HISTORICAL ASPECTS
Leprosy is an ancient disease; sacred writings from India in the sixth century B.C. give a good description of a similar or identical illness. Greek soldiers returning from Asia in third century B.C. are thought to have introduced the disease into Europe. Stigmatization of patients with leprosy remains an unfortunate but enduring legacy of the European pandemic (1000 to 1500 A.D.). Hansen's attribution of M. leprae as its etiologic agent in 1873 marks the beginning of scientific leprology.(1)
Effective chemotherapy began with the introduction of sulfones in 1943. The limited growth of M. leprae in the mouse foot pad, in 1961, provided a way to screen for therapeutic agents and to identify drug resistance.(2) Rifampin, in 1970, was the first drug to be identified as bactericidal for M. leprae and is now the cornerstone of most therapeutic regimens.
In 1919, the lepromin skin test inaugurated systematic study of host resistance as the source of disease diversity,(3) lymphocyte transformation tests being established in the 1960s as an in vitro correlate. The recognition of leprosy in the nine-banded armadillo, in 1971, provided a source of large quantities of highly purified M. leprae for a wide variety of investigations, culminating in the sequencing of the entire genome of M. leprae in 2001.(4) This landmark achievement will provide novel avenues of investigation, which, in turn, will provide new methods of intervention.
EPIDEMIOLOGY
Leprosy, primarily a disease of developing countries, is endemic in all continents, except Antarctica. In the Americas, only Canada and Chile are not endemic areas, with Texas and Louisiana being endemic states in the United States. The southern-most nations of Europe have a very low incidence, while leprosy is endemic in many Pacific islands. The Indian subcontinent has two-thirds of the world's leprosy burden. The highest case detection rates are in India, Brazil, Madagascar, Nepal, and Tanzania. During the decade of the 1990s, the prevalence of leprosy fell by 90 percent, because patients completing a course of multiple-drug therapy have been considered to be cured, but the incidence of the disease has remained unchanged.(5)
In all populations studied, lepromatous disease is more common in men than in women by a 2:1 ratio. The tuberculoid form dominates wherever the disease is common. The median age of onset is less in tuberculoid than in lepromatous patients, but in both groups, leprosy is predominantly a young person's disease, the majority of cases occurring before age 35 years. However, age is not protective; new cases of each type occur in the eighth and ninth decades of life. The incubation time for tuberculoid leprosy is up to 5 years and for lepromatous may be 20 years or longer.
The preponderance of opinion supports the traditional view that M. leprae is transmitted from human-to-human, but the presence of an M. leprae caused lepromatous-like illness in wild armadillos, (6) evidence of armadillo exposure as a risk factor for leprosy in people, (7) and the presence of an M. leprae-like organism on sphagnum moss, (8) suggest that nonhuman sources for M. leprae may be important. The route of infection is unknown, but current evidence favors respiratory transmission; evidence for congenital and percutaneous transmission has been presented, but these are probably rare. (9) In leprosy endemic areas, subclinical infection is common, as judged by serologic studies identifying M. leprae-specific antibodies. (10)
ETIOLOGY AND PATHOGENESIS
M. leprae, the cause of leprosy, is a noncultivable, gram-positive, obligate intracellular, acid-fast bacillus. The union of bulk extracted M. leprae from armadillos with the techniques of molecular biology has proven to be a fruitful marriage, its crowning accomplishment being the sequencing the bacillary genome. (4) The genome of M. leprae (3.27 megabases) is notably shorter than that of M. tuberculosis, (4.41 megabases). Even more striking, the M. leprae genome codes for 1600 genes, M. tuberculosis codes for 4000. The two species share 1439 genes in common. In M. leprae only one-half of its genome is coding sequence, this evident gene deletion and decay leaving M. leprae with few respiratory enzymes, but offering a reasonable explanation for the failure to cultivate the organism in cell-free media, as well as for its obligatory intracellular environment.
The bacillary cell wall consists of a peptidoglycan backbone linked to arabinogalactan and mycolic acids. Immunogenic proteins are associated with the cell wall, and also present in the cytoplasm. These include highly conserved heat shock proteins of molecular weight 10, 65, and 70 kDa, each bearing species-specific and cross-reacting epitopes. A lipoglycan target of both antibody and cellular immune responses, lipoarabanomannan, courses through the outer membrane and inserts into the cell membrane. Phenolic glycolipid I is a major, species specific and immunogenic, constituent of the highly nonpolar outer layer of the bacillus. Entry into nerves is mediated by the binding of the species-specific trisaccharide in phenolic glycolipid I to laminin-2 in the basal lamina of Schwann cell-axon units, (11) providing a rationale as to why M. leprae is the only bacterium known to invade peripheral nerves.
In tissues or smears, M. leprae is quantified by the biopsy index (BI), a logarithmic scale as to the numbers of bacilli per oil immersion field (OIF): a BI of 6 is 1000 or more bacilli/OIF; a BI of 5 is 100 to 1000/OIF; a BI of 4 is 10 to 100/OIF; a BI of 3 is 1 to 10/OIF; a BI of 2 is 1 bacillus/1 to 10 OIFs; a BI of 1 is 1/10 to 100 OIFs; and a BI of 0 is no bacilli in 100 OIFs.
GENETICS
A twin study has provided compelling evidence that both genetic and environmental factors are important in determining disease susceptibility and disease expression. (12) The recent report of a susceptibility locus for leprosy in India, located on chromosome 10p13, may be the beginning of going beyond the vague rubric of “polygenetic susceptibility.” (13) Major histocompatibility complex class II antigens appear to influence disease expression, that is tuberculoid versus lepromatous, but not susceptibility. (14)
PREVENTION
Protocols endeavoring to control leprosy by vaccination usually consists of BCG alone, viable BCG in combination with killed M. leprae, or killed M. leprae alone. (15) Most studies support a reduction in leprosy incidence, roughly one-third in tuberculoid cases, considerably less in lepromatous. The recent observation that lipid and lipoglycan antigens are presented to T cells (CD4–, CD8–, CD3+) by CD1+ cells opens the door to entirely new vaccination protocols. (16) Other preventive measures, such as isolation of patients or treatment of patient contacts with antimicrobials, have been disappointing.
CLINICAL MANIFESTATIONS
The diverse clinical manifestations of leprosy can be reduced to two kinds of changes, a granulomatous spectrum and the reactional states.
