Professional Documents
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22, 2009, 518537 Printed in the United States All rights reserved
DERMATOLOGIC THERAPY
ISSN 1396-0296
dth_1274
518..537
ABSTRACT: Leprosy, or Hansens disease (HD), is caused by Mycobacterium leprae, a slowly dividing mycobacterium that has evolved to be an intracellular parasite, causing skin lesions and nerve damage. Less than 5% of people exposed to M. leprae develop clinical disease. Host cell-mediated resistance determines whether an individual will develop paucibacillary or multibacillary disease. Hansens disease is a worldwide disease with about 150 new cases reported annually in the United States. Effective anti-mycobacterial treatments are available, and many patients experience severe reversal and erythema nodosum leprosum reactions that also require treatment. Leprosy has been the target of a World Health Organization multiple drug therapy campaign to eliminate it as a national public health problem in member countries, but endemic regions persist. In the United States, the National Hansens Disease Program has primary responsibility for medical care, research, and information. KEYWORDS: borderline, erythema nodosum leprosum, lepromatous, leprosy, Lucio phenomenon, Hansens disease, multibacillary, paucibacillary, reversal reactions, multiple drug therapy, tuberculoid
Introduction
Leprosy (synonyms: Hansens disease (HD), Hanseniasis, elephantiasis grecorum) is a chronic infectious disease with neural, skin, and upper airway mucosal involvement caused by Mycobacterium leprae. This bacillus was discovered by Dr. Gerhard Armauer Hansen in skin lesions of a leprosy patient in 1873, when leprosy was endemic in Norway (1).
Etiology
M. leprae is an acid-fast rod-shaped bacterium with parallel sides and rounded ends, 18 mm long and 0.3 mm in diameter. It is an obligate intracellular parasite that reproduces by binary ssion slowly, every 1213 days in the early logarithmic growth
Address correspondence and reprint requests to: Sophie M. Worobec, MD, Associate Professor of Clinical Dermatology, Department of Dermatology, College of Medicine, University of Illinois at Chicago, 1801 W. Taylor Street, Suite 3E, Chicago, IL 60612-7300, or email: drsophie@sbcglobal.net.
phase (mouse footpads), reaching the early plateau growth phase in 2040 days (2,3). Despite many attempts, researchers have been unable to culture it in vitro on any culture medium. It grows best at temperatures 2730C (8186F), below the core temperature of humans, and can remain viable for up to 5 months in the environment (4). M. leprae has been grown experimentally in normal mouse foot pads; in nine-banded armadillos, in monkeys, and in foot pads of immunodecient mice for investigational drug studies, including drug resistance and screening of new antibacterial treatments. Humans are the major host and reservoir of M. leprae but it has also been rarely isolated from chimpanzees, sooty mangabey monkeys, and cynomolgus macaques. It is also present in about 15% of wild nine-banded armadillos in the southern United States. Armadillos develop multibacillary disease and are the only veried environmental reservoir of M. leprae. Armadillos are mammals with a core body temperature in the 2833C range compared with 37C in humans. Armadillos dig in the soil, preferring
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moist soil near riverbeds and lakes in arid areas (5). Armadillo contact, especially eating armadillos, has been associated with development of human disease (6,7). Recent M. leprae genomic studies support the idea that humans migrating from Europe and Africa brought the European/North African SNP type 3 strain of M. leprae to the Americas (8) including the southern United States, long before the arrival of armadillos into the southern United States. Wild armadillos from Louisiana, naturally infected with M. leprae, have the European/North African SNP type 3 strain, consistent with their becoming infected after human migration brought leprosy to the Americas (9). M. leprae is unique among bacteria in its ability to infect peripheral nerves, with nonmyelinated Schwann cells being more susceptible to infection than myelinated ones. M. leprae has a specic cell wall phenolic glycolipid-1 (PGL-1) containing a trisaccharide that binds to the a2 side chain of laminin-2 on the basal lamina of Schwann cells. The M. leprae surface exposed protein, LBP21, also binds to laminin-2. Together, the combined binding of PGL-1 and LBP21 sufces to allow entry of M. leprae into the Schwann cell. M. leprae then causes early nerve demyelination by turning off myelin gene transcription as well as promoting myelin-free Schwann cell growth that triggers an inammatory response (10). The M. leprae genome was completely sequenced in 2001. It has undergone severe reductive evolution which renders it largely inactive (only 49.5% is protein coding), having 1600 genes encoding proteins, compared with the related Myobacterium tuberculosis genome being 91% protein coding and having 4000 genes producing proteins (11). The M. leprae genome has lost genes for catabolic and respiratory enzymes and other systems, explaining its limited ability to survive extracellularly (12). Several polymerase chain reaction (PCR) and reverse transcription PCR techniques can detect M. leprae DNA in tissue from patients, but despite being 100% specic for recognition of M. leprae DNA, such probes are no more sensitive than microscopic conrmation of M. leprae for diagnosing patients (13,14). The molecular basis for rifampin-, dapsone-, and ooxacinresistance has also been identied, and resistant mutant M. leprae isolates can be identied by PCR DNA amplication of specic DNA fragments from skin biopsy specimens followed by molecular analyses (1315). In all M. leprae strains isolated worldwide, no variation of the 16S ribosomal RNA (rRNA) gene had been found until 2008, when a variant myco-
bacterium with a proposed name of Mycobacterium lepromatosis was isolated and identied by molecular techniques in tissue samples from two patients who had died in Arizona. The two patients had diffuse multibacillary disease of a leprosy variant called diffuse lepromatous leprosy (DLL), diffuse leprosy of Lucio and Latapi, or leprosy with the Lucio phenomenon (LP) (16). The same bacillus genome has also been identied in two previously reported fatal DLL cases from Singapore (16,17). The M. lepromatosis (sp. nom. prov.) genome differs from previously reported M. leprae genome strains in 2.1% of the 16S rRNA gene and in 614% mismatches among ve less conserved genes (16). Researchers have not yet reached a consensus to classify it as a new species, subspecies, or as a separate strain of M. leprae.
