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Leprosy

Lucileia Johnson, MD, William Harper, MD, Steven M. Opal, MD, and Eleftherios E. Mylonakis, MDRevised: 20 Oct 2011Last Updated: 19 Oct 2011Copyright Elsevier BV. All rights reserved.

Key points

Leprosy is caused by Mycobacterium leprae , a slow-growing bacillus that is an obligate parasite with atropism for peripheral nerves, skin, and mucous membranes in the cooler parts of the body, such as theupper respiratory tract, anterior chamber of the eye, and the testes

Up to 300 cases are reported in the U.S. every year, with the majority in states with the largestimmigrant populations

Persons of all ages and both sexes are affected

Transmission occurs via droplets from the nose and mouth of persons with untreated, severe disease

Once the diagnosis has been established, all household contacts of the patient also should beassessed, as the risk of infection among family members is substantially higher than for other contacts

Multidrug therapy, namely with dapsone, rifampin, and clofazimine, is the only effective treatment

Long-term follow-up and regular monitoring for the development of lepra reactions are required, asspontaneous reactions may occur even after curative therapy and, if left untreated, are a major cause ofneuronal and other complications

Background

Description

M. leprae was discovered by the Norwegian Gerhard Henrik Armauer Hansen in 1873, making it the firstbacillus and the second bacterium known to be associated with a human disease

Owing to the extremely slow dividing time of M. leprae (once every 2 weeks), the incubation periodranges from 6 months to more than 40 years and averages 2 to 5 years

The cardinal features of leprosy are a skin patch with sensory loss, nerve enlargement, and acid-fastbacilli in the skin; nerve enlargement is the most important feature, as 30% of patients, including manyof those with lepromatous leprosy, may not present with a skin patch with sensory loss, and somepatients simply have a neural form of leprosy, known as neuritic leprosy

The manifestations of the disease are determined by the host's immunopathologic responses to M.leprae , resulting in a wide clinical spectrum with five distinct forms characterized by Ridley and Joplingin 1966

The polar forms of leprosy, tuberculoid leprosy and lepromatous leprosy, are immunologically stable,whereas the intermediate forms, including borderline tuberculoid leprosy, borderline leprosy, andborderline lepromatous leprosy, are immunologically unstable and lead to either a gradual declinetoward the lepromatous pole or upgrading 'reversal reactions' toward the tuberculoid pole

Tuberculoid leprosy is characterized by a vigorous cellular immune response and limited humoralimmune responses to M. leprae , usually involving the skin and nerves and resulting in few skin lesions.Lepromatous leprosy, on the other hand, is characterized by a minimal cellular immune response and avigorous humoral immune response and, consequently, extensive skin involvement

Indeterminate leprosy, an additional type, is an early form of the disease that features only a smallnumber skin lesions and no nerve involvement

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Leprosy also may be divided into paucibacillary and multibacillary forms, depending on the number ofbacilli present in skin lesions. Indeterminate leprosy, tuberculoid leprosy, and borderline tuberculoidleprosy are categorized as paucibacillary forms (characterized by a low number of bacilli), whereasborderline leprosy, borderline lepromatous leprosy, and lepromatous leprosy are consideredmultibacillary. This classification has a significant bearing on the choice of therapy

The introduction of multidrug therapy in 1981 led to a dramatic decline in prevalence and diseaseburden; of 122 countries where leprosy is considered to be endemic, the prevalence of the disease hasdecreased to less than 1 case per 10,000 persons in 119 countries

A 6- to 12-month course of multidrug therapy is highly effective in treating leprosy and is associatedwith few adverse effects and low relapse rates; if left untreated, leprosy can cause nerve damage,leading to muscle weakness and atrophy with permanent disability

Although emergence of resistance to individual medications ( eg , dapsone) has been reported withmonotherapy in the past, no resistance has been reported with the use of newer multidrug regimens

The dynamic immunopathologic host response to M. leprae during the course of leprosy may result inspontaneous lepra reactions; these are more common in patients with borderline forms of the diseaseand may be precipitated by treatment

Lepra type 1 reactions involve either a downgrading or upgrading reaction, with patients developinginflammation, neuritis, and potentially fever, and are a major cause of nerve damage. Lepra type 2reactions or erythema nodosum leprosum affect approximately half of all patients and consist of animmune complex–mediated reaction to M. leprae that has widespread, systemic effects in addition tocausing the development of new skin lesions

Systemic corticosteroids are the mainstay of treatment for lepra reactions

Epidemiology

Incidence and prevalence:

The true incidence of leprosy is difficult to measure, as, unlike tuberculosis, the annual rate of infectioncannot be quantified using the equivalent of the tuberculin skin test reactivity survey. However, it is clearthat the disease burden and prevalence of leprosy have decreased dramatically over the past 20 years,largely due to the widespread use of multidrug therapy

The most recent case detection rate for leprosy is approximately 250,000 cases per year worldwide,which represents a significant decline in the last decade, as more than 700,000 new cases werereported in 2001

Between 100 and 300 cases of leprosy are diagnosed each year in the U.S., 95% of which are acquiredin developing countries; the majority of cases are in states with the largest immigrant populations, suchas the southern states, California, Hawaii, and island possessions

Since 1985, the reported prevalence of leprosy has been reduced by more than 90%, and cure hasbeen achieved in more than 15 million patients. In 2006, the total number of active cases worldwide was259,017

The World Health Organization (WHO) reports that the current prevalence of leprosy is less than 1 caseper 10,000 persons in all countries except for Brazil, Mozambique, Madagascar, Tanzania, and Nepal,where the prevalence exceeds 2 cases per 10,000 persons

Demographics:

Leprosy has a bimodal age distribution, with peaks observed at ages 10 to 14 years and 35 to 44 years

Children seem to be more susceptible to developing leprosy than adults and tend to have thetuberculoid form rather than the lepromatous form

Although leprosy is rare in infants, those born to mothers with the disease have slow growth anddecreased birth weight; infants whose mothers have lepromatous leprosy are at increased risk ofcontracting the disease

Leprosy is more common in men than in women, with a male-to-female ratio of 1.5 to 2.0:1; however,when the disease occurs in children, both genders are affected equally

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Although leprosy occurs in all races, Africans have a higher incidence of the tuberculoid form than othergroups, and the lepromatous form is more common in light-skinned and Chinese persons