A Granulomatous Spectrum
The most detailed description of the granulomatous spectrum of leprosy came from Ridley and his associates,(17,18) integrating both clinical and histologic changes. Ridley's construct is a six-member granulomatous spectrum, ranging from high to low resistance, TT (polar tuberculoid), BT (borderline tuberculoid), BB (borderline), BL (borderline lepromatous), LLs (subpolar lepromatous), and, finally, LLp (polar lepromatous).
Conceptually, TT and LLp are clinically stable, but, between the poles, the hosts granulomatous posture may change, upgrading (or reversing) to a posture of higher resistance, often with devastating inflammation, or downgrading to a posture of lower resistance, usually silent but occasionally inflammatory. BT patients may upgrade to TT, thus, becoming stable, but LLs patients do not downgrade to LLp nor do LLp patients upgrade. Putatively, the host's granulomatous posture is the result of the degree of cell-mediated immunity directed against M. leprae.
In comparison of pre-Ridley and Ridley terminology, tuberculoid corresponds to TT and BT, borderline or dimorphic to BB and BL, and lepromatous to LLs and LLp. In virtually all TT patients, and in most BT cases, acid-fast bacilli cannot be found, whereas in BB, BL, LLs, and LLp, bacilli are demonstrable with ease. Ridley's construct is useful in classifying patients, especially for immunity. Another classification system is useful for treatment: paucibacillary, that is to say no acid-fast bacilli found, or multibacillary, that is to say one or more bacilli found.
Peripheral Nerve Changes
Four types of peripheral nerve abnormalities are common in leprosy: (1) nerve enlargement (usually perceived as asymmetry), particularly in those close to the skin, such as the great auricular, ulnar, radial cutaneous, superficial peroneal, sural and posterior tibial; (2) sensory loss in skin lesions; (3) nerve trunk palsies either with signs and symptoms of inflammation or without such overt manifestations, that is, silent neuropathy, (19) usually with both sensory and motor loss (weakness and/or atrophy) and, if long-standing, also with contracture; and (4) acral distal symmetric anesthesia, a withering away, so to speak, of the type C fibers, involving heat and cold discrimination before loss of pain or light touch, beginning in acral areas and, over time, extending centrally but sparing the palms, at least for a while. Uncommon peripheral nerve abnormalities include nerve abscesses (palisading granulomas formed about cutaneous sensory nerves) and the carpal tunnel syndrome. Anhidrosis is a common manifestation of sympathetic nerve involvement.
Dermatologic and Neural Changes
POLAR TUBERCULOID LEPROSY In TT, immunity is strong as manifested by spontaneous cure and the absence of downgrading to a posture of less host resistance. The primary skin lesion of TT is a plaque, often assuming an annular configuration secondary to peripheral propagation and central clearing. The border of the plaque or both borders of the annulus are sharply marginated. Typically, the lesion is firmly indurated, elevated, erythematous, scaly, dry, hairless, and hypopigmented, but clinically, considerable variation is encountered.
A nearby sensory nerve may or may not be enlarged, but the lesion itself is characteristically anesthetic and anhidrotic. Skin lesions are often solitary, particularly in those patients who are TT de novo, as contrasted to those who upgrade to TT from BT, where multiple lesions, usually no more than three, may be found. In both groups, immunity is sufficient to effect cure, thus, placing an upper limit of 10 cm on lesion size, but antibiotic therapy is recommended.
BORDERLINE TUBERCULOID LEPROSY In BT disease, immunologic resistance is strong enough to restrain the infection, in that the disease is limited and bacillary growth retarded, but the host response is insufficient to self-cure. These patients are somewhat unstable—resistance may increase, upgrading to TT, or decrease, downgrading to BL. The primary skin lesions of BT are plaques and papules. As in TT, an annular configuration is common and both borders are sharply marginated but annular lesions or plaques may have satellite papules. Hypopigmentation may be conspicuous in darkly pigmented patients. In contrast to TT, typically, there is little or no scaling, less erythema, less induration, and less elevation, but lesions may become much larger, that is, well over 10 cm in diameter, a single lesion sometimes involving an entire extremity over time. Multiple, asymmetric lesions are the rule, but solitary lesions are not rare.
Loss of sensation in skin lesions is the rule and nerve trunk involvement, enlargement, or palsies, usually in no more than two and asymmetric, are common. Nerve abscesses, when they occur, are most often seen in males with BT disease.
BORDERLINE LEPROSY BB is the immunologic midpoint or mid-zone of the granulomatous spectrum, being its most unstable area, with patients quickly up- or downgrading to a more stable granulomatous posture with or without a clinical reaction. Characteristic skin changes are annular lesions with sharply marginated interior and exterior margins, large plaques with islands of clinically normal skin within the plaque, giving a “Swiss cheese” appearance, or the classic dimorphic lesion. Because of instability, the BB posture is short-lived and such patients are evidently rarely seen; for example, we have yet to see a nonreactional patient meeting both clinical and histologic criteria.
BORDERLINE LEPROMATOUS LEPROSY In BL disease, resistance is too low to significantly restrain bacillary proliferation, but still sufficient to induce tissue destructive inflammation, especially in nerves. Thus, patients with BL may have the worst of both worlds. The BL category is highly variable in its clinical expression. Although seen in only a third of BL patients, the classic dimorphic lesion is the most characteristic, having an annular configuration with a poorly marginated outer border (lepromatous-like) but a sharply marginated inner one (tuberculoid-like, hence, having both morphologies or dimorphic). Poorly or sharply marginated plaques with “punched out” or “Swiss cheese” sharply marginated areas of normal skin in the interior of the plaque are also characteristic, and can be viewed as a variant of the classic dimorphic lesion. Annular lesions with sharply marginated exterior and interior borders are not uncommon. When they occur, lepromatous-like, poorly defined papules and nodules may be numerous, but are usually accompanied by some sharply marginated lesions somewhere.
