LEPROSY (MUSCULOSKELETAL PBL) -2014-

Description:

o disease affecting skin and peripheral nerves caused by infection with Mycobacterium leprae(1, 2)

o M. leprae originally described by Hansen

Also called:

o Hansen's disease

Definitions:

o indeterminate leprosy - initial stage of leprosy, lesions may heal spontaneously (about 75%) or patient will progress along spectrum of leprosy based on interaction between organism and specific immune response mounted by host(2)

o spectrum of leprosy in order of decreasing cell-mediated response(2)

tuberculoid leprosy - few skin lesions (< 6) and low bacterial load borderline - unstable balance between cell-mediated immunity and bacterial replication

that can progress to either tuberculoid or lepromatous leprosyo borderline tuberculoid leprosy < 6 skin lesions that tend to be asymmetrically

distributed and well-circumscribedo borderline leprosy ≥ 6 skin lesions that are not clearly distinguishable as tuberculoid

or lepromatous by appearanceo borderline lepromatous leprosy ≥ 6 skin lesions that tend to be widely and

symmetrically disseminated with only slight erythema or hypopigmentation lepromatous leprosy - diffuse skin lesions and high bacterial loads

o leprosy reactions - episodic immunologically mediated acute inflammatory response that can occur in up to 1/3 of patients and may be associated with irreversible nerve damage and limb deformity, can occur in treated or untreated patients(1, 2, 3)

Type 1 reaction (also called reversal reaction)o inflammatory process associated with nerve damage if treatment inadequate or

delayedo peak occurrence within first 2 months of treatment but may occur up to 12 months of

treatment or after treatmento clinical manifestations include erythema, edema, and onset of new skin lesionso peripheral nerves may be tender with potentially dramatic loss of nerve function

(nerve damage may progress silently for prolonged periods)o occurs in borderline disease and may indicate a shift toward tuberculoid leprosy

Type 2 reaction (also called erythema nodosum leprosum [ENL])o systemic inflammatory responseo occurs only in patients with borderline lepromatous and lepromatous leprosyo clinical manifestations include fever with crops of small pink skin nodules and potential

for iritis, neuritis, lymphadenitis, orchitis, bone pain, dactylitis, arthritis, and proteinuria

o may start in first or second year of antimicrobial therapy with intermittent relapse over several years

o Lucio phenomenon(3, 4)

rare type of reaction restricted to Central and South America or patients with Mexican ancestry

diffuse infiltration of skin characterized by onset of symmetrical erythematous, black, stellate, necrotic lesions

(most common in lower extremities) significant nasal mucosa involvement may occur which can lead to subsequent nasal

destruction occurs with primary diffuse lepromatous leprosy (subtype of lepromatous leprosy) may occur within 3-4 years after onset

Types:

o World Health Organization (WHO) field classification when slit-skin smear not available single lesion, paucibacillary (1 patch) paucibacillary (2-5 patches) multibacillary (> 5 patches) Reference - World Health Organ Tech Rep Ser 1998;874:1 as referenced in(1, 2)

classification based on skin lesion count reported to result in misclassification of multibacillary leprosy and risk of undertreatment

o based on comparison with skin smear and Ridley-Jopling classification in 264 untreated patients with leprosy in the Philippines

o Reference - Clin Infect Dis 2007 Apr 15;44(8):1096   EBSCOhost Full Texto Ridley-Jopling classification (in order of decreasing cell-mediated immune response to M.

tuberculosis) only used with biopsy with bacterial index (BI) to measure acid-fast bacilli in dermis polar tuberculoid (in patients with intact cellular immune response) - high degree of cell-

mediated immunity with low bacilli count and delayed hypersensitivity, present with single lesion and BI value < 2 (equivalent to paucibacillary)

borderline tuberculoid - < 6 skin lesions, BI value < 2 (equivalent to paucibacillary) mid-borderline - ≥ 6 skin lesions, BI value ≥ 2 (equivalent to multibacillary) similar to

borderline lepromatous but has potential to move to tuberculoid pole, may be distinguished by appearance of skin lesion

borderline lepromatous - ≥ 6 skin lesions, BI value ≥ 2 (equivalent to multibacillary) polar lepromatous - patient has very low or no resistance with high bacilli and numerous,

poorly demarcated lesions throughout body, BI value ≥ 2 (equivalent to multibacillary) Reference - Int J Lepr Other Mycobact Dis 1966 Jul-Sep;34(3):255 as referenced in(3)

most patients have intermediate leprosy forms (borderline tuberculoid, mid-borderline, and borderline lepromatous)(1)

lepromatous leprosy occurs in patients with absence of specific cellular immunity but intact immunity to M. tuberculosis(1)

o pure neuritic leprosy (no skin involvement) reported in 4.6% of patients (179 of 3,853) attending leprosy clinic in India (Indian J Lepr 1996 Apr-Jun;68(2):137)

o multibacillary and borderline leprosy uncommon in childhood(2)

Who is most affected:

o residents of or immigrants from Brazil, Nepal, Mozambique, Democratic Republic of the Congo

(Wkly Epidemiol Rec 2007 Jun 22;82(25):225   EBSCOhost Full Text PDF)o males twice as often as females after puberty(1)

higher rate of deformity in women attributed to delay in presentation (Lepr Rev 2002 Sep;73(3):262)

Causes:

o Mycobacterium leprae(1, 2, 3)

acid-fast gram-positive bacillus very slow growing

Pathogenesis:

o transmission(1, 3)

via aerosol spread of nasal secretions with uptake through nasal or respiratory mucosa spread in body only occurs in patients with genetic susceptibility (associated with nramp1

gene) M leprae has tropism for macrophages and Schwann cells particularly peripheral nerve

Schwann cells and shows preference for growth in cooler regions of the body cannot pass via intact skin, not spread by touching transmission can continue for decades (Lepr Rev 2002 Dec;73(4):326 as referenced in(1))

o nerve damage(1)

M leprae replicates in Schwann cells slowly over years specific T cells eventually recognize mycobacterial antigens in nerve and initiate chronic

inflammatory reactions swelling in inflexible perineurium of peripheral nerve leads to ischemia and eventually

fibrosis with axonal deatho humans are primary reservoir, but 9-banded armadillo and mouse are susceptible to M.

leprae(1, 2, 3)

o M leprae is dependent on host metabolic products which may explain long incubation periods(1)

mean 4 years for tuberculoid leprosy mean 10 years for lepromatous leprosy can vary from months to 30 years

o clinical form of leprosy determined by patient's immunologic response to M. leprae(1)

deficient cell-mediated immunity results in lepromatous leprosy intact cell-mediated immunity results in tuberculoid leprosy, limiting scope of disease borderline form most common and can progress unpredictably toward either tuberculoid

or lepromatous leprosy(2)

