LEPROSY

LEPROSY

Current Diagnosis

• Contact with other leprosy cases; travel to or residence in a leprosy- endemic country.

•   Skin lesion(s) with altered sensation.

• Thickened or enlarged peripheral nerve, with sensory loss and/or weakness in the muscles supplied by the nerve.

•   Presence of acid-fast bacilli in a slit skin smear.

• Skin biopsy with the presence of acid-fast bacilli or typical lesions, thereby aiding disease classification.

Current Therapy

Paucibacillary Leprosy (6 months)

•   ADULT (50–70 kg)

•   Dapsone: 100 mg daily

•   Rifampin (Rifadin)1: 600 mg once a month under supervision

•   CHILD (under 10 years)

•   Dapsone: 1 mg/kg per day

•   Rifampin1: 10 mg/kg once a month under supervision

Multibacillary Leprosy (12 months)

•   ADULT (50–70 kg)

•   Dapsone: 100 mg daily

•   Rifampin1: 600 mg once a month under supervision

•   Clofazimine (Lamprene)5: 50 mg daily and 300 mg once a month under supervision

•   CHILD (under 10 years)

•   Dapsone: 1 mg/kg per day

•   Rifampin1: 10 mg/kg once a month under supervision

•   Clofazimine: 1 mg/kg per day

1 Not FDA approved for this  indication.

5 Investigational drug in the United  States.

Epidemiology

Leprosy is a chronic disease caused by Mycobacterium leprae that affects skin and nerves, often resulting in physical disabilities. The disease has been found around the world, showing that transmission occurs regardless of climate. However, several studies have associated higher transmission with more humid regions.

Nevertheless, disease transmission has ceased in nearly all developed nations, most likely as a consequence of better nutrition and socioeconomic development. Currently, new autochthonous cases are found in all tropical countries, with India and Brazil having the highest number of cases annually. Some insular countries located in the Pacific and Indian Oceans have the highest rates of new case detection, indicating a high risk of transmission.

In the Gulf region of the United States, mostly in the states of Louisiana and Texas, native cases are still diagnosed. There are armadillos (Dasypus novemcinctus) in the area that have been infected with strains of M. leprae found also in autochthonous human cases.

This suggests that leprosy might be a regional zoonosis, even though M. leprae was introduced into the Americas by Europeans and Africans. There are also records of leprae infection in armadillos in Central and South America.

Furthermore, cases in African chimpanzees raise the possibility that these animals could be helping to maintain leprosy transmission in Africa.

The mechanisms of leprosy transmission are not well known due to the fact that there is no easy way to diagnose infection. It is presumed that in endemic areas infection is much more frequent than actual disease onset. The incubation period can vary from a few months to 20 years.

It is known that multibacillary cases excrete a large number of viable bacilli through nasal mucus, suggesting that transmission may be by respiratory route and, in fact, this is believed to be the main source of transmission. Because M. leprae can also remain viable in the environment for many days, especially in humid climates, the hypothesis of indirect transmission by means of small skin lesions remains. It is possible to theorize the existence of many different forms of transmission.

Leprosy cases are not uniformly distributed in a community, tending to form clusters within different geographic regions, villages, or groups of domiciles. In the majority of countries, cases are more common among men, and the 15- to 29-year-old age group tends to present the highest risk of disease. In areas where transmission is declining, the incidence tends to be higher among the elderly, affecting those who have lived during a period with a higher risk of infection.

Following the treatment of all new leprosy cases with multidrug therapy (MDT), the backlog of known cases, which had been the main problem faced by leprosy control programs in the 1980s and early 1990s, largely disappeared. Currently, control efforts target new cases so as to not only interrupt transmission but also reduce the disabilities caused by the disease. In more endemic areas, the proportion of cases diagnosed with visible disabilities (grade 2) indicates access to timely diagnosis.

Risk Factors

In endemic areas, the main risk factors are a history of household contact with leprosy cases and low socioeconomic standing. Among infected women, pregnancy is a period of greater risk for developing the disease due to immunologic modulation.

Susceptibility to leprosy is genetically mediated by a group of genes. The low frequency of genetically determined susceptibility may be the cause of the wide difference between infection and disease that is believed to exist.