Lesions range in number from solitary (something happens first, the tip of an inapparent iceberg) to numerous and widespread. Generally speaking, the annular and plaque lesions, however numerous, are asymmetric, but the lepromatous-like nodules, if numerous, are symmetric. Skin lesions are often hypesthetic or anesthetic, but not necessarily so. Nerve trunk palsies have their highest prevalence in BL disease, but are variable in number, ranging from none to serious neurologic deficits, both motor and sensory, in all four extremities. Involvement of both median and ulnar nerves, not infrequently bilateral, is characteristic. When disease is extensive, BL patients may also develop acral distal symmetric anesthesia. Untreated BL patients have slowly relentless progression of skin and nerve changes. With or without treatment, this course may be altered by a reactional state, upgrading reactions being more common than erythema nodosum leprosum ( ENL; see below). Also, BL patients may silently downgrade to an LLs granulomatous posture.
LEPROMATOUS LEPROSY In lepromatous leprosy (LL) disease, the lack of cell-mediated immunity toward M. leprae permits unrestricted bacillary replication and widely disseminated, multiorgan disease. Poorly defined, skin-colored nodules are the most characteristic lesions, usually up to 2 cm in diameter, and symmetrically distributed. Dermatofibroma-like or histiocytoma-like lesions, usually multiple, are sharply marginated erythematous papules, sometimes confluent into plaques, and are not rare in untreated Mexican-born patients, but are also seen in Filipinos and Samoans. Diffuse dermal infiltration is always present subclinically and may be overtly manifested by widening of the nasal root and fusiform swelling of the fingers, mimicking a rheumatic illness. With progressive bacillary proliferation, further cellular infiltration, and the consequent thickening of the dermis, the skin is thrown into folds producing the leonine faces often in conjunction with nodular lesions. Less-common presenting skin lesions include digitate, barely indurated patches of erythema, which in light-skinned patients are sometimes followed by a mild hyperpigmentation; in dark-skinned patients, multiple hypopigmented macules may originate in such lesions, a veil of melanin concealing the erythema. A clinical clue of LLs is a sharply marginated region in a lesion, perhaps the residual of a BL lesion in a patient who has downgraded to LLs.
Hair loss, common on the eyebrows, where it progresses laterally to medially, but also on the eyelashes and extremities, may be partially reversible if treated early. Scalp involvement is rare. Loss of eccrine sweating from sympathetic nerve involvement is common but rarely so extensive as to lead to heat intolerance. Any given skin lesion may or may not be hypesthetic but generally, in each patient, some are. Nerve trunk palsies occur, but are less common than in BL. Acral distal symmetric anesthesia is to be expected and may be so severe as to lead to debilitating trophic changes of the hands or feet. Untreated LL disease is relentlessly progressive, but this course may be altered by reactional states. LLs and LLp subjects frequently develop ENL, but LLp patients do not develop reversal reactions (see below), whereas LLs patients may.
Systemic Associations
Because of motor or sensory changes in cranial nerve V, the eye may be at risk in TT and BT disease, as well as in BB, BL, and LL leprosy. In the latter group, numerous changes in the cornea and anterior chamber are possible, iritis being a common serious change, occurring de novo or in association with reactions. Corneal insensitivity is the common, treatable change. Routine ophthalmologic examination is recommended for all patients.
In all LL patients and in BL with extensive disease, wide dissemination of the infection is the rule, but, with the exception of the upper respiratory tract (tip of the nose through the vocal cords with rhinitis, septal perforation, and nasal collapse being not uncommon), eyes and testicles (atrophy, impotence, and infertility), clinically troublesome injury is unusual. With effective chemotherapy, chronic disability from ocular or upper respiratory tract involvement is less common than previously, but has not disappeared, making ophthalmologists and otolaryngologists still vital to the successful management of patients with leprosy, to evaluate and treat acute changes, and to prevent chronic changes.
Variants
PREGNANCY AND POSTPARTUM Pregnancy is a precipitating factor for leprosy in 10 to 25 percent of women patients, presumably because of altered immunity. When pregnant, LL and BL patients are predisposed to develop ENL, but in the postpartum period, they are predisposed to develop reversal reactions, putatively due to reduced immunity in the former and restored immunity in the latter. 20 Of the drugs used to treat leprosy, none have been proven to be safe for the fetus and one is clearly contraindicated. Fetal damage attributable to dapsone evidently has not been observed, hence continuation of dapsone in multibacillary patients is usually recommended. The wishes of the patient should be carefully considered. Untreated, lactating BL and LL patients have viable bacilli in their milk, but no definable risk has been identified in infants ingesting such bacilli. (21) Dapsone in mother's milk may produce hemolysis in baby.
INDETERMINATE LEPROSY Indeterminate leprosy is a term with nearly as many meanings as it has users. We prefer the definition of Khanolkar, (22) designating an early lesion, appearing before the host makes a definitive immunologic commitment to cure or to an overt granulomatous response. Clinically, the indeterminate lesion is a hypopigmented macule, with or without a sensory deficit and acid-fast bacilli, if found, are in very small numbers. Such lesions are rare in our clinic. The term is inappropriately used to describe lesions rich in bacilli but having neither typical tuberculoid or lepromatous histological responses, such patients usually being BL and occasionally LL.
ACQUIRED IMMUNODEFICIENCY SYNDROME OR HIV INFECTION In contrast to the high incidence of tuberculosis and M. avium-intracellulare infections in AIDS or HIV patients, leprosy does not behave as an opportunistic infection in these individuals. Also, AIDS or HIV does not appear to influence disease expression (tuberculoid versus lepromatous) or the frequency of reactional states, but may be a risk factor for recurrent reversal reactions. (23)
DISABILITY OF HANDS AND FEET Approximately one-quarter to one-third of newly diagnosed patients with leprosy will eventually have some chronic disability secondary to irreversible nerve injury, usually of the hands or feet, or from eye involvement. Weakness from loss of innervation of muscles is a self-evident cause of disability. Loss of protective sensation is less obvious, but no less real. When a sharp or hot object cannot be perceived as such, injury occurs. Because this injury is more severe than if sensation were normal, infection is more apt to occur. Because the infection can produce no painful signal, the part is not rested, allowing the infection to become extensive before help is sought. Repetitive cycles of injury and infection, permitted by loss of protective pain sensation, is the source of severe tissue destruction in leprosy. Management and prevention of the problems arising from nerve injury require the skills of orthopedic surgeons, podiatrists, plastic surgeons, physical therapists, orthotists and occupational therapists.
RELAPSING LEPROSY “Multibacillary” patients who are noncompliant or who develop drug resistance are prone to relapse. Such individuals present in several ways, including (1) a reprise of their initial presentation, (2) florid dermatofibroma-like lesions (histoid lesions), (3) a reactional state, and (4) a clinical state of higher resistance than their initial presentation, for example, an initially LLs individual having BL or even BT disease.
