British Medical Bulletin Advance Access published online on November 7, 2006
British Medical Bulletin, doi:10.1093/bmb/ldl010
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The clinical and immunological features of leprosy
Clinical Research Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK
* Correspondence to: S. L. Walker, Clinical Research Fellow, Clinical Research Unit, 2nd Floor, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK. E-mail: drstevewalker{at}hotmail.com
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Abstract |
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Top
Abstract
IntroductionLeprosy is a granulomatous disease affecting the skin and nerves caused by Mycobacterium leprae. It continues to be a significant public health problem. Multidrug therapy (MDT) cures the infection, but immunological reactions may occur and neuropathy may lead to disability and deformity. It is important that the manifestations of the condition are recognized as early as possible so that early nerve damage can be identified and treated rapidly.
Keywords: leprosy • immunology • reactions • treatment
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Introduction |
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Leprosy is a chronic granulomatous infection principally affecting the skin and peripheral nerves caused by the obligate intracellular organism Mycobacterium leprae [1].
The disease causes skin lesions and neuropathy. Complications secondary to the neuropathy can result in deformity and disability. Leprosy remains a stigmatizing disease. However, multidrug therapy (MDT), which cures the infection, has led to the understanding that leprosy can be effectively treated before disability develops [2]. Since 1985, 14 million individuals have received MDT [3].
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Epidemiology |
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In all, 407,791 new cases of leprosy were diagnosed and reported to World Health Organization (WHO) in 2004 [3].
It continues to be an important health problem worldwide, but the highest new case detection rates are in India, Brazil, Democratic Republic of Congo, Tanzania, Nepal, Mozambique, Madagascar, Angola and the Central African Republic. The disease burden in India represents 64% of all new cases worldwide [3].
Transmission of M. leprae is from untreated lepromatous patients. The organism can persist outside the body under various environmental conditions [4]. It is hypothesized that in endemic areas most people have encountered it and have mounted an immune response against it [5].
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Mycobacterium leprae |
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Mycobacterium leprae is an obligate intracellular pathogen, and attempts to culture it in axenic medium have failed since it was first identified by Armauer Hansen in 1874 [6]. It can be obtained following prolonged growth in the mouse footpad and the nine-banded armadillo, which is a natural reservoir of the organism.
In 2001 the genome of M. leprae was sequenced. The organism appears to have undergone extensive reductive evolution with considerable downsizing of its genome compared with Mycobacterium tuberculosis. Almost half of the genome is occupied by pseudogenes [7].
A greater understanding of the genome of M. leprae will provide an insight into mechanisms by which the organism avoids immune surveillance, which metabolic pathways it requires the host cells it infects to provide and allow the development of techniques to culture the organism.
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Classification of leprosy |
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Classification of the patients is important to determine the appropriate treatment. Classification also enables the clinician to predict those at risk of complications and to give as accurate a prognosis as possible.
There are two systems used to classify leprosy patients. The Ridley–Jopling system [8] uses clinical and histopathological features and the bacteriological index. The different categories correlate with the activity of the host immune response (Fig. 1). It is useful as the borderline states are unstable immunologically and can be complicated by reactions.
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A simple classification based on the number of skin lesions is used in the field when slit-skin smears are unavailable. It is a quick and useful tool that can be employed by a wide variety of health care providers (Table 1).
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Genetics of susceptibility |
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There have been studies demonstrating higher concordance rates for leprosy among monozygotic compared with dizygotic twins [10]. Various genes and regions in the human genome have been linked to or associated with susceptibility to leprosy per se or with a particular type of leprosy. These are not all reproducible in different populations, which may be unsurprising.
Mira et al. [11] have identified that certain alleles in the PARK2 and PACRG region on chromosome 6 are associated with susceptibility to leprosy in Vietnamese and Brazilian cohorts. PARK2 is expressed by both Schwann cells and macrophages. It is an ubiquination E3 ligase and is involved in the delivery of polyubiquinated proteins to the proteosome complex involved in protein degradation [12].
An Indian cohort studied demonstrated that homozygotes for the different alleles of the vitamin D receptor (VDR) gene were associated with tuberculoid or lepromatous disease [13]. Upregulation of the VDR gene on macrophages is associated with increased intracellular killing of M. tuberculosis [14].
Polymorphisms of the tumour necrosis factor (TNF)-
promoter region were shown to be associated with increased susceptibility to lepromatous leprosy [15], whereas in a cohort from southern Brazil the same allele was protective against leprosy per se [16]. A study of Malawians did not find any association of this TNF promoter with leprosy [17].
Brazilian and Indian groups have demonstrated that polymorphisms of the interleukin (IL)-10 promoter are associated with resistance to leprosy [18, 19].
The differing and sometimes conflicting results of genetic studies may be attributed to differences in study design and sample size. It is also possible that different populations have distinct genetic susceptibilities.