Even before the highly effective application of antiretroviral treatment, there was no observed association between HIV infection and leprosy. However, in areas of high endemicity, there are accounts of leprosy cases associated with the immunologic reconstitution resulting from antiretroviral treatment. In developed countries, the main risk factor is originating from or having lived in a leprosy- endemic area.

Prevention

Vaccination with bacille Calmette-Guérin (BCG)1 reduces the risk of leprosy, with studies showing a variable efficacy of 20% to 80%. The revaccination of household contacts also provides protection, especially against the multibacillary forms of the disease.

Chemoprophylaxis of contacts or high-risk groups with a single dose of rifampin (Rifadin)1 has been shown to be effective for a period of 2 years.

Improving socioeconomic conditions in the general population in endemic areas is also a very effective strategy for disease control. This can be seen when comparing the current epidemiologic situation in the Hawaiian Islands with Micronesia or the Marshall Islands, where leprosy continues with a high incidence rate.

Pathophysiology

M. leprae is an intercellular microorganism with a particular tropism for skin and peripheral nerve cells. It cannot be cultivated in vitro, but can be inoculated in mouse foot pads and armadillos, although growth is quite slow.

Active M. leprae infection is characterized by a wide clinical range, varying from a disease in which few bacilli are present in the body to one in which a high bacterial load is found in skin lesions.

Upon entering the organism, M. leprae can be eliminated with a local inflammatory response. When this natural resistance fails, the bacilli multiply within macrophages, enter the lymph stream and bloodstream, reach the regional lymph nodes, and from there move on to the organs of the mononuclear phagocyte system. The mycobacterial antigens are then processed and presented by antigen- presenting cells that can be Langerhans cells, dendritic cells, or others from the monocyte-macrophage system that induce the hapten- protein conjugates to link the HLA-DR class II molecules to the CD4 + lymphocytes. In those individuals where there is stimulation of the T- helper 1 cell response, these lymphocytes will produce interferon (IFN)–gamma cytokines, β–tumor necrosis factor (β-TNF), interleukin- 2 (IL2) and IL12 that will promote the differentiation of macrophages in epithelioid cells that will undergo a fusion process resulting in giant cells. This inflammatory response will be sufficient to reduce the M. leprae in the tuberculoid form of leprosy.

On the other hand, in the absence of stimulation of the T2 subpopulation of T lymphocytes (TLs), these will produce IL4, IL5, IL6, IL8, IL10, and TNF-alpha cytokines. The IL4 and IL10 interleukins are suppressors of macrophage activation, leading to an insufficient immune cell response to combat the level of M. leprae proliferation within the macrophages. This characterizes the more infectious forms of the disease at the lepromatous end of the spectrum.

M. leprae uses adult Schwann cells as primary nonimmune cells for colonization. Nerve damage is attributed either to bacterial proliferation or to the immune response of the host to relatively few bacilli in peripheral nerves and adjacent areas of skin.

In this disease spectrum, cell-mediated immunity protects against the disease and limits bacterial dissemination at the tuberculoid pole, whereas this is suppressed at the lepromatous end. Humoral immunity is present only at the lepromatous pole where high levels of specific antibodies to M. leprae are found. These immune responses, whether cell mediated or humoral, are dynamic and present spontaneous variations of reactivity that are responsible for leprosy reaction episodes.

Clinical Manifestations

Due to the complexity of the parasite-host relation and the variable efficacy of the host’s cellular immune response, the clinical manifestations of the disease cross a wide spectrum. This can vary from an isolated nerve lesion or a single skin patch to a systemic disease that affects several organs beyond just skin and nerves, including eyes, testicles, and kidneys.

Ridley and Jopling, in 1966, proposed a case classification system that takes into consideration clinical, histopathologic, and immunologic parameters: tuberculoid, borderline-tuberculoid, borderline-borderline, borderline-lepromatous, and lepromatous.

Indeterminate leprosy can be considered to be the first clinical manifestation of the disease. It can be cured spontaneously or evolve into one of the other clinical forms.