Likely risk factors:

o recent immigrants from endemic countries(2)

o household contacts of persons with leprosy(1)

o infants of untreated mothers(4)

o independent risk factors observed in analysis of 21,870 contacts of 1,037 patients with leprosy in Bangladesh persons living under same roof and using same kitchen age - increased risk in persons aged 10-19 years and ≥ 30 years old blood relationship, especially first degree (genetic predisposition) type of leprosy - contact with patient with multibacillary, or paucibacillary with 2-5 lesions

associated with higher risk than single lesion paucibacillary

Reference - COLEP study (J Infect Dis 2006 Feb 1;193(3):346   EBSCOhost Full Text PDF)

o  novel M. leprae genotype associated with armadillo exposure in southern United States (N

Engl J Med 2011 Apr 28;364(17):1626   EBSCOhost Full Text)

Possible risk factors:

o genetic factors associated with variable susceptibility to leprosy  variants of genes in NOD2-mediated signaling pathway associated with susceptibility to

infection with M. leprae in genomewide association study with 706 patients and 1,225

controls (N Engl J Med 2009 Dec 31;361(27):2609   EBSCOhost Full Text), editorial can

be found in N Engl J Med 2009 Dec 31;361(27):2666   EBSCOhostFull Text,

commentary can be found in N Engl J Med 2010 Apr 15;362(15):1446   EBSCOhost Full Text

susceptibility loci on chromosome 10p13, based on genomes of 224 families from South

India (Nat Genet 2001 Apr;27(4):439   EBSCOhost Full Text) PARK2 and PACRG genes associated with susceptibility to leprosy, based on 975 unrelated

patients with leprosy cases and controls from Brazil (Nature 2004 Feb

12;427(6975):636   EBSCOhost Full Text) HLA DR2 and DR3 alleles associated with tuberculoid leprosy and HLA DQ1 associated with

lepromatous leprosy (Nat Rev Genet 2001 Dec;2(12):967   EBSCOhost Full Text as referenced in(1))

toll-like receptor 2 (TLR2) gene mutation more common in 45 patients with lepromatous leprosy compared to 45 patients with tuberculoid leprosy and 45 controls (FEMS Immunol Med Microbiol 2001 Jul;31(1):53)

polymorphisms in NRAMP1 gene associated with multibacillary leprosy in study of 273 patients with leprosy and 201 controls from Mali (Am J Trop Med Hyg 2001 Dec;65(6):733 PDF)

vitamin D receptor gene may be associated with tuberculoid and lepromatous leprosy (J

Infect Dis 1999 Jan;179(1):187   EBSCOhost Full Text)o leprosy as Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients

receiving antiretroviral therapy for HIV infection in countries where leprosy is endemic (BMJ

2007 Feb 3;334(7587):217   EBSCOhost Full Text full-text)o infliximab -- development of borderline lepromatous leprosy following treatment of rheumatoid

arthritis with infliximab and subsequent type 1 (reversal) reaction after discontinuation of

infliximab noted in 2 case reports (Clin Infect Dis 2006 Jul 15;43(2):e19   EBSCOhost Full Text PDF)

Factors not associated with increased risk:

o HIV infection does not appear to be associated with leprosy based on 3 case-control studies before highly active antiretroviral therapy was readily

available

Complications:

o leprosy reactions(1, 2, 3, 4)

spontaneous fluctuations in clinical state in addition to primary infection due to changes in immune response to M. leprae type 1 reaction (reversal reaction)

o occurs in 1/3 of patients with borderline formso inflammatory process associated with nerve damage and poor clinical responseo peak occurrence within first 2 months of treatment but may occur after treatmento clinical manifestations include erythema and edema of skin lesions

o peripheral nerves may be tender with potentially dramatic loss of nerve function (nerve damage may progress silently for prolonged periods)

o due to spontaneous increases in T-cell reactivity to mycobacterial antigenso infiltration of interferon gamma- and TNF-alpha-secreting CD4-positive lymphocytes in

skin lesions and nerves results in edema and painful inflammationo usually occurs in response to treatment initiationo often associated with shift from borderline leprosy toward tuberculoid formo MEDICAL EMERGENCY - rapid and sustained reversal of inflammatory process in type 1

reactions essential to prevent continuing nerve damageo risk factors for reversal reactions (in 594 newly diagnosed patients in Ethiopia followed

for 6-11 years) starting effective treatment borderline classification pregnancy or delivery within 6 months prior to diagnosis (later pregnancies not

associated with increased risk) having reversal reaction in first year after diagnosis (risk factor for later reactions) HIV diagnosis as risk factor for recurrent reversal reactions (based on 3 of 29

recurrent cases) Reference - Lepr Rev 2000 Sep;71(3):309

type II reaction (erythema nodosum leprosum)o occurs only in patients with borderline lepromatous and polar lepromatous leprosyo systemic inflammatory responseo reactive syndrome with fever, painful small pink skin nodules, malaise, wasting,

vasculitis and potential for iritis, neuritis, lymphadenitis, orchitis, bone pain, dactylitis, arthritis, and proteinuria

o may start in first or second year of antimicrobial therapy with intermittent relapse over several years

o can be triggered by treatment, vaccination, tuberculin skin testing or other immune system stimulation

o associated with high circulating concentrations of TNF-alpha and systemic toxicityo erythema nodosum leprosum develops in 10%-50% patients treated for lepromatous

leprosy (The Medical Letter 1996 Feb 16;38(968):15) Lucio phenomenon(4)

o occurs in primary diffuse lepromatous leprosy (subtype of lepromatous leprosy)o characterized by necrotic lesions of extremities and occasionally on faceo nasal mucosa significantly affected, often with nasal destructiono intermittent fever, lymphadenopathy and splenomegaly may occuro peripheral and ocular nerve involvement less frequent than with other subtypes of

lepromatous leprosy  clinical manifestations of leprosy reactions in patients with recent diagnosis in case report