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Immunology of leprosy |
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Mycobacterium leprae probably enters the body via the nose and then spreads to the skin and nerves via the circulation.
The immunological response mounted by the host dictates the clinical phenotype that develops. People with leprosy show a spectrum of clinical types. Experimentally, the polar forms of the disease are said to conform to an immunological paradigm. Tuberculoid disease is the result of high cell-mediated immunity with a largely Th1 type immune response. Lepromatous leprosy however is characterized by low cell-mediated immunity with a humoral Th2 response [20].
Intracellular pathogens are recognized by the innate immune system.
The highly conserved Toll-like receptors (TLRs) on the surface of monocytes and macrophages recognize mycobacterial lipoproteins [21]. In the case of M. leprae, this appears to takes place mainly through the TLR2/1 heterodimer and leads to monocyte differentiation into macrophages and dendritic cells [22, 23]. The latter presents antigen and causes the activation of naïve T cells by IL-12 secretion [24]. The IL-12ßR2 portion of the IL-12 receptor is expressed more on Th1 lymphocytes preferentially shifting the immune response further towards a Th1 response.
TLR stimulation also activates the nuclear transcription factor NF-
B, which modulates the transcription of many immune response genes [25].
In tuberculoid disease, interferon (IFN)-
, IL-2 and lymphotoxin- are secreted in lesions and these result in intense phagocytic activity [26]. Macrophages under the influence of cytokines, particularly TNF together with lymphocytes, form granulomas [27]. CD4+ cells are found mainly within the granuloma and CD8+ cells in the mantle area surrounding it [28]. T cells in tuberculoid granulomas produce the antimicrobial protein granulysin [29].
Lepromatous disease is characterized by poor granuloma formation. mRNA production is predominantly for cytokines IL-4, IL-5 and IL-10 [30]. IL-4 has been shown to downregulate TLR2 on monocytes [21], and IL-10 will suppress production of IL-12 [31]. This is associated with a preponderance of CD8+ lymphocytes in lepromatous lesions.
The borderline part of the spectrum is immunologically dynamic, and movement between the two polar forms occurs. These shifts in the immunological response underlie the reactions that are a feature of the borderline states.
The balance and complex interaction of cytokines, chemokines, adhesion molecules, their receptors and the cells of the innate and adaptive immune system all play a role in ultimately determining the particular immune response of the individual to the organism.
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Immunology of leprosy reactions |
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Type 1 reactions are delayed hypersensitivity reactions that occur in borderline disease (see later) [32]. Mycobacterrium leprae antigens have been demonstrated in the nerves and skin of patients experiencing type 1 reactions. The antigens were localized to Schwann cells and macrophages [33].
Schwann cells have been shown to express TLR2 [34]. Mycobacterium leprae infection may lead to the expression of major histocompatibility complex (MHC) II on the surface of the cells, and this may give rise to antigen presentation, which triggers CD4 lymphocyte killing of the cell [29]. Immunohistochemistry studies show greater TNF staining in the skin and nerves during type 1 reaction compared with non-reactional controls [35]. There is a shift towards increased Th1 immunity, and lesions in reaction express the pro-inflammatory cytokines IFN-, IL-12 and the oxygen free radical producer inducible nitric oxide synthase [36]. The expression of mRNA of various chemokines including IL-8, monocyte chemoattractant protein 1 and regulated upon activation, normal T-cell expressed, and secreted (RANTES) is higher in the skin during reaction [37].
Interestingly, the levels of circulating cytokines do not reflect the local changes taking place in the skin during type 1 reaction. Treatment of the reaction causes clinical improvement, but changes in the inflammatory cytokines lags behind by some considerable time and in some may remain unchanged [38]. A similar seemingly paradoxical finding has also been demonstrated in tuberculous meningitis [39].
Type 2 or erythema nodosum leprosum (ENL) reactions occur in borderline lepromatous and lepromatous disease. High levels of circulating TNF have been demonstrated in the plasma of some individuals with type 2 reactions [40]. In vitro peripheral blood mononuclear cells from individuals with ENL secrete increased amounts of TNF following stimulation [41].
The use of thalidomide and pentoxifylline have been shown to reduce the levels of TNF in vivo in subjects whose ENL has shown clinical improvement [42, 43]. However, a recent study by Haslett et al. [44] has demonstrated low TNF levels in individuals with milder ENL reactions, and paradoxically these levels increased during therapy with thalidomide. This effect has been noted in toxic epidermal necrolysis as well as other diseases [45]. The authors postulate that type 2 reactions with systemic involvement may produce the high circulating TNF levels previously seen and that this may not be the case in milder forms of the condition.
Thalidomide has costimulatory effects on lymphocytes as well as inhibiting macrophage TNF production, which may explain the increase in TNF during treatment in this setting.