Indeterminate Leprosy

This is characterized by one or more hypochromic macules with imprecise borders and reduced thermal sensitivity, although pain and tactile sensation may be preserved (Figure 1). These occur as areas of sensory disturbance with no alteration in skin color, sweat glands, or hair growth. Any alteration in nerve function is preliminary and, therefore, there are no physical disabilities described with this classification. Bacilloscopic readings are negative.

FIGURE 1    Indeterminate leprosy.

Tuberculoid Leprosy

This type is characterized by erythematous or hypochromic skin lesions with clear, raised borders (Figure 2). These are limited in number with an asymmetrical distribution and altered thermal, pain, and tactile sensation. Reduced perspiration and restricted partial or full alopecia may also be seen. Nerves can be affected intensively but this usually only happens to a few. Slit skin smear results are negative.

FIGURE 2    Tuberculoid leprosy in child.

Among children, tuberculoid leprosy lesions have the appearance of nodules or tubercles, generally only on the face. Although these lesions tend to regress spontaneously, treatment should continue as per standard ethical practice.

Borderline-Tuberculoid Leprosy

This form is characterized by lesions similar to those seen at the tuberculoid end of the spectrum, although they will be more numerous. In general, there are more than five lesions with a diameter of 10 cm or more, less clearly defined borders, and containing possible satellite lesions (Figure 3). These lesions tend to be more symmetrical and several nerves may be affected. However, the majority of patients with this disease type will still have a negative bacilloscopy.

FIGURE 3    Borderline-tuberculoid leprosy.

Borderline-Borderline Leprosy

This is a relatively rare variation, given that it commonly evolves quickly toward the Virchowian pole, often spurred on by reaction episodes. There are usually many foveal lesions (infiltrated plaques with expanding outer borders and well-defined inner borders with apparently normal skin in the middle) (Figure 4). Generally, nerves are intensively affected and skin smears are almost always positive.

FIGURE 4    Borderline-borderline leprosy.

Borderline-Lepromatous (Virchowian) Leprosy

A wide number of lesions are present with a range of possible clinical manifestations (infiltrations, papules, plaques, foveae, and nodules) that are common to the Virchowian form. However, with this type there is a tendency to see some delimitation between the lesions and areas of healthy skin. Bacilloscopy is positive with a high bacterial load.

Lepromatous (Virchowian) Leprosy

Lepromatous leprosy (LL) has the highest bacterial burden of human bacterial infections. Extensive lesions tend to be symmetrical, erythematous or hypochromic, infiltrated, and without clear delineation from normal skin areas. Simple lesions evolve to become papules, tubercles, and nodules that can eventually ulcerate and that are especially full of bacilli (Figure 5). There is diffuse infiltration of the face, with auricular appendages affected in the vast majority of cases and bilateral madarosis also common. Hands and feet may also be infiltrated or showing signs of xerodermia.

FIGURE 5    Lepromatous (Virchowian) leprosy (LL).

LL is a systemic disease that can affect the liver, spleen, adrenal glands, lymph nodes, eyes, and nose. Nasal obstruction can be present with little or no response to vasoconstrictors. Often the nasal cavities will be affected and the oropharynges will be full of nasal secretion highly abundant in bacilli. Subsequent nasal dryness can lead to secondary ulceration and infection with possible perforation and destruction of the nasal septum, resulting in what is commonly referred to as saddle nose. With olfactory bulb dysfunction, anosmia will often be the outcome.

Lesions to the palate, lips, gum, and uvula can further compromise the pharynx, nasopharynx, and tonsils. The eyes may show erythema, dryness, dacryocystitis, lagophthalmos, and/or diminished sensation in the cornea. Likewise, iritis and iridocyclitis may be present, so proper intervention is necessary to ensure prevention of early onset of blindness.

The testes may also be directly affected by bacilli, as witnessed by atrophy of the testicular parenchyma and diffuse fibrosis with eventual sterility and alteration of sexual function. When secondary amyloidosis is present, renal insufficiency may result.

Variations of LL

Histoid Lepromatous Leprosy (or Wade’s Lepromatous)

Nodular lesions are present, well defined, and of varying sizes. These may be round or oval with a reddish or pink color. These lesions contain a large number of bacilli and are normally associated with sulfone resistance. Histiocytes with a spongy appearance are present under histologic analysis.