(PLoS Negl Trop Dis 2009 Sep 29;3(9):e425   EBSCOhost Full Text full-text) pregnancy associated with increased risk for leprosy reactions (level 3 [lacking

direct] evidence)o based on review of retrospective case series and cohort studieso type 1 reactions more likely to occur during postpartum period, with both overt and

silent neuritiso type 2 (erythema nodosum leprosum) reactions may occur throughout pregnancy and

during lactationo no prospective, controlled studies found on complications of pregnancy in women

treated with multidrug therapy regimenso Reference - Int J Lepr Other Mycobact Dis 1999 Mar;67(1):6

leprosy reactions uncommon in childhood(2)

o nerve damage can occur independent of reactions(3)

o sensory loss may lead to(1, 2)

repeated trauma pressure necrosis pressure ulcer secondary infections

o ocular complications(1)

blindness from nerve damage and bacillary invasion 2.8% blindness and 11% potentially blinding pathology in newly diagnosed lepromatous

leprosy patientso based on case series with 691 patients in India, Philippines and Ethiopia

o Reference - Lepr Rev 2002 Sep;73(3):225 lagophthalmos (inability to close eyelid)

o may result from paresis of orbicularis oculio may occur bilaterally in late lepromatous diseaseo can lead to exposure keratitis and resultant blindnesso combination of patches over malar region or around eye plus Type I reaction may be

risk factor for lagophthalmos based on chart review of 1,226 patients with leprosy treated between 1982-1987 in

India 26 patients (2.1%) had recent lagophthalmos 85% patients with lagophthalmos had combination of patches over malar region or

around eye plus Type I reaction Reference - Lepr Rev 1991 Jun;62(2):143

o other systemic complications testicular atrophy(1)

o due to diffuse infiltration and acute orchitis that can occur with type II reactionso azoospermia and gynecomastia can result from loss of testosterone

renal involvement and amyloidosis rarely seen with effective treatment(1)

dry skin (due to autonomic disruption) that may fissure and ulcerate(2)

o chronic neuropathic pain described in 16 patients with multibacillary leprosy (Lancet 2000 Sep

23;356(9235):1080   EBSCOhost Full Text), commentary can be found in Lancet 2001 Jan

27;357(9252):313   EBSCOhost Full Texto progressive gangrene of bilateral toes in patients with tuberculoid leprosy, related to anti-

phospholipid antibodies in case report (BMC Infect Dis 2005 Sep 21;5:74   EBSCOhostFull Text full-text)

History:

Chief concern (CC):

o single or multiple skin lesions which may be(1, 2)

numb (not in majority with lepromatous disease) dry with scaly appearance hairless smooth and shiny diffuse (with lepromatous disease) hypopigmented or reddish patches

o Impaired sweating(2)

o numbness, weakness in hands and feet or face(1, 2)

o burn or ulcer in anesthetic hand or foot(1)

o borderline patients may present with(1, 4)

nerve pain sudden palsy new skin lesions eye pain, redness, impaired visual acuity systemic febrile illness

o blindness(1)

History of present illness (HPI):

o nerve damage can result in wrist drop, clawing of hand or foot drop(2)

o pure neuritic leprosy presents with asymmetrical involvement of peripheral nerve trunks and no visible skin lesions(1)

o musculoskeletal manifestations may be common based on 4 case series and 2 case reports 61% had rheumatic manifestations in series of 70 patients with leprosy in India

o 54% had arthritiso 17% had soft tissue rheumatismo 3% had enthesitis

o Reference - Indian J Dermatol Venereol Leprol 2004 Mar-Apr;70(2):76  EBSCO host   Full Text , commentary can be found in Indian J Dermatol Venereol Leprol

2004 Jul-Aug;70(4):250   EBSCO host   Full Text

symmetrical polyarthritis of wrists and fingers similar to rheumatoid arthritis reported in 20 (42%) of series of 48 patients with joint symptoms admitted to leprosy center in Pakistan (Br J Rheumatol 1994 Oct;33(10):963)

among 28 patients with leprosy in Indiao 20 presented with rheumatologic complaints initiallyo 5 patients with pure neuritic leprosy (no cutaneous features) presented with

inflammatory arthritis and/or tenosynovitis

o Reference - Rheumatology (Oxford) 2007 Apr;46(4):653   EBSCO host   Full Text polyarthritis (resembling rheumatoid arthritis) and tenosynovitis reported in case series of

30 patients with leprosy at rheumatology clinic in India (J Indian Med Assoc 2008 Mar;106(3):165)

rheumatoid-like polyarthropathy preceded neurological and cutaneous symptoms of leprosy by 10 months in case report of 70-year-old immigrant from Hong Kong diagnosed

with borderline lepromatous leprosy (Clin Exp Dermatol 2007 Nov;32(6):784  EBSCO host   Full Text )

5-year history of intermittent inflammatory arthritis and fever before neurologic manifestation and diagnosis of borderline leprosy in case report (Joint Bone Spine 2006 May;73(3):314)

Physical:

Skin:

o thorough physical exam for lesions(1)

examine for hypoesthesia to light touch, pin-prick, and temperature and for anhidrosis 51% of patients with positive skin smears did not have sensory loss in study of 594 new

leprosy cases in Ethiopia (Lepr Rev 2000 Mar;71(1):34)o findings in lepromatous leprosy(1, 2, 4)

multiple macules, papules, plaques, and nodules lesions have smooth, shiny surface and only slight hypopigmentation or erythema impaired sweating, decreased hair growth, and loss of sensation in lesions usually occur in

later disease decreased sensation begins over extensor surfaces of legs, feet, forearms, and hands (in

glove and stocking pattern) palpable enlargement of peripheral nerves (more common in late stages of polar

lepromatous leprosy)o findings in tuberculoid leprosy

disease limited to well-defined skin patches or nerve trunks(1)

few hypopigmented macular skin lesions with anesthesia(1, 2)

lesions appear dry and scaly with impairment of sweating(2)

thickened superficial nerves(1, 2)

picture of rash associated with tuberculoid leprosy can be found in Am Fam Physician 1999

Nov 1;60(7):2087   EBSCO host   Full Text  full-texto borderline forms associated with(2)

abundant skin lesions irregular anesthesia impairment of nerves

o skin fissures and ulcerations may occur(1)

o picture of borderline lepromatous type can be found in N Engl J Med 2001 Apr

26;344(17):1293   EBSCO host   Full Text

HEENT: (head eyes ears nose throat)

o lepromatous leprosy may lead to leonine facies (thickened skin predominantly on forehead, earlobes, eyebrows and cheeks)(2)

o dry insensitive cornea and conjunctiva(1)

o look for corneal trauma or ulcerations(1)