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Clinical features |
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The clinical features of the disease are determined by the host response to M. leprae.
Patients commonly present with skin lesions, numbness or weakness caused by peripheral nerve involvement or more rarely a painless burn or ulcer in an anaesthetic hand or foot. A leprosy reaction may be a presenting feature of the disease [46]. Nerve pain misdiagnosed as joint pain may result in a person being labelled as having arthritis.
In non-endemic areas, the diagnosis is frequently delayed because leprosy is not considered and patients may present to a wide range of specialists [47].
Tuberculoid disease is characterized by a single or very few lesions. These are macules or plaques with well-defined edges (Fig. 2). In dark skin, hypopigmentation predominates over the erythema or copper colour more usually seen in lighter skin. The lesions are frequently scaly, dry, hairless and anaesthetic. The anaesthesia is due to destruction of dermal nerve fibres.
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This form carries a good prognosis and lesions will often self-heal. Damage to peripheral nerves is limited.
Lepromatous disease may be present for many years before diagnosis, and the early skin changes are widely and symmetrically distributed macules. They are poorly defined with mild hypopigmentation and erythema. Flesh coloured or occasionally erythematous papules and nodules may be present. Peripheral oedema of the legs and ankles due to increased stasis occurs. The skin if left untreated thickens due to dermal infiltration giving rise to the ‘leonine facies’ (Fig. 3). Hair is lost from affected skin notably from eyelashes and eyebrows (madarosis).
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Lepromatous involvement of the nasal mucosa gives rise to the sensation of nasal stuffiness and epistaxis. Infiltration of nasal structures may lead to a saddle deformity due to septal perforation and destruction of the anteriornasal spine.
Laryngeal involvement, although extremely rare nowadays, was life threatening before effective chemotherapy was available.
Lepromatous disease may be complicated by type 2 reactions in as much as 50% of individuals [48].
The involvement of other systems seen in lepromatous disease is due to bacillary infiltration of structures and organs. Testicular atrophy results from infiltration and also the acute orchitis of type 2 reactions. Elderly men with hypogonadism are more likely to have osteoporosis [49].
Borderline leprosy shows skin lesions intermediate between the two polar forms. The morphology of lesions may be macular, papulo-nodular, plaques, annular or a geographic appearance.
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Nerve involvement |
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Nerve involvement in leprosy affects sensory, motor and autonomic function of peripheral nerves. Sensory loss is the earliest and most frequently affected modality but a predominantly motor loss can also occur.
In tuberculoid disease, granulomatous inflammation of peripheral nerves causes palpable enlargement, which may or may not be painful and causes sensory and motor loss in the distribution of the affected nerve. There is enlargement and infiltration of fascicles, which may show caseous necrosis [32]. Enlarged nerves can also be damaged because of entrapment within fibro-osseous tunnels. Reactions cause further nerve damage.
In lepromatous disease, the destruction of dermal nerves leads to a glove and stocking neuropathy; peripheral nerve involvement tends to occur late. There is bacterial proliferation within the Schwann cells, which leads to foamy degeneration of the cells which lose the ability to regenerate [32].
Leprosy most commonly affects the posterior tibial nerve causing anaesthesia on the soles of the feet followed by the ulnar, median, lateral popliteal and facial nerves [50]. Other nerves affected by the disease include the greater auricular, radial and the radial cutaneous nerves.
The presence of a skin lesion overlying a major nerve trunk is associated with a significant increase risk of impairment in that nerve [51].
Pure neuritic leprosy (PNL) affects peripheral nerve trunks in the absence of cutaneous signs. PNL may be any disease type.
Silent neuropathy is an insidious deterioration in sensory or motor function without signs or symptoms of inflammation [52].
The effect of the disease on nerves leads to disability and deformity. This occurs through impaired sensation leading to trauma and secondary infection (including osteomyelitis), which causes tissue damage. Loss of motor function produces disability, and the increased dryness of the involved skin makes it more vulnerable to damage.
It is of the utmost importance that a complete motor and sensory neurological assessment is carried out to ensure that nerve function is not deteriorating especially as this can be asymptomatic.
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Eye involvement |
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Leprosy is the cause of blindness in 3.2% of those affected by the disease [53]. Blindness can have devastating consequences for those who probably already have sensory loss of the hands and feet. The disease compromises the eye through nerve damage and by direct bacillary invasion of the skin or eye itself. These factors can occur in combination and result in the four main causes of visual loss: lagophthalmos (an inability to close the eyes normally), corneal ulceration, acute or chronic iridocyclitis and secondary cataract.
Lagophthalmos usually results in damage to the zygomatic and temporal branches of the facial (VIIth) nerve. It gives rise to exposure keratopathy. Reduced corneal and conjunctival sensation due to involvement of the ophthalmic branch of the trigeminal (Vth) nerve predisposes to corneal ulceration.