Diffuse Lepromatous Leprosy (DLL)

Described by Lucio, Alvarado, and Latapi, this is a diffuse form of LL, also called “beautiful” leprosy because this form confers a pinkish and healthy appearance to the skin. It is more frequently seen in Mexico and is characterized by the diffuse infiltration of the skin, altered sensation that starts in the hands and feet, loss of eyebrows, and telangiectasias in the face and torso. Recently a mycobacterium was isolated in cases of DLL whose DNA cannot be amplified using usual M. leprae primers. As a result, a new species has been proposed under the name Mycobacterium lepromatosis, but many specialists do not yet accept that this is a separate microorganism.

Pure Neural Leprosy

This type presents only nerve lesions without any cutaneous patches. The most common nerves affected are the ulnar, tibial, and fibular.

The radial, median, facial, trigeminal, and auricular nerves, among others, may also be damaged.

Neuropathic pain is often present spontaneously or when the nerve is palpated, either with or without thickening of the nerve. This can evolve to sensory loss, paresthesia, or muscular atrophy in the corresponding area, in addition to autonomic dysfunction and nerve abscess.

Leprosy Diagnosis

The patient is examined to locate any possible skin lesions with diminished sensation and/or areas of sensory alteration that may be due to compromised peripheral nerves. Lighting must be adequate, and it is important to observe the entire body surface moving from head to toe. Where there are possible signs of disease, thermal, pain, and tactile sensation testing should be done, also looking for areas of alopecia and/or anhidrosis. It must be noted if there is any type of physical disability.

Bacilloscopy consists of the collection and examination of skin smears taken from a suspected lesion, both earlobes, and both elbows, and helps to classify a patient as paucibacillary (PB) with a negative examination result or multibacillary (MB) when positive.

The bacilloscopic results will generally be negative in the indeterminate, tuberculoid, and borderline-tuberculoid forms, which are considered to be PB forms. Similarly, they tend to be positive for the lepromatous (Virchowian), borderline-lepromatous, and borderline-borderline, which are MB forms.

Ideally, the bacilloscopic reading should be expressed quantitatively as a bacteriologic index (BI) so that it is possible to monitor the patient’s progress during treatment. The histologic examination of a skin biopsy also helps to provide a more precise disease classification and can help to confirm diagnosis in cases that are bacilloscopy negative.

In regions with limited access to laboratory resources, clinical diagnosis is sufficient to warrant the beginning of the standard leprosy treatment regimen, keeping in mind that this is the only dermatologic disease with altered sensation in lesions. The World Health Organisation (WHO) suggests the classification of cases as either PB or MB based on the number of skin lesions, with MB cases having five or more such patches.

Available serologic testing does not show sufficient accuracy for disease diagnosis or infection. Real-time polymerase chain reaction is available for leprosy and can act as a means of confirmation for diagnosis of PB cases.

Differential Diagnosis

Differential diagnoses of leprosy include a variety of dermatologic conditions, given the wide range of clinical manifestations in leprosy. The sensory loss symptomatic of leprosy can also be difficult to determine in children and in other diseases that produce changes in the normal skin characteristics (Table 1).

Table 1

Main Differential Diagnosis by Leprosy Forms

Indeterminate Leprosy Tuberculoid Leprosy Borderline, Borderline-borderline,Borderline-lepromatous, and Lepromatous Leprosy
Seborrheic dermatitis Erythema nodosum
Eczema Dermatofitosis Diffuse (anergic) cutaneous leishmaniasis
Localized scleroderma (morphea) Granuloma annulare Cutaneous and mucosal leishmaniasis
Residual hypochromia and achromia Cutaneous leishmaniasis Systemic lupus erythematous and other rheumatologic diseases
Pityriasis versicolor Discoid lupus erythematous Neurofibromatosis  (von  Recklinghausen disease)
Vitiligo Pityriasis rosea Gibert Pityriasis rosea Gibert
Psoriasis Congenital syphilis, secondary syphilis, tertiary syphilis
Sarcoidosis
Secondary syphilis
Cutaneous tuberculosis

Treatment

Leprosy treatment, like tuberculosis treatment, has to deal with bacillar resistance and persistence. Single-drug therapy selects drug- resistant bacilli and should be avoided. Therapy duration has, as a target, the reduction of the number of persistent bacilli that could lead to relapses.

