical experience with leprosy classification is limited; fortunately, however, the resources needed for skin biopsy are highly accessible, and those for pathologic interpretation are readily available. In developing countries, clinical expertise is greater but is now waning substantially as the care of leprosy patients is integrated into general health services. In addition, access to dermatopathology services is often limited. In such instances, skin smears may prove useful, but in many locales access to the resources needed for their preparation and interpretation also may be unavailable. Use of skin smears is no longer encouraged by the World Health Organization (WHO) and is often replaced by mere counting of lesions, which, together with a lack of capacity for histopathologic assessment, may negatively affect decisions about chemotherapy, increase the potential for reactions, and worsen the ultimate prognosis. A reasoned approach to the treatment of leprosy is confounded by these and several other issues:
Even without therapy, TT leprosy may heal spontaneously, and prolonged dapsone monotherapy (even for LL leprosy) is generally curative in 80% of cases.
In tuberculoid disease, it is common for no bacilli to be found in the skin prior to therapy, and thus there is no objective measure of therapeutic success. Furthermore, despite adequate treatment, TT and particularly BT lesions often resolve minimally or incompletely, while relapse and late type 1 lepra reactions can be difficult to distinguish.
LL leprosy patients commonly harbor viable persistent M. leprae organisms after prolonged intensive therapy; the propensity of these organisms to initiate clinical relapse is unclear. Because relapse in LL patients after discontinuation of rifampin-containing regimens usually begins only after 7–10 years, follow-up over the very long term is necessary to assess ultimate clinical outcomes.
Even though primary dapsone resistance is exceedingly rare and multidrug therapy is generally recommended (at least for lepromatous leprosy), there is a paucity of information from experimental animals and clinical trials on the optimal combination of antimicrobial agents, dosing schedule, and duration of therapy.
In 1982, the WHO made recommendations for leprosy chemotherapy administered in control programs. These recommendations came on the heels of the demonstration of the relative success of long-term dapsone monotherapy and in the context of concerns about dapsone resistance. Other complicating considerations included the limited resources available for leprosy care in the very areas where it is most prevalent and the frustration and discouragement of patients and program managers with the previous requirement for lifelong therapy for many leprosy patients. Thus, for the first time, the WHO advocated a finite duration of therapy for all forms of leprosy and—given the prohibitive cost of daily rifampin treatment in developing countries—encouraged the monthly administration of this agent as part of a multidrug regimen. Over the ensuing years, the WHO recommendations have been broadly implemented, and the duration of therapy required, particularly for lepromatous leprosy, has been progressively shortened. For treatment purposes, the WHO classifies patients as paucibacillary or multibacillary. Previously, patients without demonstrable AFB in the dermis were classified as paucibacillary and those with AFB as multibacillary. Currently, in light of the perceived unreliability of skin smears in the field, patients are classified as multibacillary if they have six or more skin lesions and as paucibacillary if they have fewer. (Unfortunately, this classification method has been found wanting, as some patients near the lepromatous pole have only one or a few skin lesions.) The WHO recommends that paucibacillary adults be treated with 100 mg of dapsone daily and 600 mg of rifampin monthly (supervised) for 6 months (Table 203-2). For patients with single-lesion paucibacillary leprosy, the WHO recommends as an alternative a single dose of rifampin (600 mg), ofloxacin (400 mg), and minocycline (100 mg). Multibacillary adults should be treated with 100 mg of dapsone plus 50 mg of clofazimine daily (unsupervised) and with 600 mg of rifampin plus 300 mg of clofazimine monthly (supervised). Originally, the WHO recommended that lepromatous patients be treated for 2 years or until smears became negative (generally in ~5 years); subsequently, the acceptable course was reduced to 1 year—a change that remains especially controversial in the absence of supporting clinical trials.
Several factors have caused many authorities to question the WHO recommendations and to favor a more intensive approach. Among these factors are—for multibacillary patients—a high (double-digit) relapse rate in several locales (reaching 20–40% in one locale, with the rate directly related to the initial bacterial burden) and—for paucibacillary patients—demonstrable lesional activity for years in fully half of patients after the completion of therapy. The more intensive approach (Table 203-2) calls for tuberculoid leprosy to be treated with dapsone (100 mg/d) for 5 years and for lepromatous leprosy to be treated with rifampin (600 mg/d) for 3 years and with dapsone (100 mg/d) throughout life.
With effective antimicrobial therapy, new skin lesions and signs and symptoms of peripheral neuropathy cease appearing. Nodules and plaques of lepromatous leprosy noticeably flatten in 1–2 months and resolve in 1 year or a few years, while tuberculoid skin lesions may disappear, ameliorate, or remain relatively unchanged. Although the peripheral neuropathy of leprosy may improve somewhat in the first few months of therapy, rarely is it significantly alleviated by treatment.