Neuro:

o peripheral nerve trunk damage(1)

nerves become thickened, with or without tenderness, with peripheral patterns of sensory and motor loss

most commonly posterior tibial nerve, followed by ulnar, median, lateral popliteal, and facial nerves

o small dermal nerve damage(1)

hypoesthesia and anhidrosis in borderline-tuberculoid and tuberculoid leprosy stocking-glove sensory loss in lepromatous leprosy

o muscle wasting and contractures may occur(1)

o pure neuritic leprosy - no skin lesions with asymmetrical trunk involvement, most common in India and Nepal(1)

Making the diagnosis:

o clinical diagnosis with at least 1 of 3 signs (World Health Organization [WHO] criteria) hypopigmented or reddish patches with definite loss of sensation thickened peripheral nerves acid-fast bacilli on skin smears or biopsy material Reference - World Health Organ Tech Rep Ser 1998;874:1 as referenced in(1)

use of these 3 criteria reported to have 97% sensitivity and 98% positive predictive value for leprosy in Ethiopia (Int J Lepr Other Mycobact Dis 2002 Mar;70(1 Suppl):S1 as referenced in(1))

o skin smears have high specificity but low sensitivity(1)

o histologic diagnosis considered gold standard for diagnosis(1), skin biopsy may be necessary in paucibacillary disease or tuberculoid leprosy(2)

o World Health Organization (WHO) field classification when slit-skin smear not available single skin lesion (1 patch) paucibacillary (2-5 patches) multibacillary (> 5 patches) Reference - World Health Organ Tech Rep Ser 1998;874:1 as referenced in(1, 2)

classification based on skin lesion count reported to result in misclassification of multibacillary leprosy and risk of undertreatmento based on comparison with skin smear and Ridley-Jopling classification in 264 untreated

patients with leprosy in the Philippines

o Reference - Clin Infect Dis 2007 Apr 15;44(8):1096   EBSCOhost Full Text ML Flow test at point-of-care may predict results of slit skin smear for acid fast bacilli (level

2 [mid-level] evidence)

Testing overview:o thorough physical exam for lesions(1)

o full-thickness skin biopsy of lesion(2, 3)

sample obtained from advancing margin of active lesion, fixed in neutral buffered formalin, embedded in paraffin, and examined by experienced pathologist

especially useful for patients with paucibacillary leprosy (with scant acid-fast bacilli) can be used to classify disease along clinical spectrum

o slit-skin smears(1, 2)

obtained by making small slit in pinched skin and scraping with scalpel blade; tissue fluid obtained is smeared on slide and stained for acid-fast bacilli by Fite method

detects intradermal acid-fast bacilli (AFB) (Z-N/Fite) important (despite low sensitivity) for determining highly infectious patients and those

with greatest relapse risko ML Flow test at point-of-care may predict results of slit skin smear for acid fast bacilli (level 2

[mid-level] evidence)

Blood tests:o serology not currently effective for diagnosis(1, 3)

o phenolic glycolipid I (PGL-1) antibody testing(1, 4)

specific and sensitive for multibacillary leprosy PGL-1 only present in 40%-50%with paucibacillary leprosy not able to predict which contacts will develop leprosy phenolic glycolipid I mycobacterial antigens in blood correlated with bacterial load of

leprosy and decrease after multidrug therapy in cohort of 100 new leprosy patients (Am J Trop Med Hyg 1991 Jun;44(6):702, Clin Diagn Lab Immunol 2001 Jan;8(1):138 full-text)

o  ML Flow test at point-of-care may predict results of slit skin smear for acid fast bacilli (level 2 [mid-level] evidence) based on cohort study with partial blinding 2,137 patients in Brazil and Nepal with newly diagnosed leprosy classified according to 3

methodso WHO classification

≤ 5 lesions = paucibacillary ≥ 6 lesions = multibacillary

o ML Flow serology test for antibodies to M. leprae - positive or negative

o slit skin smear for acid fast bacilli - positive or negative ≥ 20% of ML Flow test results in each country re-read by supervisors blinded to lesion

count multibacillary leprosy (by WHO classification) reported in 39.5% of 1,071 patients in Brazil

and 35.6% of 1,066 patients in Nepal among 411 patients with positive slit skin smear

o ML Flow test was concordant (positive) in 95.5% in Brazil and 89% in Nepalo ML Flow test was discordant (negative) in 4.5% in Brazil and 11% in Nepalo WHO classification was concordant (multibacillary) in 85.5% in Brazil and 88% in Nepalo WHO classification was discordant (paucibacillary) in 14.5% in Brazil and 12% in Nepal

among 1,726 patients with negative slit skin smearo ML Flow test was concordant (negative) in 66% in Brazil and 75% in Nepalo ML Flow test was discordant (positive) in 34% in Brazil and 24.5% in Nepalo WHO classification was concordant (paucibacillary) in 78% in Brazil and 71% in Nepalo WHO classification was discordant (multibacillary) in 22% in Brazil and 29% in Nepal

186 patients in Nigeria classified by WHO classification and ML Flow test (skin smear unavailable) but incomplete data reported

Reference - Lepr Rev 2007 Mar;78(1):70   EBSCOhost Full Text DynaMed commentary -- authors claim ML Flow test of patients classified paucibacillary by

WHO system would detect majority of misclassified multibacillary patients where skin smear unavailable

Imaging studies:o  high-resolution sonography appears more accurate than clinical exam for

assessment of nerve enlargement in patients with leprosy (level 2 [mid-level] evidence) based on diagnostic case-control study 20 patients with leprosy reaction and 30 age-matched healthy control patients evaluated

o bilateral assessment of ulnar, lateral popliteal, medial and posterior tibial nerveso grading of nerve thickness by palpation compared to observation of cross-sectional

area of major peripheral nerve trunks by ultrasound and color Doppler nerves significantly thicker in patients with leprosy vs. healthy patients poor agreement (kappa 0.3) between clinical palpation and sonography for all examined

nerveso nerve enlargement by ultrasound in 5 of 34 nerves found not thickened by clinical

examo no nerve enlargement by ultrasound in 39 of 86 nerves found thickened on clinical

examo sensory or motor loss observed by color Doppler in 12 of 23 nerves found unimpaired

by clinical exam

Reference - PLoS Negl Trop Dis 2009 Aug 11;3(8):e498   EBSCOhost Full Text full-text

Biopsy and pathology:o skin biopsy findings(2, 3)

lepromatous leprosy - many acid-fast bacilli, foamy histiocytes tuberculoid leprosy - few acid-fast bacilli, granulomas, inflamed nerves