Genetic factors influence both the development of leprosy and the pattern of disease. Whole-genomescreening has revealed susceptibility loci on chromosome 10p13, close to the gene for the mannosereceptor C type 1, and on chromosome 6 within the major histocompatibility complex, where linkagehas been shown to the human leukocyte antigen (HLA) class II and tumor necrosis factor (TNF) genesin Indian and Brazilian patients, respectively. Polymorphisms in the promoters of both TNF and IL10genes have been associated with the development of leprosy, particularly multibacillary leprosy in thecase of TNF . The HLA locus also has been shown to affect the pattern of disease, with HLA-DR2 andHLA-DR3 associated with tuberculoid disease and HLA-DQ1 linked to the lepromatous form

Of the 122 countries that were classified as endemic for leprosy in 1985, 119 reached the eliminationtarget in 2009

Cases of leprosy are highly concentrated, with 83% of patients located in only six countries: India,Brazil, Myanmar (Burma), Indonesia, Madagascar, and Nepal. India alone accounts for 64% of allleprosy cases worldwide

Leprosy has virtually disappeared from Europe, and the majority of cases in North America are amongimmigrants from endemic areas. However, cases of leprosy among patients with severeimmunosuppression, such as organ transplant recipients, have been reported

Leprosy is associated with poverty and overcrowding, with improved socioeconomic conditions being amajor contributor to the decline of the disease in Europe and North America

The disease is more common in rural as opposed to urban areas

Causes and risk factors

Causes:

Leprosy is caused by chronic infection with M. leprae , an acid-fast, gram-positive bacillus that is anobligate intracellular parasite with tropism for macrophages and Schwann cells

M. leprae cannot be cultivated in vitro but is capable of limited multiplication in the mouse footpad, witha doubling time of 12 to 13 days, allowing drug sensitivity studies to be conducted

Genomic studies have shown that many of the functional genes for energy metabolism in M. leprae areabsent, having been replaced by inactivated genes or pseudogenes. This has resulted in the removal ofentire metabolic pathways and regulatory genes and may make the bacillus dependent on hostmetabolic pathways, possibly explaining the long generation time and inability to grow in culture

M. leprae is transmitted via droplets from the nose and mouth of patients with untreated disease duringfrequent and close contact. It is estimated that approximately 50% of patients have a history of intimatecontact with an infected person, usually a household member

Although leprosy is not highly infectious, patients with untreated lepromatous leprosy harbor largenumbers of M. leprae in their nasal mucosa and secretions

Risk factors:

Although the majority of cases of leprosy are sporadic, the greatest risk factor for leprosy is householdcontact with patients with untreated disease. The relative risk of infection is 8- to 10-fold higher amonghousehold contacts of patients with lepromatous leprosy and 2- to 4-fold higher for contacts of patientswith tuberculoid leprosy

Animal reservoirs of leprosy include nine-banded armadillos (15% of which are thought be to infected inthe wild in Louisiana and Texas), chimpanzees, and mangabey monkeys

Exposure to insect vectors and soil containing M. leprae also have been suggested as possible modesof transmission

Associated disorders

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Unlike tuberculosis, there is no definitive evidence of an association between human immunodeficiency virus(HIV) disease and clinical leprosy, although one study conducted in Tanzania suggested that there was anincrease in HIV prevalence among patients with leprosy.

Screening

Not applicable.

Primary prevention

Summary approach

Prevention primarily consists of avoiding close physical contact with patients with untreated disease.Patients receiving long-term therapy are no longer contagious and, therefore, do not represent a risk

In 1991, the World Health Assembly of the WHO passed a resolution to eliminate leprosy as a publichealth problem, defined as a prevalence rate of less than 1 case per 10,000 persons, by 2000. Largelyowing to the widespread use of multidrug therapy, this has resulted in a dramatic decrease in the globaldisease burden and the elimination of leprosy from 119 of the 122 countries in which leprosy wasconsidered to be a public health problem as of 2009

In order to maintain the momentum and ensure that leprosy is contained and eliminated from allcountries, the WHO states:

Political commitment needs to be sustained in countries where leprosy remains a public healthproblem

In order to reach all patients, leprosy treatment needs to be integrated into general healthservices

Partners in leprosy elimination need to continue to ensure that human and financial resourcesare made available for the elimination of leprosy

Because the stigma of leprosy is an obstacle to self-reporting and early treatment, the image ofthe disease must be changed at the global, national, and local levels, and a new environment, inwhich patients will not hesitate to seek diagnosis and treatment, must be fostered

The WHO recommends the following to contain and eliminate leprosy:

Accessible and uninterrupted multidrug therapy services for all patients through flexible andpatient-friendly drug delivery systems

Sustainability of multidrug therapy services by integration of leprosy services into general healthservices and training general health workers to treat leprosy

Encouragement of self-reporting and early treatment by promoting community awareness andchanging the image of leprosy

Monitoring the performance of multidrug therapy services, the quality of patient care, and theprogress made toward elimination via national disease surveillance systems

Population at risk

Household contacts of patients with untreated leprosy.

Preventive measures

Household contacts of patients with lepromatous leprosy, especially children, should be monitoredannually for 5 years following diagnosis

Various attempts have been made to develop a vaccine against leprosy, with the bacille Calmette-Guérin (BCG) vaccine having mixed results; other vaccines under development or being explored are theMycobacterium w, Mycobacterium ICRC, and BCG plus heat-killed Mycobacterium species vaccines

Chemoprophylaxis with dapsone is no longer recommended

Evidence

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A meta-analysis of 7 experimental studies and 19 observational studies found that the overall protectiveeffect of the BCG vaccine was 26% in the experimental studies and 61% in the observational studies.There was significant heterogeneity among the trials but few significant differences between theprotective effects of BCG vaccination against paucibacillary or multibacillary disease or betweenhousehold contacts and other contacts. However, it was noted that an additional dose of BCG vaccinewas more protective than a single dose in the prevention of leprosy, leading the authors to recommendthat an additional dose may be warranted in contacts of patients with leprosy in areas where thedisease remains a public health problem. [1] Level of evidence: 1

References

Diagnosis

Summary approach

According to the WHO, the diagnosis of leprosy is based on the presence of characteristic clinicalfeatures, consisting of a skin patch with sensory loss and nerve enlargement, supported when possibleby the demonstration of acid-fast bacilli from slit-skin preparations or a biopsy