Reactional States
Generically, the reactional states of leprosy are distinctive, tissue destructive, inflammatory processes, putatively immunologically driven, that greatly increase the morbidity of the disease and, because of the experience required for optimal patient care, justify leprology as a clinical subspecialty. When present, a reactional state is superimposed upon the underlying granuloma, but it usually dominates the clinical picture. Analogous to the p electron in photobiology, when the granulomas accept immunologically driven “energy,” the excited granuloma is able to injure tissues in ways that it cannot when in its ground state.
DELAYED-TYPE HYPERSENSITIVITY REACTION (JOPLING'S TYPE I REACTION) Although widely regarded as a delayed-type hypersensitivity (DTH) response, the nomenclature is not uniform. Reversal reaction, originally synonymous with “upgrading,” has come to be used as identical to type I, probably because most type I reactions are associated with reversal. Designation by mechanism as a DTH reaction is a rational and acceptable name. DTH reactions are particularly common in BL patients, but are not rare in LLs, BB, or BT. (24) Patients may upgrade to a more-resistant granulomatous posture, remain unchanged, or downgrade to a less-resistant disease state. Clinically, DTH reactions are characterized by the abrupt conversion of previously torpid plaques to tumid lesions, and new tumid lesions arising in clinically normal skin with or without an abrupt onset of neuritis. A purplish color is characteristic, and even if not obvious, the dusky erythema may have a purplish cast. Iritis and lymphedema (elephantiasis graecorum) may be concomitant changes. Lesions are rarely solitary, as can happen in BT upgrading to TT, often multiple, and occasionally myriad, as in BL or LLs upgrading to BT. Neuritis also ranges from mild to severe, potentially disastrous, particularly if involving multiple nerves. DTH reactions may often be a mode of presentation, and DTH reactions occurring soon after presentation and the institution of treatment may well have been DTH reactions from the beginning. Most common in the first year of treatment, DTH reactions may occur up to 7 years after starting therapy, well after treatment has stopped. The diagnosis of a DTH reaction is primarily clinical, but histologic confirmation should be sought.
ERYTHEMA NODOSUM LEPROSUM (JOPLING'S TYPE II REACTION) ENL (first described by Murata in 1912) occurs most often in LL, in up to 75 percent of cases, but is not rare in BL patients. (ENL is not erythema nodosum occurring in leprosy; it is a leprosy-specific response, which has some features in common with erythema nodosum.) It may occur before, during, or after chemotherapy. The median time of onset is close to 1 year after onset of treatment. Clinically, this reaction is characterized by crops of painful and tender, bright pink, dermal and subcutaneous nodules arising in clinically normal skin, in association with fever, anorexia, and malaise. Of the other organs involved, arthralgias and arthritis are more common in ENL than are neuritis, adenitis, orchitis/epididymitis, or iritis, but each may rarely be the initial structure affected. Involvement of both upper and lower extremities is the rule and facial lesions occur in one-half of the patients. A neutrophilic leukocytosis is often present, occasionally leukemoid in degree. Severe episodes can be associated with an abrupt fall in hematocrit, up to 5 g/dL, easily mistaken for dapsone-induced hemolysis. The response to thalidomide is dramatic in greater than 90 percent of patients, perhaps qualifying as a diagnostic criterion. When ENL is the presenting mode of leprosy, there may be little or no stigmata of the underlying multibacillary disease. ENL may be precipitated by pregnancy or pyogenic infections.
Although episodes of ENL may be occasional or sporadic, in the more severely involved patients, episodes can be frequent to virtually unremitting. In the latter, brawny induration of the anterior thighs and preaxial portion of the arms is characteristic, perhaps a reversible fibrosis. Other cutaneous variants are annular lesions mimicking erythema multiforme, vesicles or pseudovesicles in association with papillary edema, necrotic lesions, ulcers, frank subcutaneous abscesses, and pustular lesions mimicking pyodermas. The course of ENL, treated or untreated, ranges from sporadic and ephemeral, to frequent and persistent, lasting a matter of years. A severe, difficult to manage, form of ENL is a serious problem in Brazil and other parts of South America. The diagnosis of ENL, if considered, is usually not difficult, the clinical and histologic features being characteristic and the response to thalidomide often dramatic.
THE LUCIO REACTION Clinically, the Lucio reaction, first described by Raphael Lucio in 1853, consists of hemorrhagic infarcts. Particularly prevalent in Mexico and the Caribbean region, it is restricted to patients with Latapi's lepromatosis, described by Fernando Latapi in 1941, (25) a distinctive form of diffuse nonnodular lepromatous leprosy. When fully developed, Latipi's lepromatosis manifests a widening of the nasal root and fusiform enlargement of the fingers, both the consequence of diffuse dermal infiltration, as well as, a purplish suffusion of the hands and feet, numerous telangiectatic mats or eruptive telangiectasias, nasal septum perforation, total alopecia of eye brows and eye lashes, and a well-developed acral distal symmetric anesthesia. Firm subcutaneous nodules are palpable but not visible. Ocular sparing is the rule. The Lucio reaction occurs after Latapi's lepromatosis is well developed but before treatment is initiated. The necrotic lesions, arising in crops, have the serrated margins characteristic of septic infarcts and are painful but not tender. Lesions usually crust and heal with scaring. Ulceration is common, especially below the knees. Lesions vary in size and extent, ranging from a few small lesions on the ankles to many large lesions, placing life in peril. With dapsone alone, lesions may worsen, but in our experiences, new lesions cease within 1 week of beginning rifampin, suggesting a strict requirement for viable bacilli. (26)
LABORATORY FINDINGS
Most laboratory changes occur in LL or extensive BL disease. Hyperglobulinemia is the most common, giving an elevated sedimentation rate. A biologic false-positive serologic test for syphilis, anemia of chronic disease, and mild lymphopenia are also common. Clinically insignificant antiphospholipid antibodies are present in 50 percent of LL patients, and may give rise to a lupus anticoagulant or agglutination of sheep erythrocytes (Rubino factor).(27) If sought, the stained smear of the buffy coat shows bacilli up to 10 5/mL. Elevated serum lysozyme and angiotensin-converting enzyme values reflect the extensive accumulation and activation of macrophages synthesizing these proteases. Proteinuria, not uncommon, is associated with a focal glomerulonephritis, seen mostly in patients with ENL. As manifested by high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) values, but low testosterone levels, LL disease involves the testicles in a majority of men with LL, but in a minority of men with BL.