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Type 1 (reversal) reactions |
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Type 1 reactions occur in borderline disease, and 30% of individuals with borderline leprosy are at risk of type 1 reaction [54]. A type 1 reaction is characterized by acute inflammation in skin lesions (Fig. 4) or nerves or both. The skin lesions become acutely inflamed and oedematous and may ulcerate. Oedema of the hands, feet and face can also be a feature of a reaction, but systemic symptoms are unusual.
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Acute neuritis leads to nerve function impairment, which if not treated rapidly and adequately leads to permanent loss of nerve function causing peripheral sensory and motor neuropathy. Type 1 reactions are frequently recurrent and this can lead to further nerve damage [54]. Type 1 reactions can occur at any time but are frequently seen after starting MDT or during the puerperium.
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Type 2 (ENL) reactions |
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Type 2 reactions affect
50% of lepromatous and 10% of borderline lepromatous cases [48]. The greater the infiltration of the skin and the higher the bacterial index (BI), the greater risk of developing type 2 reactions [55]. Type 2 reactions are a systemic disorder affecting many organ systems. The onset is acute, but it may pass into a chronic phase and it can be recurrent. ENL produces fever and in the skin painful and tender red papules or nodules (Fig. 5), which occur in crops often affecting the face and extensor surfaces of the limbs. The lesions may be superficial or deep causing a panniculitis. Bullous ENL has been described [56] and lesions may ulcerate. Subcutaneous tissue involvement may lead to tethering and fixation to joints causing loss of function. ENL reactions may also produce uveitis, neuritis, arthritis, dactylitis, lympadenitis and orchitis. The recurrent inflammation of organs can lead to blindness and sterility.
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Pregnancy |
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A systematic literature review of the interaction between leprosy and pregnancy highlighted an association between the development of type 1 reactions and neuritis and parturition when cell-mediated immunity returns to the prepregnant level [57].
ENL reactions occur throughout pregnancy and lactation, and the onset of nerve damage is earlier than in those who are not pregnant.
There is little evidence that pregnancy promotes infection or relapse of the disease.
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Leprosy and human immunodeficiency virus |
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The fear that human immunodeficiency virus (HIV) infection would increase susceptibility to M. leprae does not appear to have been realized, nor does it alter the clinical features of leprosy. Leprosy in HIV-positive individuals does not appear to be shifted to the lepromatous pole, nor does it develop quicker. The response to MDT is also unaffected.
Mycobacterium leprae does not appear to accelerate the decline in immune function in HIV disease, which tuberculosis seems to do.
Reactions in individuals with co-infection may occur with increased frequency, but there are conflicting data concerning the response to treatment in this group.
Latent leprosy infections may be unmasked as immune reconstitution disease following the initiation of antiretroviral therapy. The improvement in immune function restores the host ability to form granulomas.
A recent detailed review highlighted that all reported cases have been borderline cases complicated by type 1 reaction [58].
The contrast between the interaction of M. leprae and HIV and that of M. tuberculosis and HIV is striking. Research addressing the interactions of these mycobacteria with HIV may provide important insights into all three diseases.
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Diagnosis |
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The diagnosis of leprosy remains a clinical one. The presence of skin lesions with definite sensory loss or thickened peripheral nerves or the demonstration of M. leprae on slit-skin smears or on histology of tissue (skin or nerve) is diagnostic (Table 2).
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Differential diagnosis |
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The manifestations of leprosy are protean and the differential diagnosis is therefore wide. The consideration of leprosy as a diagnosis and adherence to the clinical criteria for diagnosing leprosy will facilitate a correct diagnosis.
Vitiligo is depigmented rather than hypopigmented. Pityriasis alba can be difficult to distinguish from early disease. Pityriasis versicolor and dermatophyte infection may both cause diagnostic difficulty.
In some parts of the world, leprosy is a commoner cause of granulomatous skin lesions than sarcoid, granuloma multiforme, cutaneous tuberculosis and granuloma annulare.
Nerve thickening is a feature of hereditary sensory motor neuropathy type III and Refsum’s disease. Amyloid which itself can complicate leprosy can cause nerve thickening.
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Diagnosis in non-endemic areas |
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Leprosy can be a difficult diagnosis to remember especially in non-endemic regions or where the prevalence is very low. In non-endemic regions, it is important for physicians to consider the diagnosis in migrants from areas where the disease is endemic. Individuals have been reported to present with leprosy many years after leaving an endemic area [59].
An affected person may present to one of a number of specialities such as dermatology, neurology, internal medicine, orthopaedics, rheumatology, ophthalmology and urology [47, 60].
In the United Kingdom where the diagnosis of leprosy is often delayed