The presence of a skin patch with sensory loss, nerve enlargement, and/or acid-fast bacilli in the skinestablishes the diagnosis, which should be confirmed if possible with a full-thickness biopsy. Thediagnosis of leprosy can be established solely based on the presence of a skin patch with sensory lossin approximately 70% of patients; however, 30% of patients, including many of those with lepromatousleprosy, may not present with this sign, emphasizing the importance of clinical suspicion and nerveenlargement as an additional sign

In order to maximize the accuracy of the diagnosis based on clinical signs, physicians should look for athickened nerve and typical hypopigmented or erythematous skin, with or without sensory loss, and/ortypical nerve function impairment, such as loss of sensation on the palms of the hands or the soles ofthe feet

Leprosy also may present purely as a neural disease, without skin lesions, which is known as neuriticleprosy and is seen in 0.5% of patients with leprosy in Ethiopia, 4.6% of patients in India, and 8.7% ofpatients in Nepal; the diagnosis is confirmed by nerve biopsy

Clinical presentation

Patients with leprosy classically present with inflamed skin lesions and/or sensorimotor neuropathy, with nerveenlargement in those with tuberculoid leprosy. However, it is important to note that symptoms and signs maytake decades to appear due to the long incubation period of M. leprae . Furthermore, the clinical presentationdiffers depending on the form of leprosy.

Symptoms

Typical symptoms are as follows:

One or more hypopigmented skin lesions with decreased sensation to touch, heat, or pain

Skin lesions that do not heal after several weeks or months

Numbness or absent sensation in the hands and arms or feet and legs

Muscle weakness due to nerve damage, resulting in, for example, foot drop, in which damage tothe peroneal nerve causes the toe to drag when the foot is lifted to take a step

Prodromal symptoms are often so minor that the disease is not recognized until a cutaneous eruptionoccurs. Approximately 90% of patients present with numbness first, potentially years before theappearance of skin lesions

The first sensation to be lost is temperature, with patients unable to sense extremes of hot or cold. Thisis followed by light touch, then pain, and, finally, deep pressure, with the losses especially apparent inthe hands and feet. Patients with long-term leprosy may lose the use of their hands or feet due torepeated injury resulting from lack of sensation

Signs

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The signs of leprosy vary widely, depending on the form of leprosy.

Indeterminate leprosy:

One to a few hypopigmented or sometimes erythematous macules are present

Sensory loss is unusual

Tuberculoid leprosy:

Cutaneous lesions are few in number, and there is usually one large, erythematous plaque withwell-defined borders that are elevated and slope down to an atrophic center; the lesions canbecome arciform or annular and can be found on the face, limbs, or areas other than the scalpand intertriginous areas

Patients also may have a large, asymmetric, hypopigmented macule with lesional hypesthesiaand involving local alopecia

Neural involvement is common, causing tender, thickened nerves with loss of function; thegreater auricular nerve and superficial peroneal nerves are affected most commonly

A single hypopigmented anesthetic plaque with a raised border and dry surface

Borderline tuberculoid leprosy:

Cutaneous lesions are similar to those seen in patients with tuberculoid leprosy but are smallerand more numerous

The nerves are less enlarged and alopecia is less common and pronounced than in patients withtuberculoid leprosy

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Three large, well-defined, erythematous patches with reduced sensation, spreading borders, andsatellite lesions

Erythema and edema in the facial lesions of a patient with borderline tuberculoid leprosyexperiencing an upgrading reversal reaction

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Borderline leprosy:

Cutaneous lesions consist of numerous erythematous, irregular plaques that are less welldefined than those seen in patients with tuberculoid leprosy; the distribution may be the sameas in patients with lepromatous leprosy, but the lesions are more asymmetric

Hypesthesia is only moderate

Regional adenopathy may be present

Borderline lepromatous leprosy:

Cutaneous lesions are numerous and consist of macules, papules, plaques, and nodules;annular punched-out lesions resembling inverted saucers are common

Hypesthesia is often absent

Characteristic target lesion with an erythematous annular border, punched-out central area, andimpaired sensation

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Lepromatous leprosy:

Early cutaneous lesions may consist mainly of pale, small, diffuse, symmetric macules. Later inthe disease course, lepromatous infiltrations, which contain numerous bacilli and can be diffuseor in the form of nodules or plaques, occur; diffuse infiltration results in leonine (lion-like) facies,characterized by heavily furrowed, thickened skin folds on the forehead with prominentsupraorbital ridges and loss of eyebrows

Neuritic lesions are symmetric and slow to develop

There is little or no loss of sensation and no change in skin texture

No thickened nerves are seen, and sweating is normal

Alopecia affects the lateral eyebrows (known as madarosis), which spreads to the eyelashesand then the trunk; the scalp hair remains intact

Eye involvement may occur and causes pain, photophobia, decreased visual acuity, glaucoma,and blindness

Stridor and hoarseness result from laryngeal involvement and saddle-nose deformity caused bynasal infiltration

Testicular involvement may result in sterility and gynecomastia

Lymphadenopathy and hepatomegaly may result from organ infiltration

Aseptic necrosis and osteomyelitis result from repeated trauma after joint invasion

Brawny edema of the lower extremities occurs late in the disease course

Multiple, small, slightly erythematous macules with intact sensation and symmetric distribution; thesk in smear results for both the lesions and intervening sk in were positive for acid-fast bacilli

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Diffuse infiltration of the sk in by multiple nodules of varying size, each teeming with bacilli

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Tender papules associated with fever, arthralgia, and acute neuritis in a patient with lepromatousleprosy

Physical examination

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Patients with a history of living in or traveling to areas endemic for leprosy who present withhypopigmented or erythematous macules should undergo a thorough examination, focusing specificallyon the distribution of any macules and the presence of enlarged, tender nerves. Skin lesions associatedwith leprosy are present in the cooler areas of the body and are not found in the scalp, groin, or axilla

A careful sensory and motor examination, including tactile and temperature sensations, also should beconducted, with a wisp of cotton used to test for lesional hypesthesia

Questions to ask

Presenting condition:

Do you have any areas of sk in that are especially pale or particularly red? Hypopigmented orerythematous macules are common in patients with leprosy, with the number and characteristicsindicative of particular forms of the disease

If so, where are the sk in patches located? Skin lesions associated with leprosy typically are confinedto the cooler parts of the body, sparing areas such as the groin, axilla, and scalp