PATHOLOGY
Microscopic Changes
COMMON AND UNCOMMON PATTERNS Granulomatous responses are the common tissue reactions in leprosy, with epithelioid differentiation of macrophages being characteristic of TT, BT, and BB, and undifferentiated or foamy macrophages being the hallmark of BL, LLs, and LLp. Exceptions can occur, sometimes dominating the histologic picture; exceptions include (1) chronic inflammation, particularly in BL and indeterminate disease, (2) lobular panniculitis in ENL, and (3) vasculitis in ENL and the palpable-only nodules of Latapi's lepromatosis. At the level of the low-power objective, a patchy infiltrate throughout the dermis, or a bizarre “sausage-shaped” infiltrate (following neurovascular bundles) should include consideration of leprosy in the differential diagnosis.
SPECTRAL GRANULOMATOUS PATTERNS (17,18) In de novo TT lesions, small, well-developed epithelioid tubercles are surrounded by large lymphocytic mantles. In TT upgrading from BT, abundant Langhans-type giant cells and a brisk exocytosis into the epidermis are added to the preceding pattern, and caseation may be present. In BT tissues, lymphocytic mantles are less well developed, Langhans-type giant cells are inconstant, and, if present at all, epidermal exocytosis is focal. Acid-fast bacilli are not found in TT and are only rarely seen in BT. The presence of bacilli or plasma cells in what otherwise appears to be BT warrants consideration of a reversal reaction. In BB, lesions are lymphopenic, giant cells are absent, and bacilli are common. The classic BL tissue responses are a moderately dense lymphocytic infiltrate restricted to the space occupied by the macrophages, and lamination of the perineurium with infiltrating inflammatory cells. A chronic lymphohistiocytic infiltrate is an alternate pattern. In LLs, lymphocytes are present focally or sparsely distributed generally, and the laminated perineurium is not infiltrated. In LLp, lymphocytes are fewer than in LLs, and there is no perineural lamination. From BL to LLp, the extent of the granuloma and the numbers of globi (large secondary lysosomes packed with bacilli) are highly variable, but bacilli are always easily found, even if with great quantitative differences.
PATTERNS IN REACTIONAL STATES Reversal reactions, when compared with prereactional tissues, occasionally do not differ, but may show edema, epithelioid change, increased lymphocytes, Langhans-type and foreign-body giant cells, epidermal thickening, and, occasionally, enhanced bacteriolysis. (28) ENL lesions usually have neutrophils, a marked increase in lymphocytes, epidermal thickening, and a gradient of inflammatory cells, scant in the papillae and heavy in the deep dermis or subcutis. Lucio lesions feature ischemic necrosis in both epidermis and dermis, vessel occlusion by thrombosis or endothelial proliferation, and heavy bacillary parasitization of endothelial cells.(26)
Immunopathology and Immunology
Investigation into the immunology of leprosy offers three promises: (1) a better understanding of the disease itself; in particular, the immunopathogenesis of the granulomatous spectrum and the reactional states; (2) eradication or control of the disease by vaccination; and (3) development of a probe of cell-mediated immunity in humans that, when understood in the model of leprosy, will illuminate other disease processes.
CELLULAR IMMUNITY The great diversity of leprosy is exemplified by comparing its two polar forms. The high-resistance tuberculoid form is characterized by few lesions, rare organisms, epithelioid cell granulomas, and a tendency to self-cure. A sharp margin on a plaque is the inscription of anti- M. leprae DTH on the skin; a nerve trunk palsy is its inscription on a peripheral nerve. Tuberculoid leprosy appears to be an entirely different disease than the low-resistance lepromatous form, characterized by wide dissemination, abundant organisms, foamy macrophages, and, if untreated, relentless progression. Strain variation of M. leprae is an unlikely explanation for the diverse host responses in leprosy. (29) The observations of a positive lepromin skin test in tuberculoid subjects and unresponsiveness in lepromatous patients was the first objective and reproducible evidence that host immunity was the mechanism of polar diversity. (3) Lymphocyte transformation tests provided an in vitro correlate of the lepromin skin and substantial evidence that mediation of polar diversity was through the cellular-immune response. On the contrary, antibody responses to M. leprae were found to be stronger in lepromatous patients, indicating the humoral immunity does not lead to resistance to disease. Immunophenotypic studies established an important difference between the lymphocyte subsets infiltrating skin lesions and tuberculoid subjects having a predominance of the CD4 subset (CD4:CD8 = 2:1), but lepromatous patients having a predominance of the CD8 subset (CD4:CD8 = 1:2). (30) The skewing of T cell subsets in lesions was independent of those in the peripheral blood, because all patients had a normal CD4:CD8 ratio of 2:1. Therefore, it is important to study the immune response of patients at the site of disease activity, that is, the skin lesions. By using the sequential application of reverse transcriptase and polymerase chain reaction techniques to tissue extracts, studies of mRNA cytokine profiles in polar tissues have provided a functional explanation for their immunopathogenesis. (31) Tuberculoid lesions have a type 1 (T H1 or T H1-like) proinflammatory profile, in particular abundant mRNA coding for interleukin (IL)-2, interferon (IFN)-?, and IL-12, but scant mRNA coding for IL-4 or IL-10. In contrast, lepromatous tissues have a type 2 (T H2 or T H2-like) anti-inflammatory profile, in particular, abundant IL-4 mRNA and IL-10 mRNA, but little mRNA coding for the type 1 cytokines. Furthermore, CD4+ T cells in tuberculoid lesions were shown to produce IFN-?, whereas, CD8 T cells in lepromatous lesions accounted for the production of IL-4. 32 The presence of type 1 cytokines likely results in strong T cell and macrophage activation, the result being cell-mediated immunity to localize the infection. On the other hand, the type 2 cytokines found in lepromatous lesions likely lead to the strong antibody responses, but concomitantly inhibit T cell and macrophage responses resulting in progression of the infection. The importance of this paradigm is reflected in experiments designed to augment cell-mediated immunity in lepromatous patients, where the administration of recombinant IFN-? to lepromatous patients reduced the number of bacilli infiltrating tissues. (33) The decision by the host as to which cytokine profile to make, that is, type 1 or type 2, may rest with the response of the native immune system to M. leprae. Cytokines produced by the native immune system may profoundly affect the adoptive response, (34) and some of the Toll-like receptors (TLR) of the native system are triggered by mycobacterial lipoproteins (35). Reversal reactions and positive lepromin skin tests (Mitsuda reactions), long considered to be delayed-type hypersensitivity responses, 36 also have a CD4+ T cell predominance and a type 1 cytokine profile, but both differ from tuberculoid lesions by having a relative excess of M. leprae-reactive ?d T cells, perhaps related to these being recent lesions. 37 Host cytokine profiles are subject to change. LLs patients undergoing a reversal reaction switch from a type 2 to a type 1 profile; the mechanism of the switching is yet to be determined. (38)