Other diagnostic testing:o lepromin skin test(3)

not diagnostic of leprosy or exposure to M. leprae not available in United States injection of reactive agent measures granulomatous response

o Mitsuda lepromin most commonly used preparation though not approved by FDA for use in United States

o response measured as induration (in mm) 4 weeks after injectiono response not leprosy specific

negative lepromin skin test with lepromatous leprosy positive lepromin skin test with tuberculoid leprosy positive lepromin skin test can occur in persons never exposed to M. leprae

o Mycobacterium leprae polymerase chain reaction (PCR)(3)

PCR-based and reverse transcription-PCR-based techniques haveo 100% specificityo 34-80% sensitivity in patients with tuberculoid leprosyo > 90% sensitivity in patients with lepromatous leprosy

for identification of acid-fast bacilli (either profuse or sparse) if tissue site, clinical history, or other circumstances are questionable

not indicated for identification of acid-fast bacilli not identifiable by good-quality Fite-stained section

specimens suitable if freshly acquired and processed immediately (specimens can be frozen indefinitely)

specimens unsuitable from treated patients or if specimens have been refrigerated or are unfixed/unfrozen

PCR analysis can detect M. leprae in nasal swabs from unaffected exposed persons, but

does not predict clinical disease or infectivity (Clin Infect Dis 2001 Mar 15;32(6):930 EBSCOhost Full Text)

o qualitative sensory tests (sensory nerve conduction, warm perception tests) may detect nerve function impairment earlier than commonly used monofilament test and voluntary muscle test, but equipment costs may limit usefulness in leprosy-endemic countries and unclear if any test has sufficient predictive value for early detection (level 3 [lacking direct] evidence) based on prospective cohort study (INFIR study) without clinical outcomes 188 newly diagnosed adults with multibacillary leprosy followed for 2 years 74 (39%) had reaction, neuritis or new nerve function impairment 73 cases with reaction or nerve function impairment were matched to 73 controls sensory nerve conduction and warm perception tests often preceded deterioration in

monofilament testing and voluntary muscle testing by 12 weeks or more all tests had low sensitivity, highest sensitivity (37%) reported for cold detection threshold all tests had high specificities, ranging from 90-95%, except 80% for warm detection

threshold all tests had low positive predictive values, highest positive predictive value (14%)

reported for vibration perception threshold Reference - INFIR Cohort Study (PLoS Negl Trop Dis 2008 Apr 2;2(4):e212 full-text)

Treatment overview:o recommended treatments of leprosy  by World Health Organization (WHO)

for single skin lesion - single doses of rifampin 600 mg, ofloxacin 400 mg plus minocycline 100 mg

for paucibacillary disease - 6 months treatment with rifampin 600 mg/month plus dapsone 100 mg/day

for multibacillary disease - 12 months treatment with rifampin 600 mg/month plus dapsone 100 mg/day plus clofazimine 300 mg/month plus clofazimine 50 mg/day

o corticosteroids  during initial treatment of leprosy may reduce short-term (but not long-term) incidence of new reactions (level 1 [likely reliable] evidence)

o insufficient evidence to support any specific intervention for treatment or prevention of ulcers in patients with leprosy

o specialized footwear  can reduce peak pressure during walking (level 3 [lacking direct] evidence)

Treatment setting:o treatment with isolation no longer indicated (patient not infectious shortly after starting drug

therapy)

Counseling:o patient education important for effective management(1, 2)

reassurance that infectious transmission ceases within days of antibiotic treatment clear explanation of leprosy and its outcomes may improve adherence to treatments emphasis on outcome not always leading to gross deformities stress importance of care of limbs, and daily inspection for trauma

Medications:

Antibiotics:o recommended treatments of leprosy by World Health Organization (WHO)(1, 2)

treatment of paucibacillary disease - rifampin plus dapsone for 6 monthso rifampin (Rifadin, rifampicin) 600 mg (supervised) once monthlyo dapsone 100 mg/day (self-administered)

treatment of multibacillary disease - rifampin plus dapsone plus clofazimine for 12 monthso rifampin 600 mg (supervised) once monthlyo dapsone 100 mg/day (self-administered)

o clofazimine (Lamprene) 300 mg once monthly (supervised) AND 50 mg/day (self-administered)

paucibacillary leprosy with single skin-lesion may be treated with single doses of rifampin 600 mg, ofloxacin (Floxin) 400 mg, and minocycline (Minocin) 100 mg

o alternative suggested dosing for United States includes United States experts recommend increased duration of treatment or use alternative

treatment due to concern for relapse treatment of paucibacillary disease - rifampin 600 mg/day and dapsone 100 mg/day for 12

months treatment of multibacillary disease - rifampin 600 mg/day, dapsone 100 mg, clofazimine 50

mg/day for 2 years or standard WHO regimen for 2 years

Reference - Clin Infect Dis 2001 Mar 15;32(6):930   EBSCO host   Full Text  full-texto antibiotic selection recommendations from The Medical Letter (multi-drug regimen necessary

for successful treatment) drugs of choice - dapsone plus rifampin with or without clofazimine alternatives - minocycline, ofloxacin, clarithromycin Reference - Treat Guidel Med Lett 2007 May;5(57):33 TOC(1)

o clofazimine not commercially distributed in United States since 2004 clofazimine available for treatment of leprosy as investigational new drug through National

Hansen's Disease (Leprosy) Clinical Center Reference - Manufacturer's Press Release 2005 Apr 25

o rifampin most effective bactericidal drug against M. leprae single dose kills 99.99% of organisms patients with lepromatous leprosy not infectious within 2 days

Reference - Clin Infect Dis 2001 Mar 15;32(6):930   EBSCO host   Full Text  full-texto drug resistance observed with dapsone and rifampin, but frequency in population difficult to

determine as M. leprae cannot be cultivated in vitro(3)

o possible adverse effects of drug therapies dapsone

o rash, agranulocytosis, hemolysis (severe if patient is glucose-6-phosphate dehydrogenase-deficient) and methemoglobinemia(2)

o dapsone hypersensitivity syndrome in case report (J Occup Med Toxicol 2006 Jun 6;1:9 full-text)

o  HLA-B*13:01 allele associated with dapsone hypersensitivity syndrome in case-control study with genetic analysis of 1,705 patients with leprosy (N Engl J Med 2013 Oct 24;369(17):1620)

clofazimine(1)

o skin discoloration ranging from red to purple-black (most commonly reported side-effect) fades slowly after withdrawal of clofazimine

o characteristic ichthyosis on shins and forearmso pregnancy categories of antimicrobials

FDA Pregnancy Category C - rifampin, dapsone, clofazimine, clarithromycin, ofloxacin, levofloxacin