Epidemiology
Less than 5% of people exposed to M. leprae develop clinical disease, although subclinical infection with antibody formation to PGL-1 occurs in 1.735% of people living in endemic areas. These tests are reective of past exposure in an endemic area and are not helpful in making a diagnosis of leprosy. The modes of leprosy transmission are not known, but could possibly occur by: (i) exposure to nasal and oral secretions of patients harboring bacilli, (ii) skin to skin contact, (iii) congenital transmission (18), (iv) dermal inoculation via tattoo needles (19), (v) from infected soil or sphagnum moss, and (vi) exposure to insect or arthropod vectors (12). Nasal inhalation of M. leprae with bacilli lodging on the inferior turbinates, followed by a brief bacteremia, followed by bacilli binding to Schwann cells and macrophages, is a widely accepted leprosy transmission hypothesis (14,20). Epidemiological studies show that household contact with a person with untreated multibacillary disease in an endemic area carries an eventual risk of disease of up to 10% with children being at greater risk. Brazil reports 80% of HD cases in the Americas. A recent case-control study in northeastern Brazil (21) showed a low level of education (correlating with poverty); having ever experienced food shortage; bathing weekly in open water (creek, river, or lake); hunting or shing 10 years previously; low frequency (< biweekly) of changing bed linens or hammocks (indicating lack of access to fresh water); and living in a house with a sand or mud oor were signicantly associated with leprosy. These risk factors indicate that both direct and indirect modes of transmission can occur.
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Prior BCG vaccination was protective, corresponding to a vaccine effectiveness of 52%, which matches the protective effect seen in other studies. In 1991, the World Health Assembly passed a resolution to eliminate leprosy as a public health problem by the year 2000. Elimination per countrywide status was dened as a prevalence of less than 1 case per 10,000 people in any single country. The World Health Organization (WHO) leprosy elimination campaign mobilized leprosy control programs in the developing world and provided anti-mycobacterial chemotherapy to at least 11 million patients. In 2007, the WHO reported that leprosy was eliminated from 118 countries out of 122 countries where leprosy was considered as a public health problem in 1985 (22), with leprosy remaining prevalent above elimination levels in only four countries. As shown in FIG. 1, by the start of 2008, both D.R. Congo and Mozambique had reached WHO elimination status. Timor-Leste, not an independent country in 1985, was added to the list of countries not achieving elimination status (23). The WHO reported that the number of registered patients fell from 5 million in 1985 to 700,000 in 2001 and to 212,802 in early 2008 (23). This drop
was accompanied by a change in case denition to include only those patients with active disease who are undergoing multidrug therapy, and a halving of treatment duration time (24). Patients completing the ofcial WHO treatment regimen are considered free of the disease. However, at least 14 million people worldwide who have nished antimicrobial treatment still suffer complications as a result of leprosy, and leprosy remains a leading cause of neurological disability in developing countries. The WHO criterion for elimination does not equate to eradication (24); leprosy remains endemic in many areas (25) (FIG. 2). In 2009, leprosy is still present (i.e., not eradicated) in Asia, the Caribbean, parts of North America; Central and South America, parts of Europe (Spain, Portugal, Italy, Greece), parts of Australia, and Africa. India, which has the worlds highest number of patients who have had or have leprosy, reached WHO national level elimination status in December 2005 (26). Pockets of high endemicity remain in some areas of Angola, Brazil, Central African Republic, Democratic Republic of Congo, India, Madagascar, Mozambique, Nepal, and United Republic of Tanzania (25). In endemic areas, leprosy is still a public health
FIG. 1. Countries with leprosy less than WHO elimination levels: 1985 and 2008 (used by permission of The Nippon Foundation).
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problem requiring attention to early diagnosis, adequate anti-mycobacterial chemotherapy, early management of nerve damage, and follow-up postchemotherapy with attention to possible relapses, reactional states, and care of disabilities and rehabilitation as needed (27). Although eradication of leprosy may yet require generations to achieve, control is now possible through sustained efforts at early detection and treatment (28,29). It is a mystery why in some countries such as Norway, leprosy completely disappeared prior to effective chemotherapy and despite lack of total isolation. Between 1856 and 1920, case detection rates in Norway declined from 36.9 per 100,000 person-years to 0.3 per 100,000 person-years. Some researchers theorize that improvement in living conditions and an isolation policy led to decrease in transmission (30). HD is a reportable disease in the United States. It has been endemic in Louisiana, Texas, and Hawaii. Puerto Rico, American Samoa, and some US Trust Territories also have endemic areas. In 2006, a total of nine HD cases were reported from Hawaii, and one from Puerto Rico. The 2006 reports from Hawaii were almost entirely among immigrants from Micronesia or the Trust Territories where HD is endemic (31). FIG. 3 shows the annual number of new HD cases reported in the United States (31,32). A total of 7166 HD cases were registered in the United States from 1976 through the end of 2006. In 2006, there were 137 new cases from 30 states with an age range of 783 years. Nationwide in 2006, 116 (85%) of the 137 newly registered patients had been born outside the United States. Others were US-born individuals who have lived for extended periods in endemic areas, both within the United States and also ex-United States. As FIG. 4 shows, the states with the highest numbers of cases (92/137 or 67%) were California, Florida, Louisiana, New York, Massachusetts, and Texas. A total of 20 pa-
tients were reported from Texas (11) and Louisiana (9) of whom half were US-born individuals with no history of living outside the United States (31).