ANTIBODY IMMUNITY ENL is widely regarded to be mediated by immune complexes. There are large amounts of anti- M. leprae antibodies in both LL and BL patients. All classes of antibodies are represented and their specificities directed against a number of substrates including specific and cross-reacting peptides, but these antibodies do not confer disease protection. Also, the blood of BL and LL patients contains abundant antigens including intact bacilli, up to 10 5/mL. Therefore, it is readily conceivable that BL and LL patients should be subject to immune complex-mediated tissue injury. The best direct support for the hypothesis that ENL is immune complex mediated is the presence of split complement products in serum, which is consistent with extravascular complement activation within tissues. (39) Inferential evidence is that of neutrophil infiltration, suggesting an Arthus phenomenon, and an excess of glomerulonephritis in ENL patients. Also, the cytokine profile in ENL is type 2, despite a preponderance of the CD4+ subset. (38) However, evidence for immune complex mediation is far from persuasive—it has not been reproduced and it is confounded by a number of observations, including human leukocyte antigen (HLA)-DR framework antigen in lesional epidermis, (40) an increase in IFN-? containing cells by hybridization studies, (41) an excess of IL-2–staining cells as compared with LL tissue, (42) and the precipitation of ENL by the administration of rIFN-?. (43) Also, other thalidomide responsive syndromes, such as rheumatoid arthritis, tuberculosis cachexia, multiple myeloma, and Behçet's syndrome, are not directly immune complex mediated. Perhaps both immune complexes and cellular immunity are important in the pathogenesis of ENL. Little is known concerning the immunopathogenesis of the Lucio reaction. Extant evidence favors immune complex mediation. The abundant acid-fast bacilli in endothelial cells could be the optimum location for presentation of antigen to antibody. Also, the cryoprecipitate from Lucio serum is more indicative of complement activation than that from ENL patients. (44)
DIAGNOSIS
A firm diagnosis of leprosy requires the satisfaction of one of two criteria: a consistent peripheral nerve abnormality or the demonstration of mycobacteria in tissues.
The diagnosis begins with a suspicion of leprosy, which should be aroused by the presence of any of several known risk factors, including (1) birth or residence in an endemic area, which is almost sine qua non for the diagnosis, (2) a blood relative with the disease, which could reflect transmission, common genetic makeup, or common environmental exposure, and (3) armadillo (seven-banded) exposure in North American.
The possibility of leprosy also should be suggested by particular clinical constellations such as (1) simultaneous skin lesions and peripheral nerve abnormalities, (2) a differential diagnosis that includes granuloma, vasculitis, or lymphoma, (3) a peripheral neuropathy of unknown type in a patient in or from an endemic area, the so called pure neuritic leprosy, and (4) simultaneous palsies of cranial nerves V and VII, considered to be leprosy until proven otherwise.
Because M. leprae does not grow in cell-free media, demonstration of mycobacteria by their acid-fast property is used most commonly in diagnosis. Acid-fast bacilli in tissue sections are best shown by carbolfuchsin staining, using modifications of the Ziehl-Neelson method, collectively called Fite-Farraco stains . M. leprae, like Nocardia species, is only weakly acid-fast. In smears, either the Ziehl-Neelson method or oramine-rhodamine staining with fluorescent microscopy is satisfactory. Because of characteristic clinical and histologic changes, positive specification of M. leprae is rarely required.
Characteristic histologic changes are extremely helpful in suggesting or corroborating a diagnosis of leprosy, but, excepting the presence of epithelioid cell granulomas within nerves, are not absolutely diagnostic.
False Negatives
The six errors that lead to missing the diagnosis of leprosy are (1) failure to consider the diagnosis, usually from ignoring birth or residence in an endemic area; (2) failure to inform the pathologist of the suspicion of leprosy—an infiltrate may not be granulomatous, thus no acid-fast bacilli stain will be done by the pathologist if there is no known clinical suspicion; (3) an inadequate neurologic exam, in particular, the patient is not properly instructed to distinguish between dull and sharp (if the patient is not instructable, absence of a histamine-induced axon reflex flare, with a positive symmetric control, is good evidence of type C pain fiber loss); (4) presence of pinprick perception does not exclude loss of heat and cold discrimination; (5) improper staining for bacilli in biopsy specimens—in a conventional Ziehl-Neelson stain M. leprae, being only weakly acid-fast, may be decolorized altogether; and (6) tissue sampling error—the advancing border should be selected for biopsy not the clearing center.
False Positives
The four errors that lead to improperly diagnosing leprosy are (1) inflammatory lesions may have blunted pain perception (histamine tachyphylaxis), producing diminished sensation similar to that seen in some leprosy lesions; (2) atypical mycobacterial infection may have the abundant acid-fast bacilli characteristic of lepromatous disease; (3) environmental mycobacteria-like water, including that used to process tissue sections, as suggested by bacilli in the embedding medium, or not associated with cellular infiltrates; (4) from time-to-time, cunning artifacts are misinterpreted as acid-fast bacilli. If a patient, suspected of having leprosy, has no history of residence in a known endemic area, then one of these errors should be seriously considered.
ALTERNATIVE METHODS Alternative methods of establishing a diagnosis have been pursued but, at present, are of limited value. M. leprae specific antibodies are most prevalent in multibacillary cases, where there is no need for better diagnosis, and are, in endemic areas, far more prevalent than the disease, thus further restricting their utility. (10) Polymerase chain reaction (PCR) may be negative in up to one-half of paucibacillary cases, making a positive signal of value but a negative signal of no help. PCR should be most helpful in the diagnosis of patients with lesions having acid-fast bacillus, but no stigmata of leprosy, and negative cultures.(45) Lepromin skin testing, because of the high rate of positive reactions in unexposed adults, is not useful in diagnosis, but can be of value in classification of diagnosed patients; all TT and most BT (85 percent in our experience) being positive (3 mm or more of induration at 21 days) and BB through LLp being negative (less than 3 mm).