Do you have any patches of sk in that are numb or where you no longer feel sensations such as hot orcold? Sensory loss is common in patients with leprosy, particularly in those with paucibacillary forms

Have you noticed any thickened, tender lines on your sk in? Thickened nerves are a common feature ofpaucibacillary leprosy

Do you have any patches of sk in with hair loss? Alopecia of macules is common in patients withpaucibacillary leprosy, and alopecia of the lateral eyebrows is seen in patients with multibacillarydisease. Scalp hair remains unaffected

Have you noticed any lumps under the sk in, such as around the groin, armpit, or neck, that have notgone away? Adenopathy is sometimes seen in patients with multibacillary leprosy

Contributory or predisposing factors:

Do you come from or have you lived in Asia, Africa, or South America? Leprosy is endemic in a numberof countries in these regions and should be suspected in any patient from these areas with thecharacteristic signs

Has leprosy been diagnosed in anyone in your household or in someone with whom you have closecontact? The risk of contracting leprosy is significantly increased in household and close contacts ofpatients with leprosy

Has anyone in your household or someone with whom you have close contact spent a lot of time inAsia, Africa, or South America? Due to the extremely long incubation period, it is possible that leprosymay have been transmitted before it was diagnosed in the contact

Have you had close contact with wild animals, such as armadillos, chimpanzees, or monkeys? Nine-banded armadillos, chimpanzees, and mangabey monkeys are all recognized animal reservoirs ofleprosy

Do you live in overcrowded conditions? Overcrowding and poverty are associated with leprosy

Diagnostic testing

The presence of acid-fast bacilli in the skin is best demonstrated by slit-skin smears , which should betaken from the edges of at least two lesions and both ear lobes. If this is not possible, a skin biopsyspecimen should be stained for acid-fast bacilli using a modified Wade-Fite stain. The extent ofbacillary load may be quantified as a bacterial index on a logarithmic scale of 1+ to 6+. Themorphologic index, which is the number of viable bacilli per 100 bacilli detected, also may becalculated. Histologic findings vary but can include dermatitis, giant cells, infiltration of nerve bundleswith mononuclear cells, and granulomas. Lepromatous lesions typically contain numerous acid-fastbacilli and fat-laden macrophages, with a paucity of lymphocytes. In contrast, tuberculoid lesionscontain few, if any, acid-fast bacilli but show granulomatous changes

In patients with neuritic leprosy, a nerve biopsy from a sensory nerve such as the superficial radial nervemay be diagnostic

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The lepromin skin test does not confirm the diagnosis of leprosy but is useful in distinguishinglepromatous leprosy from tuberculoid leprosy

Histamine testing allows detection of postganglionic nerve damage

Polymerase chain reaction (PCR) testing for M. leprae deoxyribonucleic acid (DNA) and antibody testsfor antibodies to M. leprae –specific phenolic glycolipid (PGL)-1 and other M. leprae –specific proteinspresent in patients with lepromatous leprosy also may be conducted, but these tests are expensive andare more commonly confined to epidemiologic studies

Slit-skin smearsSkin biopsyNerve biopsyLepromin skin testHistamine testPCRPGL-1 antibody testing

Differential diagnosis

Other skin diseases may be differentiated from tuberculoid leprosy by the absence of lesionalhypesthesia and the presence of nerve involvement elsewhere

In contrast, lepromatous leprosy lesions are not hypesthetic, and a biopsy may be necessary in orderto distinguish them from lesions due to other systemic infections, such as leishmaniasis andsecondary or tertiary syphilis, as well as other nodular or infiltrative skin conditions

Other causes of nerve enlargement, such as primary amyloidosis and familial polyneuropathy, areexcluded by biopsy and family history

CryptococcosisBlastomycosisSporotrichosisNocardiosisLeishmaniasisAmyloidosisNeurofibromatosisSarcoidosisSyphilisPsoriasisVitiligoContact dermatitis

Treatment

Summary approach

In the early stages of leprosy, treatment is aimed at preventing disability, but the ultimate goal is toachieve a cure. According to the WHO, early detection and treatment of leprosy with multidrug therapyhas prevented disability in approximately 4 million patients, and leprosy has been cured in more than14 million patients over the past 20 years, with cure achieved in approximately 4 million patients since2000

Urgent treatment is necessary in patients experiencing lepra reactions or spontaneous fluctuations intheir clinical status, with the goals being to stabilize the patient's condition and minimize anycomplications; if left untreated, lepra reactions represent a major cause of neuronal and othercomplications

The WHO recommends multidrug therapy regimens for adults with leprosy consisting of combinationsof dapsone, rifampin, and clofazimine; treatment is the same in pediatric patients but with reduceddoses. After the first dose of multidrug therapy, the disease is no longer contagious, due to interruptedtransmission, and very few relapses occur after completion of the treatment course

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Multidrug therapy was first introduced in 1982, without formal clinical trials, when reported rates ofprimary and secondary dapsone resistance reached 30%. Since then, multidrug-resistant strains of M.leprae have not emerged, although there is no widespread monitoring of clinical outcomes and relapserates

Dapsone , an inhibitor of folic acid synthesis derived from sulfonamides, is the mainstay of treatment forboth lepromatous leprosy and tuberculoid leprosy, although lepromatous leprosy requires moreintensive treatment for a longer duration. The bactericidal effects against M. leprae at full dose, lowcost, and low toxicity of dapsone make it an important antileprosy medication. When used alone,stepwise dapsone resistance emerges as a major problem, but this is prevented with the use ofcombination therapy.