Standard MDT with dapsone, rifampin (Rifadin),1 and clofazimine5 for 12 months for MB cases and 6-month MDT with dapsone and rifampin for PB cases has dramatically changed the prognosis for leprosy patients. However, the evidence is rather weak on the efficacy of this drug regimen, especially regarding the necessary length of time for treatment, both in terms of the proportion of relapse cases and other outcomes, such as physical disability. The use of rifampin once a month was determined for financial reasons, and there is no study comparing this schedule with daily use. For this reason, research on new drugs and treatment regimens continues.

Shorter regimens were used but had shown high relapses rate: daily doses of rifampin and ofloxacin (Floxin)1 for 4 weeks; single-dose course of rifampin, ofloxacin and minocycline (Minocin)1 for single- lesion patients.

Fluoroquinolones (pefloxacin,2 ofloxacin, and moxifloxacin [Avelox]1), macrolides (clarithromycin [Biaxin]1), and tetracycline (minocycline) are effective against M. leprae. Only rifampin, its derivative rifapentine (Priftin),1 and moxifloxacin are bactericidal drugs; all others are bacteriostatic.

In cases of intolerance or resistance to dapsone, this can be removed from the drug regimen. Where similar intolerance or resistance is related to rifampin, this should be substituted with a daily dose of 400 mg of ofloxacin. This alternate course lasts 6 months for PB cases and 24 months for MB.

For those who cannot take either dapsone or rifampin, PB patients can be treated with ofloxacin (400 mg/day), minocycline (100 mg/day), and clofazimine (50 mg/day) in self-administered doses for 6 months.

Similarly, MB patients can use this regimen during the first 6 months of treatment (intensive phase), followed by 18 months with daily doses of ofloxacin or combined daily doses of minocycline and clofazimine (maintenance phase).

Leprosy Reactions and Control

Over the course of this chronic disease, it is common to experience acute inflammatory episodes called leprosy reactions. These reactions can take place before diagnosis, as well as during or after MDT treatment. They are commonly grouped into (a) type 1 (reversal) reactions (T1Rs) resulting from vigorous cell-mediated immune response; and (b) type 2 reactions (T2Rs), the clinical manifestation of which is frequently erythematous nodosum leprosum (ENL) that comes about mainly from immunocomplex deposits. In patients with borderline-lepromatous leprosy, it is possible to have both reaction types simultaneously. There is also Lucio’s phenomenon, which is an immune system response with important clinical manifestations. Its physiopathology is not well understood, with abundant infection of M. leprae in endothelium, which can lead to thrombosis in the most superficial vases from immunocomplex deposits with hemorrhaging and cutaneous infarction.

In the literature, a robust positive association has been demonstrated between bacterial load and the frequency of leprosy reactions. A reaction can be set off by various factors, such as pregnancy, childbirth, vaccinations, puberty, intercurrent infections, stress (physical, psychological, or surgical), use of potassium iodate/iodide (SSKI), and immune reconstruction inflammatory syndrome (IRIS) linked to anti-retroviral and/or immune-based therapies.

Those patients who experience leprosy reactions during MDT treatment should continue taking their regimen without modification while also beginning a specific and concurrent treatment for the appropriate reaction type.

Type 1 Reaction or Reversal Reaction

Clinically speaking, lesions become more erythematous and infiltrated, and those with previously diminished sensation can become more sensitive to touch. Desquamation may occur and some lesions may even ulcerate. New lesions can erupt along with edema in the hands, feet, and face, as well as general systemic symptoms. These reactions can last for years in some patients. It is important to begin an immediate intervention given that neuritis is the most common, serious, and potentially disabling clinical manifestation of T1R.

The drug of choice for T1R treatment is prednisone (or prednisolone [Millipred]) with a dosage of 1 to 2 mg/kg/day for at least 12 weeks, at which point it can be tapered off until discontinuing medication around the 24th week.