TREATMENT
Medical management is directed at the infection itself, or if present, at a reactional state. For paucibacillary disease (TT or BT) the World Health Organization (WHO) recommends the combination of unsupervised dapsone (bacteriostatic) 100 mg daily and supervised rifampin (bactericidal) 600 mg monthly for a duration of 6 months. 46 We prefer dapsone 100 mg daily for 2 to 3 years, with or without rifampin 600 mg monthly, with follow-up examination at 1 and 2 years after discontinuing treatment.
For multibacillary disease (BB, BL, and LL) the WHO recommends unsupervised dapsone 100 mg daily, supervised rifampin 600 mg monthly and clofazimine 50 mg daily, unsupervised, and 300 mg monthly supervised for a routine duration of 2 years. 46 The rationale for this regimen is that rifampin will kill all susceptible organisms, including those resistant to dapsone, and dapsone will eventually eliminate all susceptibles, including those resistant to rifampin; clofazimine is added to obviate the risk of primary dapsone resistance. This regimen is considered by the WHO to be curative and is the cornerstone of the anticipated reduction of the prevalence of leprosy to less than 1 case per 10,000 people. The report of a 20 percent relapse rate within 8 years after completion of this regimen suggests a need for alternative approaches, 47 particularly in heavily bacillary patients (biopsy index of 5 or more).
For the treatment of multibacillary disease, other regimens may be used. Because the incidence of primary dapsone resistance is low in our patient population, we often use the combination of rifampin 600 mg daily and dapsone 100 mg daily for 3 years followed by dapsone 100 mg daily indefinitely or cessation of treatment. Alternative regimens of rifampin 600 mg daily in combination with either minocycline (bactericidal) 100 mg daily or clarithromycin (bactericidal) 500 mg daily for 2 to 3 years, followed by monotherapy, has been well tolerated, except for hyperpigmentation from the minocycline. 48 Short-term therapy with three microbicidal agents (rifampin, minocycline, and ofloxacin or moxifloxacin) is currently experimental. 49
In reversal reactions, because of the risk of permanent nerve damage, prompt institution of prednisone therapy (0.5 to 1 mg/kg per day) is recommended (but still wanting a controlled trial). The dose of prednisone is titrated against overt nerve tenderness, the patient's symptoms, and careful sensory evaluation of hands and feet, for example with graded Weinstein filaments. Once instituted, therapy should be tapered slowly and continued for a minimum of 6 months. If response of neuritis to prednisone is not prompt, then rest, enforced with splinting of effected extremities, is also recommended. In ENL, thalidomide use is dramatically effective in a majority of patients, if not interdicted by its teratogenic effects. For outpatients, we usually start with 100 to 200 mg nightly of thalidomide and, if it is only partially effective, we add prednisone in a 0.5 to 1.0 mg/kg range, tapering the prednisone over the subsequent 6 to 8 weeks. Higher doses of thalidomide are usually restricted to inpatients in whom excessive sleepiness is not a problem. If not available, corticosteroids in conjunction with clofazimine at 200 mg per day may be effective. Thalidomide is slowly tapered to 100 mg and then to 50 mg daily.
Adverse reactions to dapsone seen in the near term include the dapsone syndrome, a rare, potentially fatal infectious mononucleosis-like condition and three kinds of hemolytic anemia, almost universally from a direct membrane effect, uncommonly from a glucose-6-phosphate deficiency, and rarely from an idiosyncratic response (see also Chap. 254). In the long-term, dapsone is associated with peripheral neuropathy, usually motor with a sensory component, and, rarely, bone marrow suppression, especially agranulocytosis.
The serious problem with rifampin is hepatotoxicity. Red urine is alarming but banal. As a P450 inducer, rifampin may lessen the effect of other drugs, for example, oral contraceptives resulting in pregnancy, or reduced anti-inflammatory activity of corticosteroids. Once monthly use is rarely associated with severe hemolysis and acute renal failure.
Clofazimine produces skin darkening from the clofazimine itself in the near-term and from a ceroid-lipofuscin pigment in the long-term. 50 At usual doses of 50 to 100 mg a day, gastrointestinal intolerance, dry skin, and acquired ichthyosis are common. Prolonged administration of large doses may produce a novel enteropathy secondary to mucosal and enteric lymph node drug accumulation. Accumulation in the spleen may predispose to rupture.
Thalidomide, infamous for teratogenicity, may produce constipation and dizziness. Neuritis, a common side effect in nonleprosy patients, appears to be rare in ENL patients (see also Chap. 264).
Long-term use of minocycline may be limited by hyperpigmentation, 48 much more common in leprosy than in acne, perhaps related to the large accumulation of macrophages in leprosy. We have seen both diffuse hyperpigmentation and intense hyperpigmentation at the site of lesions, usually on the legs or feet.
Corticosteroids, in addition to their well-known side effects, may also exacerbate coexisting diseases, for example, tuberculosis, hepatitis B, and some gastrointestinal parasites.