Despite the drawbacks of the WHO’s recommendations for multidrug therapy, these regimens have been used almost exclusively worldwide. Although two of the three recommended drugs (dapsone and clofazimine) are only bacteriostatic against M. leprae and bactericidal agents have been identified since the WHO formulated its recommendations, significant studies employing the available alternatives in newly designed regimens have not been initiated. Given the recent findings that moxifloxacin, like rifampin, is profoundly bactericidal in leprosy patients and that short-course chemotherapy for tuberculosis is possible only when two or more bactericidal agents are used, a moxifloxacin/rifamycin-based regimen including either minocycline or clarithromycin appears promising; such a regimen may prove to be more reliably curative than WHO-recommended multidrug therapy for lepromatous leprosy and may allow a considerably shorter course of treatment. THERAPY FOR REACTIONS Type 1
Type 1 lepra reactions are best treated with glucocorticoids (e.g., prednisone, initially at doses of 40–60 mg/d). As inflammation subsides, the glucocorticoid dose can be tapered, but steroid therapy must be continued for at least 3–6 months lest recurrence supervene. Because of the myriad toxicities of prolonged glucocorticoid therapy, the indications for its initiation are strictly limited to lesions whose intense inflammation poses a threat of ulceration; lesions at cosmetically important sites, such as the face; and cases in which neuritis is present. Mild to moderate lepra reactions that do not meet these criteria should be tolerated and glucocorticoid treatment withheld. Thalidomide is ineffective against type 1 lepra reactions. Clofazimine (200–300 mg/d) is of questionable benefit but in any event is far less efficacious than glucocorticoids. Type 2
Treatment of ENL must be individualized. If ENL is mild (i.e., if it occurs without fever or other organ involvement and with occasional crops of only a few skin papules), it may be treated with antipyretics alone. However, in cases with many skin lesions, fever, malaise, and other tissue involvement, brief courses (1–2 weeks) of glucocorticoid treatment (initially 40–60 mg/d) are often effective. With or without therapy, individual inflamed papules last for <1 week. Successful therapy is defined by the cessation of skin lesion development and the disappearance of other systemic signs and symptoms. If, despite two courses of glucocorticoid therapy, ENL appears to be recurring and persisting, treatment with thalidomide (100–300 mg nightly) should be initiated, with the dose depending on the initial severity of the reaction. Because even a single dose of thalidomide administered early in pregnancy may result in severe birth defects, including phocomelia, the use of this drug in the United States for the treatment of fertile female patients is tightly regulated and requires informed consent, prior pregnancy testing, and maintenance of birth control measures. Although the mechanism of thalidomide’s dramatic action against ENL is not entirely clear, the drug’s efficacy is probably attributable to its reduction of TNF levels and IgM synthesis and its slowing of polymorphonuclear leukocyte migration. After the reaction is controlled, lower doses of thalidomide (50–200 mg nightly) are effective in preventing relapses of ENL. Clofazimine in high doses (300 mg nightly) has some efficacy against ENL, but its use permits only a modest reduction of the glucocorticoid dose necessary for ENL control. Lucio’s Phenomenon
Neither glucocorticoids nor thalidomide is effective against this syndrome. Optimal wound care and therapy for bacteremia are indicated. Ulcers tend to be chronic and heal poorly. In severe cases, exchange transfusion may prove useful.
TABLE 203-2Antimicrobial Regimens Recommended for the Treatment of Leprosy in Adults ||Download (.pdf) TABLE 203-2Antimicrobial Regimens Recommended for the Treatment of Leprosy in Adults
|Form of Leprosy ||More Intensive Regimen ||WHO-Recommended Regimen (1982) |
|Tuberculoid (paucibacillary) ||Dapsone (100 mg/d) for 5 years ||Dapsone (100 mg/d, unsupervised) plus rifampin (600 mg/month, supervised) for 6 months |
|Lepromatous (multibacillary) ||Rifampin (600 mg/d) for 3 years plus dapsone (100 mg/d) indefinitely ||Dapsone (100 mg/d) plus clofazimine (50 mg/d), unsupervised; and rifampin (600 mg) plus clofazimine (300 mg) monthly (supervised) for 1–2 years |
Vaccination at birth with bacille Calmette-Guérin (BCG) has proved variably effective in preventing leprosy: the results have ranged from total inefficacy to 80% efficacy. The addition of heat-killed M. leprae to BCG does not increase the effectiveness of the vaccine. Because whole mycobacteria contain large amounts of lipids and carbohydrates that have proved in vitro to be immunosuppressive for lymphocytes and macrophages, M. leprae proteins may prove to be superior vaccines. Data from a mouse model support this possibility.
Chemoprophylaxis with dapsone may reduce the number of tuberculoid leprosy cases but not the number of lepromatous cases and hence is not recommended, even for household contacts. In addition, single-dose rifampin prophylaxis is of doubtful efficacy. Because leprosy transmission appears to require close prolonged household contact, hospitalized patients need not be isolated.
In 1992, the WHO—on the basis of that organization’s treatment recommendations—launched a landmark campaign to eliminate leprosy as a public health problem by the year 2000 (goal, <1 case per 10,000 population). The campaign mobilized and energized nongovernmental organizations and national health services to treat leprosy with multiple drugs and to clean up outdated registries. In these respects, the effort has proved hugely successful, with >6 million patients completing therapy. However, the target of leprosy elimination has not yet been reached. In fact, the success of the WHO campaign in reducing the number of cases worldwide has been largely attributable to the redefinition of what constitutes a case of leprosy. Formerly calculated by disease prevalence, the count is now limited to cases not yet treated with multiple drugs. Worldwide, the annual incidence of leprosy has not fallen. Furthermore, after the completion of therapy, when a patient is no longer considered to represent a “case,” half of all patients continue to manifest disease activity for years; relapse rates (at least for multibacillary patients) are unacceptably high; disabilities and deformities go unchecked; and the social stigma of the disease persists.
During most of the twentieth century, nongovernmental organizations, particularly Christian missionaries, provided a medical infrastructure devoted to the care and treatment of leprosy patients—the envy of those with other medical priorities in the developing world. With the public perception that leprosy is near eradication, resources for patient care are rapidly being diverted, and the burden of patient care is being transferred to nonexistent or overloaded national health services and to health workers who lack the tools and skills needed for the disease’s diagnosis and classification and for the selection of nuanced therapy (particularly in cases of reactional neuritis). Thus the prerequisites for a salutary outcome increasingly go unmet.