Tuberculoid Leprosy

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. The skin lesions of tuberculoid leprosy consist of one or a few hypopigmented macules or plaques 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. 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.

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, and patients have positive lepromin skin tests (see “Diagnosis,” below). 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.

Source: Harrison_s_Principles_of_Internal_Medicine_16th_Edition

EPIDEMIOLOGY OF LEPROSY…2nd (Transmission).

The route of transmission of leprosy remains uncertain and may 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 without signs of leprosy from endemic areas and in 19% of occupational contacts of lepromatous patients.

Several lines of evidence implicate soil transmission of leprosy: (1) in endemic countries such as India, leprosy is primarily a rural and not an urban disease; (2) M. leprae products have been demonstrated to be resident in soil in endemic locales; and (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 infection to mice. Skin-to-skin contact is generally 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 coworkers of these patients are not at risk for leprosy.

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

a disseminated infection following intravenous inoculation of live M. leprae.

Source: Harrison_s_Principles_of_Internal_Medicine_16th_Edition

EPIDEMIOLOGY OF LEPROSY…1st (Demographics).

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 to 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 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, it is generally agreed that the annual incidence of new cases is rising (529,000 estimated new cases in 1995 and 719,000 in 2001, with 60% of the latter number from India alone).

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 people appear to be naturally immune to leprosy and do not develop disease manifestations following exposure. The time of peak onset is in the second and third decades of life. The most severe polar 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 HLA associations are known for both polar forms of leprosy (see below). In India and Africa, 90% of cases are tuberculoid; in Southeast Asia, 50% are tuberculoid and 50% lepromatous; and in Mexico, 90% are lepromatous.

Source: Harrison_s_Principles_of_Internal_Medicine_16th_Edition

ETIOLOGY OF LEPROSY

M. leprae is an obligate intracellular bacillus (0.3 to 1 µm wide and 1 to 8 µm long) that is acid-fast, indistinguishable microscopically from other mycobacteria, and ideally detected in tissue sections by a modified Fite stain. Strain variability was recently discovered 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+ to 6+ in untreated patients, falling by one unit per year during effective therapy; the rate of fall is independent of the relative potency of effective antimicrobial therapy. A rising MI or BI suggests relapse and perhaps—if the patient is being treated—drug resistance; the latter possibility can be confirmed or excluded in the mouse model.

As a result of reductive evolution, almost half of the M. leprae genome contains nonfunctional genes; only 1605 genes encode for proteins. 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 recent finding of strain variability among M. leprae isolates provides a powerful tool with which to address anew the organism’s epidemiology and pathobiology. The bacterium’s complex cell wall has a peptidoglycan backbone, which is linked to arabinogalactan and mycolic acids. Lipoarabinomannan is a key component of the cell membrane, and the outer capsule contains large amounts of an M. leprae–specific phenolic glycolipid (PGL-1), which is detected in serologic tests.

Among the mycobacteria, M. leprae is unique in exhibiting dopa oxidase activity and an acid-fastness that is pyridine-extractable. 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).

Source: Harrison_s_Principles_of_Internal_Medicine_16th_Edition