Genetic factors
Although only about 5% of exposed individuals develop clinical disease, subclinical infection is probably common: there is no test for detecting exposure to the bacillus and subsequently mounting a protective immune response (13,14). Leprosy sometimes clusters in families, and twin studies have shown higher concordance rates for disease susceptibility among monozygotic twins (6085%) than in dizygotic twins (520%) (33,34). The human Nramp1 gene (now designated SLC11A1) on chromosome region 2 q35 has been linked to leprosy susceptibility among Vietnamese families, but may be only one of several genes contributing to disease susceptibility (35). A locus in the promoter gene of PARK2 and a coregulated gene PACRG, has been associated in a Vietnamese patient population and a second analysis of Brazilian patients with overall susceptibility to M. leprae infection (36). This was the rst report of a positional cloning being used to identify genes with susceptibility to an infectious disease in two unrelated populations. These two genes also have a close linkage to early onset Parkinsons disease susceptibility genes (37) and are expressed in both Schwann cells and macrophages. Two genetic studies have linked HLA-DR2 and DR3 with the development of tuberculoid HD, and in one study, with both lepromatous and tuberculoid HD. HLA DQ1 has been linked to development of lepromatous leprosy. Other studies have looked
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at microsatellite markers on chromosome 10p13, the TAP2 gene, tumor necrosis factor alpha (TNF-a) gene alleles and human Toll-like receptors, and the human vitamin D receptor gene (VDR) alleles and their associations with development of leprosy (13). Polymorphisms in Toll-like receptor 4 (TLR4) have been associated with protection against leprosy among Ethiopians (38).
ings and reects the individual patients immune status in ghting the disease. It guides the choice and length of antimicrobial therapy and predicts the probability and type of reactions. The average number of bacteria seen using an oil immersion objective are quantied on Ridleys logarithmic scale, called the Bacterial Index (BI) which varies from 6+ to 1+ as follows: 6+ Many clumps of bacilli (over 1000) in an average eld 5+ 1001000 bacilli in average eld 4+ 10100 bacilli in average eld 3+ 110 bacilli in average eld 2+ 110 bacilli in 10 elds 1+ 110 bacilli in 100 elds Organisms which stain solidly are considered viable and nonviable organisms stain in a granular, beaded, or irregular pattern. This observation, that granular staining bacteria are nonviable, was rst proposed by Hansen in 1895 (1). The morphological index (MI) is the % of solid staining bacteria, based on examining 200 red-staining bacteria lying singly, not in globi, and the MI is used to monitor whether a patients disease is active, and response to treatment. An increased MI indicates worsening and a decreased MI indicates improvement. Unavailable in the United States, and not Food and Drug Administration (FDA)-approved for skin testing, lepromin is a heat-killed M. leprae sonicate preparation, which on skin testing causes a strong reaction in patients at the tuberculoid pole with a strong cell-mediated immunity (CMI) TH1 response, but causes no response in patients at the lepromatous pole with specic anergy to M. leprae. Lepromin testing provided the rst conrmation that specic host immunity was responsible for determining polarity on the Ridley Jopling classication system (15,42). However, the lepromin test is not diagnostic of leprosy because many people who have never been exposed to M. leprae will have a positive reaction. Read at 4 weeks (unlike the Day 2 or 3 readings of tuberculin tests), it essentially measures a persons ability to mount a granulomatous response to mycobacterial antigens (13,15).
Indeterminate leprosy
One or several (1) hypopigmented or faintly erythematous patches (FIG. 7) are found in persons who are susceptible to infection and whose immunological status is still to be elucidated. There may be sensory loss of temperature
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High resistance Borderline Tuberculoid tuberculoid (TT) (BT) Number of lesions Bacillary load Lepromin test reactivity Histology 1-3 0 3+ Few 1+ 2+
Little or no Unstable resistance resistance Borderline Borderline Lepromatous Lepromatous (BB) (BL) (LLsp and LLp) Few or many Numerous and Many asymmetrical symmetrical 2+ + 3+ + 4+ 0
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discrimination, or ability to feel light touch, and it should be in the differential diagnosis of an individual who lives or has lived in an endemic area or is a family/household member of an index case. The differential diagnosis includes pityriasis alba, pityriasis versicolor, postinammatory hypopigmentation, and hypopigmented vitiligo (44). Pfaltzgraff and Bryceson cautioned that especially in children, the diagnosis should not be made unless there is a conrmatory biopsy (45). For suspected indeterminate HD, the optimal biopsy site is the center of the lesion (46), unlike dened cases, where the optimal biopsy site is within the active lesional border. In the United States, some HD specialists will biopsy both a central and a border lesional area. There is no reason to include adjacent normal skin. Usual biopsy size is 4 mm, but Ridley and Jopling preferred a 5-mm biopsy. The biopsy should include the entire depth of the dermis and be into the upper subcutaneous fat (1). Skin histological ndings may show a histiocytic or lymphocytic inltrate, with reaction around or within a dermal nerve or in the subepidermal zone or around arrector pilaris muscles. AFB are absent or scanty according to the histologic description given by Ridley and Jopling (42). However, Scollard et al. have cautioned that an indeterminate diagnosis should only be applied if both nerve involvement and AFB are seen because a diagnosis of HD
can have signicant impact on a patient and his/ her family (13).