Rifampin is the most effective bactericidal agent against M. leprae and, thus, is a key component ofmultidrug therapy, although it is too expensive for use at the recommended dosage in many developingcountries. The WHO states that rifampin should be administered once a month in conjunction with atleast one other effective medication in order to prevent resistance. Dosage recommendations in theU.S. differ from those of the WHO, largely due to the absence of cost considerations applicable todeveloping countries; the National Hansen's Disease Program (NHDP) recommends dailyadministration of rifampin (600 mg/d) for 12 months in patients with paucibacillary leprosy and for 24months in patients with multibacillary leprosy

Clofazimine , a fat-soluble phenazine dye that is deposited within the skin, fat stores, andmacrophages, is administered daily and has similar activity against M. leprae as dapsone, as well asanti-inflammatory activity that makes it moderately effective against lepra type 2 reactions and,possibly, lepra type 1 reactions

The standard WHO multidrug regimen for adults with multibacillary leprosy is rifampin, 600 mg once amonth; dapsone, 100 mg/d; and clofazimine, 300 mg once a month and 50 mg/d, for 24 months. Thestandard regimen for adults with paucibacillary leprosy is rifampin, 600 mg once a month, and dapsone,100 mg/d, for 6 months

In the U.S., the NHDP regimen for adults with multibacillary leprosy is dapsone, 100 mg/d; rifampin,600 mg/d; and clofazamine, 50 mg/d, for 24 months. The NHDP regimen for adults with paucibacillaryleprosy is dapsone, 100 mg/d, and rifampin, 600 mg/d, for 12 months

More recently, clinical trials have found that ofloxacin and minocycline rapidly kill M. leprae andeffectively reduce dermal infiltration in patients with lepromatous leprosy. The two drugs currently arerecommended for treatment of single-lesion paucibacillary leprosy; the treatment regimenrecommended by the WHO for adults is ofloxacin, 400 mg; minocycline, 100 mg; and rifampin, 600 mg

Ethionamide is an effective alternative antileprosy agent that is used primarily in patients who cannottolerate first-line antileprosy medications or when medication resistance is recognized during treatmentof multibacillary disease. However, ethionamide may cause gastrointestinal problems and liverdysfunction, especially when used in combination with rifampin, and, therefore, is not recommendedunless liver function can be monitored regularly

Treatment of lepra reactions:

The only effective treatment for lepra type 1 reactions is the addition of a corticosteroid, such asprednisone , to the antimicrobial treatment regimen. Corticosteroid therapy generally should notbe initiated unless there is neuritis, skin inflammation that may become ulcerated, orinvolvement of cosmetically important areas; treatment of minor inflammation is not indicated

First and second lepra type 2 reactions, or erythema nodosum leprosum, may be treated withaspirin, if mild, or with short courses of prednisone for several days to a week, with withdrawalover 2 to 3 months. Clofazimine at higher daily doses suppresses erythema nodosum leprosumafter 4 to 6 weeks and can be used to prevent additional episodes

Thalidomide is the medication of choice for recurrent or poorly controlled, severe type 2 leprareactions, as it inhibits the release of tumor necrosis factor from macrophages and offers promptrelief, but should only be used in men and postmenopausal women under strict supervision dueto its teratogenicity. Thalidomide is relatively contraindicated in patients with lepra type 1reactions as it may upregulate T-helper cell type 1 responses and worsen neuronal damage

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Surgery may be necessary in patients with profound nerve inflammation presenting with a nerveabscess or loss of nerve function secondary to compression; prompt drainage often can restore nervefunction. Lagophthalmos, or the inability to close the upper eyelid, may require elective surgery, andpatients with lepromatous leprosy may need nasal reconstruction and other cosmetic procedures.Tendon transfers may correct functional disabilities in the extremities but should not be done until 6months after initiation of therapy or the occurrence of a significant reaction, particularly in the affectednerve distribution

Physical therapy should be offered to patients with muscle weakness

Medications

DapsoneRifampinClofazimineMinocyclineOfloxacinPrednisoneThalidomideEthionamide

Special circumstances

Pregnancy ideally should be planned when leprosy is well controlled, but rifampin, dapsone, andclofazimine are all safe for use during pregnancy; rifampin should be administered only as a singlemonthly dose, but dapsone and clofazimine doses do not need to be altered

In pregnant women with lepra type 1 or lepra type 2 reactions, prednisone and clofazimine can beadministered, but thalidomide should be avoided. It is advisable to postpone pregnancy temporarilyduring the posttreatment period if there is evidence of a reaction, relapse, or neuritis

Infants are at relatively high risk of contracting leprosy from untreated mothers, especially those withborderline leprosy or lepromatous leprosy

Surgical therapy is sometimes appropriate for patients with sustained nerve damage or othercomplications

Consultation

Consultation with an ophthalmologist, plastic surgeon, orthopedic surgeon, otolaryngologist, neurosurgeon,and/or neurologist may be required due to the various complications that may arise in patients with leprosy.

Follow-up

Plan for review:

The WHO recommends that patients with paucibacillary leprosy be monitored for 2 years and patientswith multibacillary leprosy be monitored for 5 years

The patient's eyes, nose, and nerves should be examined at follow-up visits to ensure timely recognitionof reactive disease; sensation and muscle strength in the hands and feet also should be checkedregularly

A complete blood count should be obtained at frequent intervals during treatment with dapsone and lessfrequently after completion of the treatment course

Prognosis:

If left untreated, leprosy leads to progressive and permanent damage to the skin, nerves, limbs, andeyes; thus, early recognition is important, as it limits the damage caused by the disease, eliminatesthe risk of transmission, and allows for a normal lifestyle

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Although both lepromatous leprosy and tuberculoid leprosy are associated with skin and peripheralnerve involvement, the tuberculoid form has more severe manifestations; for example, nerve involvementresults in loss of sensory and motor function, which may lead to frequent trauma and, ultimately,amputation

In patients with lepromatous leprosy, infiltration by bacteria may lead to destruction of nasal cartilage,ocular involvement, and thickening of the skin

The main factors affecting prognosis are access to therapy, compliance, and early initiation oftreatment

Most cases of indeterminate leprosy evolve into tuberculoid leprosy or lepromatous leprosy, dependingon the patient's immunity to the disease; spontaneous resolution may occur in patients with strongimmunity, and the disease may remain in the indeterminate stage in some patients

Patients with tuberculoid leprosy may experience spontaneous resolution within a few years, leavingpigmentary disturbances or scars, or progression of disease, leading to borderline lepromatous leprosyor, rarely and in untreated cases, to lepromatous leprosy

Borderline tuberculoid leprosy can remain in the same stage, convert back to the tuberculoid form, orprogress. Borderline leprosy may remain in the same stage, convert back through borderline tuberculoidleprosy to tuberculoid leprosy, or progress. Likewise, borderline lepromatous leprosy may remain in thesame stage, improve, or progress

Unlike other forms of leprosy, lepromatous leprosy cannot convert back to the less severe borderline ortuberculoid forms of the disease

Patients with leprosy may experience recurrence, with the greatest risk in those who do notsuccessfully complete a course of multidrug therapy. Although comprehensive monitoring is lacking,there have been very few reports of resistance to multidrug therapy since its introduction

Occurrence of lepra type 1 and type 2 reactions is associated with a poor prognosis

