Hansen Disease (Mycobacterium leprae)

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Chapter 208 Hansen Disease (Mycobacterium leprae)

Dwight A. Powell, Vijay Pannikar

Hansen disease (leprosy) is a chronic disease resulting from infection with Mycobacterium leprae and moderated by the ensuing host response. The respiratory mucosa, skin, and peripheral nervous system are most prominently affected, with occasional testicular and ocular involvement. Humans were long believed to be the sole host of M. leprae, but naturally acquired infection has been documented in armadillos in the southeastern USA, and experimental infection has been established in primates, nude mice, and armadillos.

The sequelae of leprosy include chronic skin lesions, madarosis, sensory neuropathy resulting in the loss of digits or limbs, and paresis secondary to motor nerve dysfunction. The highly visible nature of these debilities led to the historical stigmatization of the “leper.” The psychological and sociologic sequelae of this stigma can be as debilitating as the disease itself and can result in delays in seeking medical attention. To combat this prejudice, the term leprosy patient has replaced the word leper, and Hansen disease, after Armauer Hansen who identified M. leprae as the cause of leprosy, is the accepted designation.

Etiology

M. leprae is an acid-fast bacillus of the family Mycobacteriaceae. It is an obligate intracellular pathogen with a generation time of 14 days. M. leprae grows optimally at 27-30°C and cannot be cultured in vitro. The incubation period of leprosy in humans ranges from 3 mo to 20 yr (average 3-5 yr). The rare occurrence of leprosy in infants as young as 3 mo of age suggests that in utero transmission can occur or that very short incubation periods are possible in certain situations.

Epidemiology

Since the introduction of multidrug therapy by the World Health Organization (WHO) in 1982, there has been a steady decline in the prevalence of leprosy. In 1991, the WHO called for the elimination of leprosy as defined by a worldwide prevalence of <1/10,000 population. That goal was achieved by the year 2000 in all but 15 of the 122 countries where leprosy was considered a public health problem in 1985. Those countries are mainly in Asia, Africa, and South America. In 1985, there were 10-12 million cases of leprosy worldwide, and in 2004, the prevalence was 457,792 cases. In 1998, 750,000 new cases were detected, and in 2008, there were 218,605 new cases registered for treatment. By 2008, 80% of the world’s leprosy patients resided in India, Brazil, or Indonesia. Approximately 150 cases are reported annually in the USA, of which 85% are in immigrants. Small numbers of endemic cases are reported from Texas, Hawaii, and Louisiana.

Human-to-human transmission is responsible for an overwhelming majority of secondary cases, with the highest risk among family members and other close contacts. Leprosy occurs at all ages, but infections in infants are extremely rare. The incidence rates peak during childhood and early adulthood in endemic areas. HIV infection has not been documented to alter the risk for leprosy in areas of high prevalence for both pathogens.

Pathogenesis

Possible modes of transmission include contact with desquamated infected epidermis, ingestion of infected breast milk, and bites of mosquitoes or other vectors. However, at present the basis for most infections appears to be transmission from untreated lepromatous patients following prolonged contact with infected nasal secretions containing a high bacterial load. Skin testing and serologic studies suggest that up to 90% of infected persons develop immunity without ever manifesting clinical disease. Studies in endemic areas using polymerase chain reaction (PCR) show widespread presence of the organism in nasal secretions from asymptomatic persons.

M. leprae appears to be transported hematogenously from the nasal mucosa to skin and peripheral nerves. Using the armadillo model of neuritis, M. leprae organisms have been shown to colonize the perineural space and gain access to the interstitium of the endoneural space. Once there, organisms are available for phagocytosis by Schwann cells and interstitial macrophages surrounding peripheral nerve axons. Intracellular replication of M. leprae follows, with varying degrees depending on the host cellular immune response. M. leprae attachment to and ingestion by Schwann cells has been shown to depend on receptors on the lamin-2 glycoprotein in the basal lamina and the α-dystroglycan complex in the Schwann cell basement membrane. M. leprae–specific phenolic glycolipid-1 appears to be the ligand mediating this binding.

Once inside the Schwann cell, M. leprae replicates slowly over years. At some stage, specific T cells recognize the presence of mycobacterial antigens within the cells and initiate a chronic inflammatory reaction. Genetic susceptibility to leprosy has been linked to the natural resistance associated with macrophage protein-1, which is present only in certain racial groups. Factors that can lead to the development of localized vs disseminated disease are the degree of expression of Toll-like receptors on monocytes and the production of interferon-γ (IFN-γ) by T cells.

Once M. leprae colonizes the surface of nerves and infects endoneural macrophages and Schwann cells, several mechanisms of skin and nerve injury can occur, depending on the host immune response. One end of the spectrum is tuberculoid leprosy (TL), in which there is a vigorous and specific cell-mediated immune response to M. leprae antigens. In tissue biopsies there are tightly organized granulomas composed of epithelioid cells and lymphocytes, but bacilli are scant or absent. Macrophages, when present, do not contain intracellular organisms. Caseation is rare. Heavy cellular infiltration is found in the dermis, with destruction of cutaneous nerve fibers.

At the other end of the spectrum is lepromatous leprosy (LL), in which there is total and specific anergy to M. leprae both by skin testing and by in vitro assays of cell-mediated immunity. Large amounts of circulating and tissue-based antibody to mycobacterial antigens is present, but it affords no protective immunity. Bacilli are found in enormous numbers in the skin, nasal mucosa, and peripheral nerves. There is continual bacillemia as well as bacillary invasion of all major organs except the central nervous system. Tissue granulomas are poorly formed and are composed chiefly of loose aggregates of foamy histiocytes. Macrophages teeming with undigested bacilli are common. There is extensive, symmetric involvement of peripheral nerves, although the cutaneous nerve endings are usually spared.

An M. leprae-specific suppressor T-cell population is found in the circulation of patients with LL, with increased numbers of suppressor T cells found in the skin granulomas. T cells from lepromatous patients also produce less interleukin 2 and less IFN-γ after stimulation with M. leprae antigens than do T cells from tuberculoid patients or normal controls.

Borderline or dimorphous leprosy is subdivided into 3 subclasses that lie between the tuberculoid and lepromatous poles: borderline tuberculoid, borderline, and borderline lepromatous.

Clinical Manifestations

The manifestations of Hansen disease reflect the host response to the infection.

Indeterminate Leprosy

Indeterminate leprosy (IL) is the earliest clinically detectable form of leprosy. Although it is diagnosed in only 10-20% of infected patients, most patients with advanced leprosy have passed through this stage. Usually there is a single hypopigmented macule 2-4 cm in diameter with a poorly defined border and without erythema or induration. Anesthesia is minimal or absent, particularly if the lesion is on the face. Tissue samples can show granulomas, but bacilli are rarely demonstrable. The diagnosis is usually made by exclusion of other skin disorders in contacts of leprosy patients, especially in children. The lesions heal spontaneously in 50-75% of patients with IL and progress to 1 of the classic forms in the remainder.

Tuberculoid Leprosy

In tuberculoid leprosy, there is usually a single, large (often >10 cm in diameter) lesion with a well-demarcated, elevated erythematous rim (Fig. 208-1

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