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tive surface, except on the face where the rich dermal nerve supply may result in preservation of sensation. About 30% of nerves have to be destroyed before sensory impairment can be detected, therefore pain may be the rst neurological symptom (1). Temperature discrimination may be the rst sensory modality lost within facial lesions. Often an enlarged nerve is palpable nearby, e.g., an ulnar nerve if the skin lesion is near the elbow. Skin histology consists of small tuberculoid granulomas, sometimes with Langhans giant cells present, with well-organized lymphocytic mantles consisting of mostly CD4 positive cells, around neurovascular bundles. The Grenz zone may be involved, unlike the Grenz zone sparing seen in multibacillary disease. Few or no AFB may be seen. Dermal nerves can be swollen by epithelioid granulomas, or completely destroyed, or sometimes contain AFB and/or areas of caseation necrosis. Borderline tuberculoid (BT) Skin ndings. Clinical ndings are similar to that of TT HD but with more numerous skin lesions and smaller satellite lesions around the larger lesion; however, solitary lesions can occur but are larger (FIG. 9), often over 10 cm in diameter (15,47). Skin histology shows a narrow Grenz zone, with more diffuse granulomas with less frequent or absent foreign body giant cells; dermal nerves show moderate inltration or only Schwann cell proliferation. A few AFB may be found in the nerves, but not lying freely in the dermis.
Enlarged supercial nerves may be found, the most common ones being the ulnar, median and radial cutaneous, common peroneal, posterior tibial and sural, and the great auricular and zygomatic arch of the facial nerves. It is wise to remember that even in normal, very lean muscular individuals, the ulnar and the great auricular nerves can be palpable (48). It is important to become familiar with normal nerve size by practicing on many disease-free individuals and to palpate the nerve on the opposite side of the body for comparison (49). A diagnosis of HD cannot be based solely on nding an enlarged nerve as these ndings are consistent but not diagnostic, and need conrmatory evaluation. Borderline (BB) Skin ndings. Lesions are more numerous, generalized but still asymmetrically distributed but less well dened and smaller satellite lesions are common (FIG. 10). Histology differs from BT in that AFB can be found in the dermis as well as in nerves, there is a dened Grenz zone, and granulomas are mostly epithelioid with few lymphocytes and no giant cells. Nerves show slight swelling and cellular inltration. Borderline lepromatous (BL) Skin ndings. There may be a single original or rst appearing lesion, or symmetrical lesions that are too numerous to count which consist of macules,
Hypopigmented skin lesion with palpable enlarged great auricular nerve (marked by arrows)
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FIG. 10. BB Hansens disease. Treated irregular annular lesion on elbow with smaller satellite lesions and redbrown clofazimine hyperpigmentation. FIG. 11. Borderline lepromatous Hansens disease with widespread erythematous plaques containing islands of clear skin within the plaques (image courtesy of Dr. Thomas H. Rea, Los Angeles).
papules, plaques, and nodules. The classic dimorphic lesion: annular with diffuse outer border and sharply demarcated inner border is seen in 1/3 of patients. But many variations are seen, ranging from annular lesions with sharply demarcated inner and outer margins or poorly dened plaques with well-demarcated Swiss cheese type islands of clearing within the plaques (15) (FIG. 11). If multiple lesions are present, the smaller lesions predominate and there is no sensory loss over the lesions. Nerve involvement appears later and tends to be symmetrical. Classic ndings of polar lepromatous disease such as saddle nose, madarosis, and leonine facies are usually not present (47). Dermal histology shows macrophage granulomas with slight foamy change and lymphocytes in clumps or widely distributed among the granulomas. Dermal nerves can show an onion skin lamination, and have a cellular inltrate. There is a clear Grenz zone and many AFB are present in clumps, globi (clumped within a distended macrophage) or singly. Polar lepromatous (LL) This stage starts from indeterminate HD in those with little resistance, or as a downgrading progression of BL HD (15). Diffuse dermal inltration is always present and can be nodular or non-nodular. Findings can include small hypopigmented macules similar to that seen in pityriasis versicolor but symmetrically distributed all over the body, or consist of lepromatous inltrates that can be
diffuse, plaque-like, or nodular. Macules are ill dened and show no sensory loss or loss of sweating. Sweating is eventually lost with compensatory hyperhidrosis in areas of sparing. Hair loss starts over the lateral third of the eyebrows, then may involve the eyelashes (madarosis) and the body but scalp hair is preserved (FIG. 12). Nodular inltration can be seen on acral parts: the earlobes, nose, chin, elbows, hands, buttocks, and knees. These nodules can enlarge and destroy underlying structures such as the nasal cartilage causing a saddle nose deformity and erode the alveolar ridge leading to loss of teeth. Epistaxis is a common early nding; leonine facial nodular inltration can be seen in advanced disease. Skin histology shows attening of the epidermis with a clear Grenz zone, with a deeper diffuse foamy histiocytic inltrate with few lymphocytes and plasma cells. The foamy appearance is a result of lipids in the M. leprae cell walls and a Fite stain shows numerous AFB in globi or lying freely within the dermis. Sensory loss tends to be symmetrical over the distal limbs (starts in a glove and stocking distribution). Peripheral neuropathy can occur in diabetes mellitus, vitamin B12, and/or folate deciency and alcoholism. These other diseases can coexist and should be screened for and treated if present, but they do not cause the nerve enlargement seen in
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leprosy. Bone involvement can contribute to osteoporosis and fractures. Testicular involvement can result in gynecomastia and testicular atrophy with complaints of impotence and infertility. LL has been subdivided into polar (LLp) and subpolar (LLs) types. In LLp, reactional states do not occur as there is no upgrading toward greater immune resistance. Patients with LLs are prone to severe reactional states because of their bacterial burden.