Complications:

The most common complications in patients with leprosy are reactional states, which can result inpermanent neurologic sequelae and, hence, disability and deformity

Lepra type 1 reactions affect patients with borderline disease. A downgrading reactionrepresents a shift toward the lepromatous pole before initiation of treatment, and a reversalreaction represents a shift toward the tuberculoid pole after initiation of treatment; both arebelieved to be associated with a change in cellular immunity and may result in inflammation,neuritis, and, possibly, fever. In reversal reactions, T-helper cell dermal infiltration increasessignificantly, with an associated increase in local cytokines, especially interferon-γ. If not treatedearly, lepra type 1 reactions can lead to irreversible motor and sensory loss

Lepra type 2 reactions ( erythema nodosum leprosum) occur in the first few years of disease inapproximately half of all patients with lepromatous leprosy and may precede initiation oftreatment, thereby precipitating the diagnosis, or may occur up to 10 years after initiation oftreatment, when patients have negative slit-skin smear results. Erythema nodosum leprosum ischaracterized by the presence of erythematous and painful papules or subcutaneous nodulesthat may pustulate and ulcerate, along with fever, neuritis, lymphadenitis, orchitis, arthritis(particularly in large joints, such as the knees), and glomerulonephritis. Histologically, erythemanodosum leprosum appears to be a polymorphonuclear vasculitis or panniculitis and is believedto be due to circulating immune complexes or events associated with increased T-helper cellfunction; levels of circulating tumor necrosis factor also may increase. Patients may developanemia from erythrocyte destruction or bone marrow suppression and hepatic inflammation, withabnormalities in liver function test results. An unusual lepra type 2 reaction (sometimesdesignated a lepra type 1 reaction) characterized by cutaneous hemorrhagic infarcts, known asthe Lucio phenomenon, occurs in patients with diffuse lepromatous leprosy and is common inMexico and Central America

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Peripheral nerve involvement, specifically nerve trunks and microscopic dermal nerves, as aconsequence of the infection and the host inflammatory response or neuritis associated with leprareactions accounts for the majority of complications. The ulnar nerve at the elbow is affected mostcommonly, leading to distal hypoesthesia and clawing of the fourth and fifth digits in patients withsevere disease. The perineal, median, and zygomatic branches of the facial nerves and the posteriorauricular nerves also may be involved. Small nerve fibers that respond to hot and cold, fine touch, andpain are particularly affected, whereas larger nerve fibers responsible for position and vibration sensationgenerally are spared

Plantar ulcers with secondary infection are a major cause of morbidity and should be treated withdebridement and appropriate antibiotics. More complicated ulcers require surgical removal, and wideexploration and good drainage are needed if dead tissue is present

Ocular involvement may be severe. In patients with lepromatous leprosy, M. leprae invades the anteriorchamber, whereas erythema nodosum leprosum may cause iritis, leading to glaucoma. Cornealinsensitivity and involvement of the zygomatic branch of the facial nerve, causing lagophthalmos, maylead to corneal trauma, scarring, and blindness. Routine use of lubricating eye drops is indicated inpatients with corneal involvement

The nasal mucosa and cartilage are affected in patients with lepromatous leprosy, with untreateddisease often resulting in chronic nasal congestion and, at times, epistaxis, as well as nasal cartilageperforation and collapse in rare cases

Impotence is sometimes seen in men with lepromatous leprosy due to decreased serum testosteronelevels and increased follicle-stimulating hormone and luteinizing hormone levels, resulting inhypospermia, aspermia, and infertility. Treatment consists of monthly intramuscular injections oftestosterone enanthate, 200 mg, or liberal application of 5% testosterone cream to the scrotum twicedaily

Amyloidosis and renal failure occasionally are seen in patients with lepromatous leprosy and areassociated with severe, recurrent erythema nodosum leprosum

There is no evidence that pregnancy causes new disease or relapse, but there is a temporalassociation between the development of lepra type 1 reactions and neuritis and parturition, when cell-mediated immunity returns to prepregnancy intensity. Women with lepromatous leprosy mayexperience erythema nodosum leprosum throughout pregnancy and lactation, which is linked to earlierloss of nerve function than in nonpregnant patients

Patient education

Patients in whom leprosy is diagnosed should be given an explanation of the diagnosis, treatment, andprognosis. It is also important to address any fears resulting from the cultural stigma of leprosy;psychological counseling may be necessary, as patients may have difficulty coming to terms with thediagnosis or may feel rejected by society

Patients should be reassured that leprosy, even advanced leprosy with many sores, is curable if theyadhere to and complete the prescribed multidrug therapy regimen

Patients should be made aware that damage to the extremities, including clawing of the fingers insevere cases, is caused largely by neuropathy, which results in the inability to feel trauma. Patientswho have lost sensation in their feet or hands should be advised to inspect their extremities regularly fortrauma and to wear protective clothing and footwear, consisting simply of canvas shoes with protectiveinsoles

Patients should be taught how to identify the onset of anesthesia or weakness in the limbs and eyesand how to recognize the onset of lepra reactions, which require immediate medical attention

Patients with bone or joint destruction should be instructed to minimize weight bearing

Patients with plantar ulceration should be advised of the importance of rest and avoidance of weightbearing to promote healing

Patients with weakness or paralysis should be encouraged to participate in a regular physical therapyregimen

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Online information for patients

American Academy of Family Physicians: Leprosy

International Federation of Anti-Leprosy Associations (ILEP): Facts About Leprosy

LEPRA Health in Action

National Institute of Allergy and Infectious Diseases: Leprosy (Hansen's Disease)

U.S. Department of Health and Human Services: National Hansen's Disease (Leprosy) Program

WHO: Leprosy

Resources

Summary of evidence

Evidence

Primary prevention

A meta-analysis of 7 experimental studies and 19 observational studies found that the overall protectiveeffect of the BCG vaccine was 26% in the experimental studies and 61% in the observational studies.There was significant heterogeneity among the trials but few significant differences between theprotective effects of BCG vaccination against paucibacillary or multibacillary disease or betweenhousehold contacts and other contacts. However, it was noted that an additional dose of BCG vaccinewas more protective than a single dose in the prevention of leprosy, leading the authors to recommendthat an additional dose may be warranted in contacts of patients with leprosy in areas where thedisease remains a public health problem. [1] Level of evidence: 1

Treatment

Dapsone:

An RCT comparing the efficacy of standard multidrug therapy with dapsone and rifampin versus a 4-week regimen of ofloxacin plus rifampin in 124 patients with paucibacillary leprosy found that, after 10years of follow-up, one relapse occurred in the group receiving ofloxacin plus rifampin and two relapsesoccurred in the group receiving standard therapy, leading the investigators to conclude that bothtreatment regimens were effective. [2] Level of evidence: 1

Rifampin:

An RCT comparing the efficacy of standard multidrug therapy with dapsone and rifampin versus a 4-week regimen of ofloxacin plus rifampin in 124 patients with paucibacillary leprosy found that, after 10years of follow-up, one relapse occurred in the group receiving ofloxacin plus rifampin and two relapsesoccurred in the group receiving standard therapy, leading the investigators to conclude that bothtreatment regimens were effective. [2] Level of evidence: 1

An observational study of 105 patients receiving rifampin and clofazimine after withdrawal of dapsonedue to toxicity found that dual therapy produced negative slit-skin smear results in all 36 patients withpositive results at onset. [3] Level of evidence: 2

Clofazimine:

An RCT comparing the efficacy of standard multidrug therapy with dapsone and rifampin versus a 4-week regimen of ofloxacin plus rifampin in 124 patients with paucibacillary leprosy found that, after 10years of follow-up, one relapse occurred in the group receiving ofloxacin plus rifampin and two relapsesoccurred in the group receiving standard therapy, leading the investigators to conclude that bothtreatment regimens were effective. [2] Level of evidence: 1

An observational study of 105 patients receiving rifampin and clofazimine after withdrawal of dapsonedue to toxicity found that dual therapy produced negative slit-skin smear results in all 36 patients withpositive results at onset. [3] Level of evidence: 2

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A systematic review evaluating the efficacy of interventions for erythema nodosum leprosum (lepra type2 reactions), including aspirin, prednisolone, betamethasone, thalidomide, clofazimine, and others,identified 13 RCTs involving a total of 445 patients. The reviewers concluded that the sample sizes weresmall and the heterogeneity of treatments precluded pooling of data, but clofazimine appeared to besuperior to thalidomide and prednisolone, and thalidomide was superior to aspirin. [4] Level of evidence:1

Minocycline:

A multicenter RCT comparing the efficacy of a combination of rifampin, ofloxacin, and minocyclineadministered as single dose with that of the standard 6-month WHO multidrug therapy regimen forpaucibacillary leprosy in 1,483 patients with single-lesion paucibacillary leprosy (1,381 of whomcompleted the study) found that combination therapy with rifampin, ofloxacin, and minocycline wasalmost as effective as the standard WHO multidrug therapy regimen. Mild adverse effects and leprosyreactions were minimal in both groups, occurring in less than 1% of patients. [5] Level of evidence: 1

Ofloxacin:

A multicenter RCT comparing the efficacy of a combination of rifampin, ofloxacin, and minocyclineadministered as single dose with that of the standard 6-month WHO multidrug therapy regimen forpaucibacillary leprosy in 1,483 patients with single-lesion paucibacillary leprosy (1,381 of whomcompleted the study) found that combination therapy with rifampin, ofloxacin, and minocycline wasalmost as effective as the standard WHO multidrug therapy regimen. Mild adverse effects and leprosyreactions were minimal in both groups, occurring in less than 1% of patients. [5] Level of evidence: 1

An RCT comparing the efficacy of standard multidrug therapy with dapsone and rifampin versus a 4-week regimen of ofloxacin plus rifampin in 124 patients with paucibacillary leprosy found that, after 10years of follow-up, one relapse occurred in the group receiving ofloxacin plus rifampin and two relapsesoccurred in the group receiving standard therapy, leading the investigators to conclude that bothtreatment regimens were effective. [2] Level of evidence: 1

Prednisone:

An RCT evaluating the efficacy of adding low-dose prednisolone to multidrug therapy in preventing leprareactions and nerve function impairment in 636 patients with newly diagnosed multibacillary leprosyfound that low-dose prophylactic prednisolone administered during the first 4 months of multidrugtherapy reduced the incidence of new reactions and nerve function impairment in the short term.However, the effect was not sustained at 1 year. The investigators suggested that the presence of nervefunction impairment at diagnosis may influence the response to low-dose prednisolone. [6] Level ofevidence: 1

A systematic review examining the efficacy of steroids for the treatment of nerve damage due to leprosyidentified three RCTs differing in design and patient parameters. Two trials compared prednisoloneversus placebo and found no significant difference in outcome between groups after 12 months of follow-up. The third study evaluated three different prednisolone regimens, including high- and low-dosetherapy for 3 and 5 months. Patients assigned to the 3-month course required supplemental steroidsmore often than those receiving treatment for 5 months. The reviewers concluded that additional trialsare needed to establish efficacy and optimal regimens. [7] Level of evidence: 1

A prospective, randomized trial comparing the efficacy of prednisolone versus thalidomide in 60 patientswith erythema nodosum leprosum found that patients receiving thalidomide experienced more rapidimprovement and remained free of relapse longer than those receiving prednisolone. [8] Level ofevidence: 2

Thalidomide:

A systematic review evaluating the efficacy of interventions for erythema nodosum leprosum (lepra type2 reactions), including aspirin, prednisolone, betamethasone, thalidomide, clofazimine, and others,identified 13 RCTs involving a total of 445 patients. The reviewers concluded that the sample sizes weresmall and the heterogeneity of treatments precluded pooling of data, but clofazimine appeared to besuperior to thalidomide and prednisolone, and thalidomide was superior to aspirin. [4] Level of evidence:1

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A prospective, randomized trial comparing the efficacy of prednisolone versus thalidomide in 60 patientswith erythema nodosum leprosum found that patients receiving thalidomide experienced more rapidimprovement and remained free of relapse longer than those receiving prednisolone. [8] Level ofevidence: 2

Ethionamide:

A 6-month observational study randomly assigned 50 patients with untreated lepromatous leprosy todirectly observed monotherapy with ethionamide or prothionamide. Clinical improvement was noted in74% of the patients receiving ethionamide and 83% of those receiving prothionamide. Because of thesmall sample size, however, the results must be interpreted with caution. The WHO has not endorsedthe routine use of thioamides in the treatment of leprosy. [9] Level of evidence: 2