FDA Pregnancy Category D - minocyclineCorticosteroids:

o low dose prednisolone during first 4 months of multidrug treatment for multibacillary leprosy reduces short-term incidence of new reactions and nerve function impairment (level 1 [likely reliable] evidence) based on randomized trial 636 patients aged 15-50 years with newly diagnosed multibacillary leprosy treated with

multidrug treatment for 1 year and randomized at onset to prednisolone (20 mg/day for 3 months then tapered over 1 month) vs. placebo

90% follow-up rates and intention-to-treat analysis comparing prednisolone vs. placebo

o 4% vs. 15% had skin or nerve reaction at 4 months (NNT 9)o effect not sustained at 1 year when 22% vs. 17% had skin or nerve reaction (not

statistically significant) prednisolone only effective in patients without pre-existing nerve function impairment

Reference - TRIPOD 1 trial (BMJ 2004 Jun 19;328(7454):1459   EBSCO host   Full Text  full-

text), editorial can be found in BMJ 2004 Jun 19;328(7454):1447   EBSCO host   Full Text full-text

DynaMed commentary -- non-significant increased risk at 1 year suggests that prednisolone may delay instead of prevent reactions

o  corticosteroids may not improve nerve function in patients with leprosy (level 2 [mid-level] evidence) based on Cochrane review with inadequate statistical power for prespecified outcomes systematic review of 3 randomized and quasi-randomized trials evaluating corticosteroids

for treatment of nerve damage in 513 patients with leprosy no significant difference in nerve function improvement comparing prednisolone to placebo

at 12 months in 2 trialso 1 trial evaluated patients with mild sensory impairment for < 6 monthso 1 trial evaluated patients with nerve function impairment for 6-24 monthso confidence intervals do not rule out clinically relevant differences

3-month course of prednisolone associated with significantly greater need for additional corticosteroids compared to 5-month course of high-dose or low-dose regimen in 1 trial comparing 3 corticosteroid regimens for severe type 1 reactions

Reference - Cochrane Database Syst Rev 2007 Apr 18;(2):CD005491 (review updated 2011 Aug 10)

o  addition of IV methylprednisolone to oral prednisolone does not appear to reduce type 1 reactions of leprosy but may reduce deterioration of sensory function (level 2 [mid-level] evidence) based on small randomized trial 42 patients aged 16-65 years with leprosy with type 1 reactions or nerve function

impairment were randomized to methylprednisolone IV plus prednisolone orally vs. prednisolone orally alone for 16 weeks

no significant difference between groups in clinical improvement, sensory function, need for additional prednisolone, or adverse events at 337 days follow-up

methylprednisolone associated with fewer patients with deterioration of sensory function at end of treatment (p = 0.046)

Reference - PLoS Negl Trop Dis 2011 Apr 12;5(4):e1041   EBSCO host   Full Text  full-textOther medications:

o thalidomide appears highly effective for type II reactions (erythema nodosum leprosum) but

caution warranted due to teratogenic effects (Lancet 1994 Feb 19;343(8895):432  EBSCO host   Full Text , Indian J Lepr 1990 Jul-Sep;62(3):316, Microbes Infect 2002 Sep;4(11):1193)

o limited evidence suggests thalidomide and clofazimine may prevent new skin lesions caused by erythema nodosum leprosum (level 2 [mid-level] evidence) based on Cochrane review of trials with methodologic limitations systematic review of 13 randomized trials evaluating interventions for erythema nodosum

leprosum in 445 patients with leprosy methodologic limitations included

o randomization method not reportedo allocation concealment not statedo lack of intention-to-treat analysis

meta-analysis not possible due to heterogeneity of interventions comparing thalidomide vs. control in single trials

o significant remission of skin lesions in 52% vs. 21.4% in aspirin group (risk ratio [RR] 2.43, 95% CI 1.28-4.59)

o adverse effects in 41.7% in thalidomide 100 mg group vs. 90% in thalidomide 300 mg group (RR 0.46, 95% CI 0.23-0.93)

comparing clofazimine vs. control in single trialso absence of new lesions in 91.7% vs. 25% in prednisolone group (RR 3.67, 95% CI 1.36-

9.91)o adverse effects in 100% vs. 50% in prednisolone group (RR 1.92, 95% CI 1.10-3.35)o recurrence in 2.8% vs. 36.1% in thalidomide group (RR 0.08, 95% CI 0.01-0.56)

no significant differences in any outcomes comparingo indomethacin vs. aspirin, chloroquine, or prednisolone in 2 small trialso levamisole vs. placebo in 1 small trialo pentoxifylline  vs. thalidomide in 1 small trial

Reference - Cochrane Database Syst Rev 2009 Jul 8;(3):CD006949o infliximab reported to be effective for recurrent erythema nodosum leprosum (level 3 [lacking

direct] evidence) in case report (N Engl J Med 2006 Aug 17;355(7):739   EBSCO host   Full Text)

o cyclosporine has insufficient and conflicting evidence for use in treatment of type 2 reactions(3)

o no controlled trials evaluating azathioprine or methotrexate(3)

Surgery and procedures:o surgery may be indicated for(1, 2)

debridement of foot ulcer, if not responding to medical treatment and reduction in weight-bearing

contractures of hands and feet foot drop lagophthalmos entropion (turning in of the edges of eyelid) ectropion (turning out of the edges of eyelid)

o  addition of peripheral nerve decompressive surgery to prednisolone may not improve sensory or motor nerve function in patients with leprosy and nerve damage for < 6 months (level 2 [mid-level] evidence) based on Cochrane review with limited evidence systematic review of 2 randomized trials evaluating decompressive surgery for nerve

damage (< 6 months duration) in 88 patients with leprosy both trials compared decompressive surgery plus prednisolone vs. prednisolone alone, no

significant differences in sensory or motor nerve function through 2 year follow-up adverse effects related to decompressive surgery not adequately described Reference - Cochrane Database Syst Rev 2012 Dec 12;(12):CD006983

Consultation and referral:o treatment and leprosy reactions best managed by tropical disease specialist or dermatologist

with specific expertise(2)

o leprosy is reportable to federal agencies in United States and Canada(2)

o consultation and laboratory services available from National Hansen's Disease (Leprosy) Clinical Center