nodes, bone marrow, liver, and spleen being heavily infected. Secondary amyloidosis with renal impairment and glomerulonephritis (1) was more common prior to the multidrug therapy (MDT) era. Glomerulonephritis may be seen in patients undergoing ENL reactions. The diffuse lepromatous leprosy (1,15) variant has been called beautiful leprosy, (Spanish: bonita lepra) because in its early stages it causes skin smoothening and a younger appearance and is not associated with nodules. Later, telangiectasia, madarosis, hoarseness, arthritic symptoms, and glove stocking sensory loss have been noted. It is most common in Western Mexico, Costa Rica, and along the Caribbean and rarely seen elsewhere, although recently two fatal cases were reported from Singapore and rare cases have been reported throughout the world (17). Slit skin smears can be positive for AFB and dermal blood vessels can show numerous AFB bacilli within vascular endothelial cells. These patients are at risk for a very dangerous vasculitic reactional state called Lucio phenomenon which causes stellate necrotic ulcers especially on the lower extremities and a bluish discoloration of hands and feet. The condition is often complicated by secondary infection and sepsis, and can be fatal.
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Multibacillary
Adjust dose for child less than 10 years on basis of body weight: rifampin 10 mg/kg monthly and dapsone 2 mg/kg daily (26). Adjust dose for child less than 10 years on the basis of body weight: rifampin 10 mg/kg monthly, clofazimine 1 mg/kg daily and 6 mg/kg monthly, dapsone 2 mg/kg daily (26). Note: The standard child blister pack may be broken up so that the appropriate dose is given to children under 10 years of age. Clofazimine can be spaced out as required. The WHO states that, A patient with a high BI may rarely need to be treated for longer than 12 months. Only specialists at referral centers should make this decision.
b
areas of the body (earlobes, elbows, and knees). These smears were examined for AFB and the patients were considered paucibacillary if the smears are negative and the patient had ve or fewer skin lesions, and multibacillary if the smears are positive for AFB. In 1998, the WHO eliminated requiring slit smear examinations for AFB and any neurological assessment (24), and adopted the following simplied, but controversial, classication system for eld programs:
Paucibacillary single lesion leprosy (one skin lesion present), Paucibacillary leprosy (two to ve skin lesions), and Multibacillary leprosy (more than ve skin lesions).
Treatment
WHO treatment recommendations A WHO Study Group recommended MDT in 1982 because of increasing resistance to dapsone, which is weakly bacteriocidal against M. leprae. MDT consists of three drugs: dapsone, rifampin, and clofazimine. Rifampin is the most effective bactericidal drug against M. leprae, with patients considered noninfectious within several days of rifampin therapy. Clofazimine is weakly bactericidal and has some anti-inammatory action. In combination, dapsone and clofazimine potentiate each other and the use of triple combination therapy hinders the possible development of rifampin drug resistance. Other drugs with strong bactericidal effects include: minocycline, clarithromycin, ooxacin, and levooxin (12,15).
The WHO posits that MDT is safe, effective, and easily administered under eld conditions. Table 1 shows the MDT currently recommended by the WHO (50). The WHO has shortened the treatment period for multibacillary disease to 1 year, a change that remains controversial (12,14,27). Currently, ex-United States, the WHO has provided free MDT in convenient monthly calendar blister packs to all patients who qualify for treatment. Since 1995, drug funding was provided by the Nippon Foundation and since 2000, through Novartis and the Novartis Foundation for Sustainable Development. The WHO recently recommended a single-dose treatment, consisting of rifampin, ooxacin, and minocycline (ROM) for paucibacillary patients who have a single skin lesion (51). This recommendation assumes that the host response will eliminate any residual viable bacteria. However, longer therapy whenever possible is also recommended. The rationale for more extended treatment is as follows: not all single lesions are paucibacillary, and not all bacterial organisms in a lesion are metabolically active, in which state they are susceptible to these drugs, over a single time interval. Leprosy lesions are not a synchronous culture of bacteria which can be instantaneously killed (52). The half lives for these drugs are 35 hours for rifampin, 78 hours for ooxacin, and 1218 hours for minocycline, and any dormant bacteria will not be affected by this drug combination (52). Therefore, especially if this treatment approach is used under eld conditions, in which slit skin smears (which would have a negative BI in paucibacillary disease) or skin biopsies are not done as part of initial evaluation to conrm
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a Only available as an investigational new drug (IND) through the NHDP, which holds the IND for its use in the United States for treating Hansens disease (HD). In order for physicians to obtain the drug for treating HD, they have to be registered as an investigator under the NHDP IND. b This drug is recommended in place of clofazimine, as clofazimine cannot be used in children in the United States.