REFERENCES
1. Skinsnes OK: Immunopathology of leprosy: The century in review. Int J Lepr Other Mycobact Dis 41:329, 1973
2. Shepard CC: The experimental disease that follows injection of human leprosy bacilli into foot pads of mice. J Exp Med 112:445, 1960
3. Mitsuda K: On the value of a skin reaction to a suspension of leprous nodules. Int J Lepr 21:347, 1953
4. Cole ST et al: Massive gene decay in the leprosy bacillus. Nature 409:1007, 2001
5. Anonymous. Leprosy—global situation. Wkly Epidemiol Rec 75:226, 2000
6. Walsh GP et al: Leprosy-like disease occurring naturally in armadillos. J Reticuloendothel Soc 18:347, 1975
7. Thomas DA et al: Armadillo exposure among Mexican-born patients with lepromatous leprosy. J Infect Dis 156:990, 1987
8. Mostafa HM et al: Acid-fast bacilli from former leprosy regions in coastal Norway showing PCR positivity for Mycobacterium leprae. Int J Lepr Other Mycobact Dis 63:97, 1995
9. Ducan ME et al: A clinical and immunological study of four babies of mothers with lepromatous leprosy, two of whom developed leprosy in infancy. Int J Lepr Other Mycobact Dis 51:7, 1983
10. Cho SN et al: Prevalence of IgM antibodies to phenolic glycolipid I among household contacts and controls in Korea and the Philippines. Lepr Rev 63:12, 1992
11. Ng V et al: Role of the cell wall phenolic glycolipid-1 in the peripheral nerve predilection of Mycobacterium leprae. Cell 103:511, 2000
12. Chakravartti MR, Vogel F: A twin study on leprosy, in Topics in Human Genetics, edited by PEEA Becher. Stuttgart, Georg Thieme, 1973, p 1
13. Siddiqui MR et al: A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nat Genet 27:439, 2001
14. de Vries RR et al: HLA class-II immune response genes and products in leprosy. Prog Allergy 36:95, 1985
15. Convit J et al: Immunoprophylactic trial with combined Mycobacterium leprae/BCG vaccine against leprosy: Preliminary results. Lancet 339:446, 1992
16. Sieling PA et al: CD1-restricted T cell recognition of microbial lipoglycans. Science 269:227, 1995
17. Ridley DS. Histological classification and the immunological spectrum of leprosy. Bull World Health Organ 51:451, 1974
18. Ridley DS: Pathogenesis of Leprosy and Related Diseases. London, Wright, Butterworth, 1988, p 158
19. van Brakel WH, Khawas IB: Silent neuropathy in leprosy: An epidemiological description. Lepr Rev 65:350, 1994
20. Lyde CB: Pregnancy in patients with Hansen's disease. Arch Dermatol 133:623 1997
21. Pedley JC: The presence of M. leprae in human milk. Lepr Rev 38:239, 1967
22. Khanolkar VR: Pathology of leprosy, in Leprosy in Theory and Practice, edited by RG Cochrane, TF Davey. Bristol, John Wright and Sons, 1964, p 125
23. Gebre S et al: The effect of HIV status on the clinical picture of leprosy: A prospective study in Ethiopia. Lepr Rev 71:338, 2000
24. Scollard DM et al: Epidemiologic characteristics of leprosy reactions. Int J Lepr Other Mycobact Dis 62:559, 1994
25. Latapi F, Zamora AC: The “spotted” leprosy of Lucio (la lepra “manchada” de Lucio). Int J Lepr 16:421, 1948
26. Rea TH, Levan NE: Lucio's phenomenon and diffuse non-nodular lepromatous leprosy. Arch Dermatol 114:1023, 1978
27. Panunto-Castelo A et al: The Rubino test for leprosy is a beta 2-glycoprotein 1-dependent antiphospholipid reaction. Immunology 101:147, 2000
28. Rea TH, Sieling PA: Delayed-type hypersensitivity reactions followed by erythema nodosum leprosum. Int J Lepr Other Mycobact Dis 66:316, 1998
29. Clark-Curtiss JE, Walsh GP: Conservation of genomic sequences among isolates of Mycobacterium leprae. J Bacteriol 171:4844, 1989
30. Modlin RL et al: T lymphocyte subsets in the skin lesions of patients with leprosy. J Am Acad Dermatol 8:182, 1983
31. Yamamura M et al: Defining protective responses to pathogens: Cytokine profiles in leprosy lesions. Science 254:277, 1991
32. Salgame P et al: Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 254:279, 1991
33. Nathan CF et al: Local and systemic effects of intradermal recombinant interferon-gamma in patients with lepromatous leprosy. N Engl J Med 315:6, 1986
34. Hsieh C-S et al: Development of Th1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547, 1993
35. Brightbill HD et al: Host defense mechanisms triggered by microbial lipoproteins through Toll-like receptors. Science 285:732, 1999
36. Barnetson RS et al: Cell mediated and humoral immunity in “reversal reactions.” Int J Lepr Other Mycobact Dis 44:267, 1976
37. Modlin RL et al: Lymphocytes bearing antigen-specific gamma/delta T-cell receptors in human infectious disease lesions. Nature 339:544, 1989
38. Yamamura M et al: Cytokine patterns of immunologically mediated tissue damage. J Immunol 149:1470, 1992
39. Bjorvatn B et al: Immune complexes and complement hypercatabolism in patients with leprosy. Clin Exp Immunol 26:388, 1976
40. Rea TH et al: Epidermal keratonocyte Ia expression, Langerhans cell hyperplasia, and lymphocytic infiltration in skin lesions of leprosy. Clin Exp Immunol 65:253, 1986
41. Cooper CL et al: Analysis of naturally occurring delayed-type hypersensitivity reactions in leprosy by in situ hybridization. J Exp Med 169:1565, 1989
42. Modlin RL et al: In situ identification of cells in human leprosy granulomas with monoclonal antibodies to interleukin 2 and its receptor. J Immunol 132:3085, 1984
43. Sampaio EP et al: Prolonged treatment with recombinant interferon gamma induces erythema nodosum leprosum in lepromatous leprosy patients. J Exp Med 175:1729, 1992
44. Quismorio FP et al: Lucio's phenomenon: An immune complex deposition syndrome in lepromatous leprosy. Clin Immunol Immunopathol 9:187, 1978
45. Williams DL et al: Detection of M. leprae and the potential for monitoring antileprosy drug therapy directly from skin biopsies by PCR. Mol Cell Probes 6:401, 1992
46. WHO Study Group. Chemotherapy of leprosy. WHO Tech Rep Ser 847, 1994
47. Jamet P et al: Relapse after long-term follow up of multibacillary patients treated by WHO multidrug regimen. Int J Lepr Other Mycobact Dis 63:195, 1995
48. Rea TH. Trials of daily, long-term minocycline and rifampin or clarithromycin and rifampin in the treatment of borderline lepromatous and lepromatous leprosy. Int J Lepr Other Mycobact Dis 68:129, 2000
49. Ji B, Grosset J: Combination of rifapentine-moxifloxacin-minocycline (PMM) for the treatment of leprosy. Lepr Rev 71(Suppl):S81, 2000
50. Job CK et al: Skin pigmentation from clofazimine therapy in leprosy patients: A reappraisal. J Am Acad Dermatol 23:236, 1990