Other management:o  insufficient evidence to support any specific intervention for treatment or

prevention of ulcers in patients with leprosy based on Cochrane review systematic review of 8 randomized trials evaluating measures designed to promote healing

of existing ulcers and prevent new ulcers in 557 patients with leprosy and peripheral nerve damage

trials were small and had poor methodologic quality and interventions were heterogeneous zinc tape associated with nonsignificant trend toward benefit compared to more traditional

dressings in 3 trials topical ketanserin associated with better effect on wound healing than clioquinol cream or

zinc paste in 1 trial with wide confidence intervals topical phenytoin associated with statistically significant beneficial effects on ulcer healing

compared to saline dressing in 2 trials (results not combined for meta-analysis) canvas shoes no more effective than PVC-boots in 1 trial double rocker shoes did not promote healing more than below-knee plasters in 1 trial Reference - Cochrane Database Syst Rev 2008 Jul 16;(3):CD004833

o  specialized footwear for foot ulcers may be beneficial(1)

ulcers in leprosy heal if protected from weight-bearing (Lepr Rev 1999 Mar;70(1):63 as referenced in(1))

footwear can reduce peak pressure during walking (level 3 [lacking direct] evidence)o based on trial of 6 types of footwear used in leprosy programs and patients' prescribed

footwear in 10 leprosy patientso all footwear (except extra depth shoe without insole) had significantly lower peak

pressure than barefoot walkingo peak pressure during walking inversely correlated to insole thicknesso Reference - Lepr Rev 1994 Sep;65(3):262

cheap canvas shoes with cushioned insoles protective, cost-effective, and preferred to orthopedic shoes in randomized trial (Lepr Rev 1998 Jun;69(2):182 as referenced in(1))

review of plastic footwear for leprosy can be found in Lepr Rev 1990 Mar;61(1):73o  early mobilization following surgical correction of foot drop may shorten

rehabilitation stay without increasing risk of tendon pullout in patients with Hansen's disease (level 2 [mid-level] evidence) based on small randomized trial 24 patients with Hansen's disease and surgically corrected foot drop deformity were

randomized to early mobilization (active motion at 5 days) vs. 4 weeks of immobilization

mean rehabilitation stay was 43 days for early mobilization group vs. 59 days for immobilized group (p < 0.001)

no tendon pullout in either group no significant differences in active range of motion, ankle strength or 6-minute walking

distance in mean follow-up 19 months Reference - Clin Orthop Relat Res 2010 Sep;468(9):2477 full-text

o community-based socioeconomic rehabilitation may be helpful (Lepr Rev 2000 Dec;71(4):422 as referenced in(1))

Follow-up:o suggested follow-up for 5-10 years after treatment completion(2)

o 0.01%-0.14% annual relapse rate after multidrug therapy stopped (Clin Infect Dis 2001 Mar

15;32(6):930   EBSCO host   Full Text )o 5%-10% expected to have type 1 reversal reaction within first year, follow-up every 3 months

for first year is advised (Clin Infect Dis 2001 Mar 15;32(6):930   EBSCO host   Full Text  full-text) as referenced in(2)

Prognosiso clinical course may vary with classification of leprosy(1, 2)

course may have slow progression or sudden type I reactions with conversion to other forms

borderline tuberculoid leprosy can be associated with rapid and severe nerve damage lepromatous disease associated with chronicity and long-term complications including

o nerve damageo hypoesthesiao muscle weaknesso thickening of skin in forehead, earlobes, eyebrows, and cheeks

multibacillary leprosy (> 5 skin patches) associated with higher risk for reversal reactions and impairment of nerve function

o response to treatment generally good(2)

neurologic deficits often at least partially reduced with early treatment skin lesions usually resolve within 1 year, but may persist for up to 5 years in

multibacillary disease relapse or reaction may occur after cessation of multidrug therapy

o risk of leprosy reaction appears highest in first year of multidrug therapy (level 2 [mid-level] evidence) based on prospective study with high loss to follow-up 375 patients in Ethiopia with borderline lepromatous or lepromatous leprosy monitored

for reversal reactions during and after multidrug therapy reactions included in study were limited to patients

o not treated with dapsone before multidrug therapyo requiring prednisolone treatment

follow-up for 3.5 years - about 30-40% patients did not attend follow-up clinics after treatment ended (based on patient registration records)

reversal reactionso 43.6% with borderline lepromatous leprosy within 2 years

4.9% at diagnosis 26.3% in first year 12.4% in second year

o 19.2% with lepromatous leprosy within 2 years 0% at diagnosis 12.8% in first year 6.4% in second year

erythema nodosum leprosum reactionso 2.7% with borderline lepromatous leprosy within 2 years

0.8% at diagnosis 1.1% in first year 0.8% in second year

o 11.1% with lepromatous leprosy within 2 years 2.8% at diagnosis 5.5% in first year 2.8% in second year

reactions gradually decline after first year, but can occur into fourth year after treatment Reference - Int J Lepr Other Mycobact Dis 1992 Jun;60(2):173

o prediction rules may predict nerve function impairment

BANDS prediction rule may predict risk of nerve function impairment at 2 years (level 2 [mid-level] evidence)o based on prospective cohort derivation study without external validationo 2,510 patients from Bangladesh Acute Nerve Damage Study (BANDS) with new

diagnosis of leprosy classified according to World Health Organization criteria and followed for 2 years

o 166 patients (6.6%) developed nerve function impairment defined as ≥ 2 points in sensory score

based on ballpoint pen test - touch with pen in relevant sensory area at standard test sites, score based on number of points with absent sensation

nerves tested include ulnar (five sites), median (seven sites), and posterior tibial nerves (11 sites)

≥ 2 point reduction in Medical Research Council grade of movement tested for any of facial, ulnar, median and lateral popliteal nerves

clinical diagnosis of nerve function impairmento risk of nerve function impairment within 2 years was

1.3% (95% CI 0.8-1.8%) for 1,957 patients with paucibacillary leprosy and no nerve-function loss at baseline

16% (95% CI 12-20%) for 407 patients with either paucibacillary leprosy and nerve-function loss at baseline or multibacillary leprosy and no nerve-function loss at baseline

65% (95% CI 56-73%) for 146 patients with multibacillary leprosy and any nerve-function loss at baseline

o Reference - Lancet 2000 May 6;355(9215):1603   EBSCOhost Full Text,

commentary can be found in Lancet 2000 Nov 18;356(9243):1767  EBSCOhost Full Text

multibacillary leprosy plus phenolic glycolipid I (PGL-I) antibodies may predict high risk of nerve function impairment (level 2 [mid-level] evidence)o based on prospective cohort derivation study without external validationo 864 patients in Bangladesh with newly diagnosed with leprosy were followed for

median 46 monthso 115 patients (13%) developed nerve function impairment defined as decision to start

corticosteroids due to any of nerve function reduction by ≥ 2 points in sensory and/or motor function tests corneal anesthesia nerve tenderness score of 2 (palpation of nerve causes patients to jump or cry) mixed mild symptoms of neuritis

o rates of developing nerve function impairment based on WHO classification and anti-PGL-I antibodies 3.5% (95% CI 2.2-5.4%) in 549 seronegative paucibacillary patients 13% (95% CI 8.5-19%) in 176 seropositive paucibacillary patients and

seronegative multibacillary patients 53% (95% CI 45-62%) in 139 seropositive multibacillary patients

o Reference - PLoS Negl Trop Dis 2008 Aug 27;2(8):e283 full-texto DynaMed commentary

article reported to validate BANDS prediction rule but used "long-standing nerve function impairment" as part of rule where original article used "any nerve function loss"

definition of nerve function impairment event and exclusion criteria regarding nerve function impairment status at diagnosis not comparable