paucibacillary disease, it is essential that long-term follow-up be carried out. A reason for relapse posttreatment is initial mistaken diagnosis of multibacillary disease as paucibacillary when resources for bacteriological assessment are lacking. Worldwide, including in developed countries, treatment failure may result from: noncompliance, drug resistance, relapse after apparent cure, and persistence. Persisters are viable M. leprae that in mouse foot pad resistance studies are sensitive to all anti-mycobacterial agents given, but persist in the patients macrophages and nerves despite bactericidal tissue levels. The nding of persisters correlates with relapse 69 years after nishing MDT. Therefore, patients should be followed at least annually after nishing treatment whenever possible for signs of relapse, reaction, and nerve damage (47). The WHO recommends screening of household members and family at time of patient diagnosis, along with education about possible clinical signs of leprosy. Treatment of leprosy includes not only antimycobacterial chemotherapy, but also patient education about the disease, treatment of reactions, monitoring for and care of nerve damage, care of any disability, social support, physical and occupational therapy, and rehabilitation.
Table 2 gives general NHDP medication treatment guidelines for immunologically competent patients (54,55). The NHDP also recommends the following alternative anti-microbial agents:
Minocycline, 100 mg daily, can be used as a substitute for dapsone in individuals who do not tolerate this drug. It can also be used instead of clofazimine, although evidence of the efcacy of its anti-inammatory activity against Type 2 reactions is not as substantial as the evidence for clofazimine. Clarithromycin, 500 mg daily, is also effective against M. leprae, and can be used as a substitute for any of the other drugs in a multiple drug regimen. In children, this drug is recommended in place of clofazimine, as clofazimine cannot be used in children in the United States. Ooxacin, 400 mg daily, may also be used in place of clofazimine, for adults. This is not recommended for children.
For immunologically compromised patients, these protocols may be modied, and consultation with the NHDP is recommended. In the United States, the occurrence of leprosy in children is rare. The NHDP strongly recommends contacting the NHDP for management of leprosy in children. Five-year follow-up every 6 months is recommended in the United States for paucibacillary cases and 10-year follow-up at 6-month intervals for multibacillary patients. Examination of household and family contacts at time of diagnosis and annually is also recommended. Patient and accompanying person(s) education about the disease and reactional states is vital. Adjunctive therapies are targeted at prevention of ocular, neurological, orthopedic impairments along with cosmetic surgery as needed (e.g., for nasal reconstruction, replacement of hair at lateral eyebrows) as well as provision of occupational and physical therapy.
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Same patient one year after T1R treatment & continued antimicrobial regimen.
T1R with neuritis should be treated immediately as an emergency as there is risk of permanent nerve damage and loss of function even within the rst 24 hours. Skin necrosis can cause permanent scarring, color change, or atrophy. Prednisone at 4060 g (0.51 mg/kg) daily is the treatment of choice and should be started immediately and dosage adjusted downwards or upwards as response is achieved/not achieved. Treatment may be needed for 46 months and tapered very slowly; alternate day dosage may be tolerated. If a nerve continues to be painful whereas others improve, neurosurgical evaluation for decompression of a nerve abscess has been recommended; however, the efcacy of this surgical intervention has not been demonstrated conclusively (10). Cyclosporin in doses of 510 mg/kg can be used if prednisone fails to control the reaction or as a steroid sparing agent. Azathioprine acts slowly and has no effect on intraneuronal edema and should only be used as a long-term CS sparing agent (60). Mycophenolate mofetil (MM) is more expensive than azathioprine and its use was reported in three patients with different reactional states with one (a BL patient with T1R) beneting and the MM had to be stopped after 3 months as a result of severe gastrointestinal side effects (61). Methotrexate (MTX) has been used very successfully as a CS sparing agent (62). HIV-1 and M. leprae co-infected patients have developed T1Rs leading to their being diagnosed with HD, as part of immune reconstitution inammatory syndrome (IRIS) after effective chemotherapy of their HIV disease (63). T1R reaction occurs as part of IRIS, in co-infected patients, as the CD4 T helper cell count increases, at time intervals of 6 weeks to 6 months poststart of highly active antiretroviral therapy (HAART). In BT disease, this T1R can be as subtle as a single
erythematous edematous plaque with skin biopsy conrmation need to establish diagnosis (64). If neuritis occurs in these co-infected HD-HIV patients suffering from T1R reactions, CS therapy is indicated with close monitoring for accelerated development of Kaposis sarcoma, avascular bone necrosis, and activation of cytomegalovirus and Mycobacterium avium infections (65). Type 2/ENL reactions (FIG. 14) occur within 2 years of starting antibacterial therapy and present clinically with eruptive painful erythematous nodules and plaques over the entire body along with fever, anemia and joint swelling, and pain. The nodules, in severe reaction, may develop bullae, pustules, or necrosis. Severe ENL has systemic symptoms of fever and malaise, and can manifest arthritis, dactylitis, uveitis, iridocyclitis and episcleritis, neuritis, lymphadenitis, myositis, and orchitis (1,15,66). In the absence of an awareness of HD, ENL may be initially misdiagnosed as lupus erythematosus or seronegative rheumatoid arthritis. ENL reactions are very responsive to thalidomide, which is available in the United States through the Celgene Corporationss System for Thalidomide Education and Prescribing Safety (S.T.E.P .S.) program. In the United States, only physicians who are registered with the S.T.E.P.S. program can prescribe thalidomide. It is teratogenic, causing phocomelia, and should not be given to women of childbearing potential unless they are enrolled in the S.T.E.P.S. program and on several forms of birth control. The initial recommended dosage is up to 400 mg daily for those weighing over 50 kg. It is sedating and preferably given at bedtime. Lower doses of 100200 mg can be tried in less severe ENL, or in combination with prednisone for more severe ENL. Thalidomide can also cause a sensory neuropathy, which is rare in HD