Type 2 Reaction

This occurs in multibacillary patients, and ENL is the most frequent clinical manifestation of T2Rs. Other variations of T2R are polymorphic erythema and vasculitis.

Clinically, ENL is a systemic condition with the eruption of painful and often symmetrical erythematous nodules on the arms and legs.

When deeper, these nodules are more easily palpated than the more visible ones, but will often ulcerate. Neuritis is frequent, although it is less aggressive than seen in T1Rs. The systemic impact can produce edema, myalgia, fever, malaise, asthenia, weight loss, cephalalgia, iritis, episcleritis, iridocyclitis, glaucoma, epistaxis, arthralgia, orchiepididymitis with testicular atrophy, glomerulonephritis, chronic renal insufficiency, hepatosplenomegaly, and amyloidosis.

The most common medication used for ENL is thalidomide (Thalomid) in variable dosage, from 100 to 400 mg/day, depending on the severity of the reaction. The distribution of thalidomide is restricted in some countries due to its teratogenic effects. For this reason, it should be given under strict supervision with proper medical, ethical, and legal measures in place.

For ENL associated with neuritis, iritis, orchitis, and/or hand-foot reactions, or in women of childbearing age, a course of corticosteroids should be given (prednisone at 1–2 mg/kg/day).

In chronic cases and those that are nonresponsive to treatment, it is possible to administer clofazimine along with steroids, at the initial dosage of 100 mg three times per day for a maximum of 12 weeks. This should be reduced to 100 mg twice daily for another 12 weeks and finally 100 mg/day for 12 to 24 weeks.

Cyclosporine (Neoral, Sandimmune)1 may also offer some benefit to the patient with serious ENL, as can the association of azathioprine (Imuran),1 methotrexate,1 and corticosteroids.

Lucio’s Phenomenon

Lucio’s phenomenon can occur in forms of lepromatous leprosy. The skin lesions can be discreet and limited in number, pinkish or cyanotic, often very painful, and potentially necrotizing and ulcerative. This condition can lead to death. Treatment is based on a course of corticosteroid therapy appropriate for each patient.

Differential Diagnosis between Relapse and Reaction

Relapse rates are very low whereas reactions are quite frequent, even after completing treatment. Table 2 shows the main differences between reaction type 1 and relapse.

Table 2

Differences between Reaction Type 1 and Relapse 

Reversal Reaction                                                                                               Relapse
Generally occurs during course of MDT or within 6 months of treatment completion Normally takes place well after the end of MDT, at least a year after treatment completion
Sudden and unexpected onset Slow and insidious onset
Can be accompanied by fever and malaise In general, no systemic symptoms present
Old lesions become erythematous, shiny, and infiltrated Old lesions may present erythematous edges
In general, many new lesions Few new lesions
There may be ulceration of the reaction lesions Ulceration may occur on arms and legs in addition to the lesions
Regression  with desquamation No desquamation present
Can quickly affect several nerve trunks, with presence of pain, sensory alteration, and decreased motor function May affect a single nerve and functional alterations often take place very slowly
Excellent response to corticosteroid therapy Does not respond well to corticosteroid therapy
Bacteriologic index stable or falls Bacteriologic index rises

Abbreviation: MDT = multidrug therapy.

Complications

Leprosy complications are the result of permanent nerve damage.

Lesions to the large nerve trunks, such as the ulnar, median, and tibial, cause motor and sensory loss leading to disabilities such as claw hand and footdrop.

The absence of sensation in the hands, soles of the feet, and cornea leaves these areas predisposed to common wounds and pressure ulcers. This reality demands that patients take specific care to avoid ulcers and detect them as soon as possible to prevent secondary infection. In addition, corneal ulcers can result in blindness.

Acknowledgment

We thank Dr. Anna Maria Salles for the patient’s pictures.

References

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10.       Van Veen N.H., Lockwood D.N., Van Brakel W.H., et al. Interventions for Erythema Nodosum Leprosum (Review), Cochrane Collaboration. Hoboken, NJ: John Wiley & Sons; 2012 p. 53.

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2  Not available in the United  States.

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