References

References

Evidence references[1] Setia MS, Steinmaus C, Ho CS, Rutherford GW. The role of BCG in prevention of leprosy: a meta-analysis.Lancet Infect Dis. 2006;6:162-70CrossRef[2] Balagon MF, Cellona RV, Abalos RM, Gelber RH, Saunderson PR. The efficacy of a four-week, ofloxacin-containing regimen compared with standard WHO-MDT in PB leprosy. Lepr Rev. 2010;81:27-33[3] Sapkota BR, Shrestha K, Pandey B, Walker SL. A retrospective study of the effect of modified multi-drugtherapy in Nepali leprosy patients following the development of adverse effects due to dapsone. Lepr Rev.2008;79:425-8[4] Van Veen NH, Lockwood DN, van Brakel WH, Ramirez J Jr, Richardus JH. Interventions for erythemanodosum leprosum. Cochrane Database Syst Rev. 2009:CD006949CrossRef[5] Efficacy of single dose multidrug therapy for the treatment of single-lesion paucibacillary leprosy. Single-lesion Multicentre Trial Group. Indian J Lepr. 1997;69:121-9[6] Smith WC, Anderson AM, Withington SG, et al. Steroid prophylaxis for prevention of nerve functionimpairment in leprosy: randomised placebo controlled trial (TRIPOD 1). BMJ. 2004;328:1459CrossRef[7] Van Veen NH, Nicholls PG, Smith WC, Richardus JH. Corticosteroids for treating nerve damage in leprosy.Cochrane Database Syst Rev. 2007:CD005491CrossRef[8] Kaur I, Dogra S, Narang T, De D. Comparative efficacy of thalidomide and prednisolone in the treatment ofmoderate to severe erythema nodosum leprosum: a randomized study. Australas J Dermatol. 2009;50:181-5CrossRef[9] Fajardo TT, Guinto RS, Cellona RV, Abalos RM, Dela Cruz EC, Gelber RH. A clinical trial of ethionamideand prothionamide for treatment of lepromatous leprosy. Am J Trop Med Hyg. 2006;74:457-61Guidelines

The WHO has produced the following:

Regional Office for South-East Asia, WHO. Global Strategy for Further Reducing the Leprosy Burdenand Sustaining Leprosy Control Activities (2006-2010): Operational Guidelines . New Delhi: WHO; 2006

Leprosy Elimination Group, WHO. Guide to Eliminate Leprosy as a Public Health Problem . Geneva:WHO; 2000

The NHDP , a division of the U.S. Department of Health and Human Services, has produced the following:

Recommended Treatment Regimens . Baton Rouge, LA: NHDP

The Centre for Disease Control , a division of the Northern Territory Department of Health (Australia), hasproduced the following:

Guidelines for the Control of Leprosy in the Northern Territory, 2010 . Casuarina, Australia: Centre forDisease Control; 2010

The International Council of Ophthalmology has produced the following:

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Eye Disease in Leprosy (Initial Evaluation and Management) . San Francisco, CA: International Councilof Ophthalmology; 2011

Further reading

Boggild AK, Keystone JS, Kain KC. Leprosy: a primer for Canadian physicians. CMAJ. 2004;170:71-8

Britton WJ, Lockwood DN. Leprosy. Lancet. 2004;363:1209-19

Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacteriumleprae vaccine for prevention of leprosy and tuberculosis in Malawi. Karonga Prevention Trial Group.Lancet. 1996;348:17-24

Tejasvi T, Khaitan BK, Khanna N, Pandhi RK, Singh MK. Evaluation of a new fixed duration (12 weeks)multi-drug regimen of bactericidal drugs in multibacillary leprosy. Indian J Lepr. 2006;78:329-37

Matthews SJ, McCoy C. Thalidomide: a review of approved and investigational uses. Clin Ther.2003;25:342-95

Van Veen NH, Schreuders TA, Theuvenet WJ, Agrawal A, Richardus JH. Decompressive surgery fortreating nerve damage in leprosy. Cochrane Database Syst Rev. 2009:CD006983

Reinar LM, Forsetlund L, Bjørndal A, Lockwood D. Interventions for skin changes caused by nervedamage in leprosy. Cochrane Database Syst Rev. 2008:CD004833

Codes

ICD-9 codes

030 Leprosy, including Hansen disease, infection with M. leprae

030.0 Lepromatous [type L]; lepromatous leprosy (macular, diffuse, infiltrated, nodular, neuritic)

030.1 Tuberculoid [type T]; tuberculoid leprosy (macular, maculoanesthetic, major, minor, neuritic)

030.2 Indeterminate [group I]; indeterminate [uncharacteristic] leprosy (macular, neuritic)

030.3 Borderline [group B]; borderline or dimorphous leprosy (infiltrated, neuritic)

030.8 Other specified leprosy

030.9 Leprosy, unspecified

373.4 Infective dermatitis of eyelid of types resulting in deformity. Code first underlying disease asleprosy (030.0-030.9), lupus vulgaris (tuberculous) (017.0), yaws (102.0-102.9)

711.4 Arthropathy associated with other bacterial diseases [0-9]. Code first underlying disease asdiseases classifiable to 010-040, 090-099, except as in 711.1, 711.3, and 713.5, leprosy (030.0-030.9),tuberculosis (015.0-015.9). Excludes: gonococcal arthritis (098.50), meningococcal arthritis (036.82)

FAQ

How often should patients with leprosy be monitored?Monthly follow-up is recommended

How long after treatment can relapse occur?Relapse can occur 10 years or more after completionof treatment; thus, long-term follow-up is needed

Why is the incubation period so long? M. leprae divides very slowly (approximately once every 2weeks)

Why hasn't M. leprae ever been cultured in vitro ? M. leprae is an obligate mammalian pathogenthat has lost the metabolic gene products necessary for growth on artificial media, such asmycobacterial culture plates

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Who should manage patients with leprosy today—specialized treatment centers or generalinternal medicine clinicians and family practice physicians?If at all possible, patients with leprosyshould be managed locally by infectious disease specialists or dermatologists familiar with thediagnostic methods and standard treatment protocols. Treating the disease locally removes the stillextant social stigma associated with leprosy and facilitates access to family and social support. Expertassistance and advice is readily available from local or regional leprosy centers linked with public healthfacilities

Contributors

Lucileia Johnson, MD

William Harper, MD

Steven M. Opal, MD

Eleftherios E. Mylonakis, MD