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patients but has been reported and can limit its long-term use. Other adverse effects include but are not limited to: dizziness and orthostatic hypotension, neutropenia, and hypersensitivity reactions. Male patients using it can excrete it in semen and must use a latex condom when having sexual contact with a woman of childbearing potential, and should not donate sperm. Patients who have received thalidomide for the treatment of multiple myeloma have had an increased risk for venous thrombolic events, therefore all patients receiving this drug should be advised to seek immediate medical help if they develop signs and symptoms of thromboembolism. Prednisone is also effective and provides rapid relief when thalidomide is unavailable or cannot be used. High doses exceeding 60 mg daily (0.5 mg1 mg/kg) may be needed. Clofazimine in high doses of 300 mg daily has also been used (15), but is not uniformly successful (14). Many patients intensely dislike the skin pigmentation it produces. There is a report of a 52-year-old woman with persistent severe ENL despite the use of prednisolone 40 mg daily, thalidomide 300 mg daily starting dose, and pentoxifyline 400 mg TID; being treated with iniximab. Iniximab 5 mg/kg was infused IV over 4 hours after premedication with intravenous prednisolone 25 mg, and 1 gram acetaminophen and 10 mg cetirizine orally with improvement noticed within several hours; the infusions were repeated at Weeks 2 and 6 with no further treatment and no signs of ENL for 1 year after the last infusion (67). Another patient with severe ENL had MTX added to corticosteroid therapy, as thalidomide was not available, with excellent control of
ENL (68). Because of high bacterial loads in BL and LL disease, ENL may persist for several years. A strong family support system and caring staff is essential to help a patient through this. LP is a rare, poorly understood vasculitic reaction, which occurs in DLL. Most patients who develop it have had undiagnosed DLL and not been previously treated for HD. Its cause is unknown and it is often accompanied by profound anemia (69). Early signs may include irregularly shaped erythematous patches that darken and heal or progress to bullae with underlying necrosis, leaving deep irregularly shaped stellate ulcers, most commonly below the knees, that are painful and slow to heal. LP is treated by intensive wound care and watchfulness for complications of secondary infection and sepsis. CS and thalidomide are ineffective (14). Rea and Modlin have reported that new lesions of LP cease once rifampin therapy is started (15). Both cryoglobulinemia and antiphospholipid antibodies have been reported in this reaction and plasmapheresis therapy may be helpful (14). In the United States, consultation with the NHDP is recommended (69).
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treatment for single lesion paucibacillary treatment until after delivery (71). Clofazimine can cause pigmentation of the infants skin during lactation (69). Dapsone in the mothers milk can induce hemolysis in the infant (15). Dapsone, rifampin, clofazimine, clarithromycin, ooxacin, and levooxacin are Food and Drug Administration (FDA) Category C, which means that fetal risk cannot be ruled out, but the potential benets may outweigh the risk. Minocycline (FDA Category D: Positive evidence of risk) should not be used during pregnancy. Consultation with the NHDP physicians is appropriate for patients in the United States. CMI is suppressed during pregnancy and restored after parturition. ENL reactions occur throughout pregnancy and lactation and can be severe. For 70 years, retrospective reports have documented the rst diagnosis of leprosy, or worsening symptoms during pregnancy. This may be partly a result of increased medical care contact during pregnancy. In 1981 prior to the uniform use of MDT, Duncan et al. showed in an prospective study that reversal reactions (T1R) and neuritis were more frequent in the immediate postpartum period (72). There is a lack of prospective case-controlled studies on the course of MDT-treated leprosy during pregnancy and the effect on mothers and the subsequent development of children (73). In 2007, Duncan et al. published a follow-up prospective, open-ended cohort study which started in 1975 with follow-up of mothers and their children until 2003, about the development of children of mothers with leprosy: they had lower birth weights, smaller placentae, grew more slowly, and had higher infant mortality with delay of the pubertal growth spurt and menarche for the girls, with catch-up by the late teens. The changes were most marked in children of mothers with lepromatous, especially LL disease (74). A very complex treatment management case has been described of a 31-year-old woman, with no prior diagnosis of leprosy, being diagnosed postpartum with BT disease and neuritis with T1R, and treated with the WHO regimen for paucibacillary disease and prednisone 40 mg daily who then developed a perforated duodenal ulcer which was successfully treated, followed by u-like symptoms and rifampin-induced hemolysis complicated by acute renal failure; rifampin was stopped and her prednisone dose was increased along with supportive care followed by recovery of renal function and continued treatment of her HD and neuritis (75).
HD and tuberculosis (TB) Newly diagnosed HD patients should be screened for TB prior to initiating treatment. Rifampin should be adjusted upwards to doses appropriate for TB treatment. HD and HIV disease No change in standard treatment of HD. Rifampin, especially if given daily, can decrease levels of antiprotease inhibitors. Drug intolerance because of side effects or comorbidities, e.g, allergy, G96PD deciency, or hepatitis Consultation with the US NHDP is recommended for alternate therapeutic regimens. HD unmasked after treatment with biologicals for arthritic symptoms Recently, a Louisiana man with diffuse polyarthritis and a Texan woman with rheumatoid arthritis after receiving iniximab, were diagnosed with leprosy. The diagnosis in both was established clinically and histologically, and conrmed by molecular identication of M. leprae DNA in the biopsy specimens. The man had no signicant contact with armadillos, and no known prior HD nor contact with humans with HD. The second patients husband, who had died the prior year, had hunted and handled armadillos; had a rash and numbness of his hands and feet but had avoided doctors; and had no medical diagnosis for these problems. Neither patient had traveled outside the United States. Their cases illustrate two important points: 1. M. leprae infection progressed more rapidly in both of these patients than is typical. They were diagnosed with BL HD within 12 years after receiving iniximab, which is shorter than the typical incubation time for multibacillary HD. Both patients probably had preexisting, subclinical HD, and this disease progression is comparable with the activation of latent tuberculosis after iniximab treatment. 2. After the iniximab was stopped, both patients developed Type I lepra reactions which happens in about 40% of BL patients (76). One of them, who had also been treated with MTX, had re-occurrence of the T1R, after the MTX was stopped, indicating a protective effect of the MTX on suppressing T1R. Scollard et al. have theorized that, The reactions in our patients
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may have been the result of rapid restoration of preexisting immunity that had been transiently impaired by iniximab treatment, which is similar to the T1Rs that occur as an immune reconstitution phenomenon in persons with HD and AIDS after receiving HAART (77). A 47-year-old Brazilian man presenting with joint pain and swelling, and no known family nor personal history of leprosy, was treated in Florida for seronegative rheumatoid arthritis with prednisone 10 mg/day, MTX 20 mg /week for 5 months without improvement, followed by adalimumab 40 mg, two doses subcutaneously 2 weeks apart. Five weeks after his last adalimumab dose, he developed erythema and edema of his ears, hands and feet, and over 50 erythematous and edematous papules and plaques on his trunk. His neurosensory examination was normal. Skin biopsy and slit skin smears showed granulomas and were positive for AFB with BIs of +1 to +4, with globi, and he was diagnosed with BT HD with T1R. Antimycobacterial MDT was initiated with dapsone 100 mg/day, minocycline 100 mg/day, and rifampin 600 mg monthly. Prednisone was increased to 60 mg daily and then tapered to 30 mg daily over 2 months with resolution of skin lesions. His initial joint pain and swelling may have been his rst sign of T1R which then worsened after stopping adalimumab, a TNF-a antagonist (78).
Role of US states in HD
Public health services of each state provide background information on infectious diseases, including HD. Several states (e.g., New York, Georgia) do not require reporting new cases of HD. The State of Louisiana Ofce of Public Health has an Infectious Disease Epidemiology Section website with an exceptionally lucid, well-written manual on HD (79). The NHDP collects HD incidence in the states and provides annual statistical summaries.
control of the US Public Health Service as the National Leprosarium. In 1933, Sister Hilary Ross and Dr. George Fite started a laboratory for drug testing. From 1940 to 1947, Dr. Faget proved the efcacy of sulfone medications for the treatment of leprosy at Carville. From 1970s into the 1990s, while working at Carville, Dr. Robert Hastings made thalidomide available under an investigational new drug (IND) protocol for the treatment of ENL in the United States at a time when it was otherwise banned in the United States. Dr. Robert Jacobson headed research into drug resistance and the development of MDT leading to the United States Public Health Service (USPHS) recommending it in 1981, followed by WHO adoption of MDT in 1982. In 1981, Regional Hansens Disease Clinics were established by the USPHS to provide outpatient care throughout the United States for HD patients. Eleven community health programs were established in: Boston, Chicago, Los Angeles, Miami, New York, Puerto Rico, San Diego, San Francisco/ Martinez, Seattle, Texas, and Hawaii. Later, another center was added in Arizona. At present (2009), the NHDP maintains a network of Outpatient Hansens Disease Clinics and a Private Physician Program. Thalidomide is now available through the S.T.E.P .S. program and clofazimine is available through an IND held by the NHDP . The NHDP website www.hrsa.gov/hansens has information about its programs. The US Department of Health and Human Services also has toll free phone service at 1-800-642-2477, weekdays 9 am to 5:30 pm EST for consultation and/or referral to physicians nationwide who have expertise in treating HD (Hawaii: 1-808-733-9831).
Concluding remarks
Leprosy is a treatable disease that can be managed mostly on an outpatient basis. Severe reactions may require hospitalization. To eradicate any infectious disease, a highly effective vaccine is needed (13). Hopefully, the tremendous progress seen in the past decades in controlling this disease and dening the causative organisms will lead to further advances and prevention of infection.
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