Prevention:o leprosy in close contacts rare(1)

last case in United Kingdom in 1923 examine household contacts for clinical signs of leprosy and advise them to report any

new skin lesions promptlyo bacille Camille-Guérin (BCG) vaccine

BCG given to children < 12 years old in United Kingdom(1)

effectiveness rates vary from 20%-80%(3)

neonatal BCG appears effective against leprosy (level 2 [mid-level] evidence)o based on cohort studyo 112,744 schoolchildren in Brazilian Amazon born between 1983-1991 with no or 1 BCG

scar entered into studyo 74% protection in neonatal BCG vaccination for all leprosy types

o 93% protection in persons with multibacillary leprosyo 67% protection in persons with paucibacillary leprosyo Reference - Lepr Rev 2004 Dec;75(4):357

BCG appears modestly effective against leprosy (level 2 [mid-level] evidence)o based on population-based case-control study in Indiao 364 cases of leprosy (identified from survey of 2,175,514 persons) were paired with

matched controls and assessed for BCG vaccinationo significant protective association between BCG and leprosy (odds ratio [OR] 0.46, 95%

CI 0.34-0.6)o BCG effectiveness

54% (95% CI 39-66%) overall 68% (95% CI 26-86%) against multibacillary leprosy 57% (95% CI 29-74%) against paucibacillary leprosy 48% (95% CI 22-65%) against single skin lesion leprosy

o Reference - Public Health 2005 Mar;119(3):209 efficacy of repeat BCG vaccination inconsistent in 2 randomized trials

o repeat BCG vaccine may further increase protection against leprosy but not against tuberculosis (level 2 [mid-level] evidence) based on randomized trial with low follow-up rates 121,020 persons in rural area of northern Malawi (virtually the entire population

1986-1989) previously unvaccinated persons randomized to BCG alone vs. BCG plus

killed M. leprae previously vaccinated persons randomized to second BCG vs. BCG plus

killed M. leprae vs. placebo 66,155 persons without BCG scar were randomized to 1 of 2 groups

BCG vaccine alone BCG plus killed M. leprae (dose of killed M. leprae vaccine increased from 5 x

107 to 6 x 108 bacilli during the trial) 54,865 persons with positive or doubtful BCG scar were randomized to 1 of 3

groups placebo BCG alone BCG plus killed M. leprae (6 x 108 bacilli)

follow-up at 5-9 years achieved for 63% previously unvaccinated and 66% previously vaccinated participants

139 new cases of leprosy occurred during follow-up (107 considered as definitely post-vaccination cases)

comparing BCG alone vs. placebo in scar-positive patients certain or probable leprosy found after vaccination in 0.068% vs. 0.124% (p =

0.05, NNT 1,786) certain or probable, definitively postvaccination, leprosy in 0.06% vs. 0.112%

(p barely > 0.05, NNT 1,923) addition of killed M. leprae did not significantly improve protection over primary

BCG vaccination or secondary BCG vaccination no evidence that any of the trial vaccines contributed to protection against

pulmonary tuberculosis

Reference - Lancet 1996 Jul 6;348(9019):17   EBSCOhost Full Texto repeat vaccination with BCG does not appear to protect against leprosy

(level 2 [mid-level] evidence) based on subgroup analysis of open-label, cluster randomized trial in Brazil 152,438 children aged 7-14 years randomized by school to intradermal injection

with BCG, Moreau strain (n = 72,980) vs. no-treatment control (n = 79,458) children followed for up to 6 years, 8 months subgroup analysis reported for 92,770 children with 1 BCG scar at baseline leprosy reported in 56 cases in revaccinated group vs. 61 cases in control group in

this subgroup analysis (incidence rate ratio 0.99, 95% CI 0.68-1.45) Reference - BCG-REVAC trial (PLoS Negl Trop Dis 2008 Feb 13;2(2):e167 full-text)

review of BCG can be found in Scand J Infect Dis 2001;33(4):243   EBSCOhost Full Text addition of killed M. leprae appeared to increase effectiveness of BCG in 1

randomized trial (Indian J Lepr 1998 Oct-Dec;70(4):369) but not in another randomized

trial (Lancet 1996 Jul 6;348(9019):17   EBSCOhost Full Text), both limited by low follow-up rates

o dapsone chemoprophylaxis may reduce rate of leprosy in household contacts in endemic countries (level 2 [mid-level] evidence) based on systematic review of trials of varied quality systematic review of 6 randomized trials, 6 controlled trials and 2 uncontrolled trials

evaluating chemoprophylaxis for prevention of leprosy in endemic countries and in household contacts

most studies evaluated chemoprophylaxis in children or young people all randomized trials were conducted in India trials not evaluated for quality criteria most trials evaluated dapsone

o oral dapsone evaluated in 4 randomized and 6 controlled trialso intramuscular acedapsone evaluated in 2 randomized trials and 1 uncontrolled mass

intervention trialo 1 uncontrolled mass intervention trial evaluated rifampicin

all randomized trials had statistically significant results supporting efficacyo NNT rates to prevent 1 case of leprosy for dapsone ranged from 15 to 27 in household

contacts in 3 trialso NNT 393 for dapsone in 1 trial with cluster randomization of villageso NNT for acedapsone 17 and 25 in 2 trials

controlled trials of dapsone had results similar to randomized trials Reference - J Infect 2000 Sep;41(2):137

o single dose rifampicin given to contacts of patients with newly diagnosed leprosy appears effective for prevention of leprosy for 2 years (level 2 [mid-level] evidence) based on cluster randomized trial with low follow-up rates and without intention-to-treat

analysis 28,092 close contacts of 1,037 patients with newly diagnosed leprosy in Bangladesh were

randomized by index-patient cluster to single dose rifampicin vs. placebo orally in second month of index patient’s treatmento 600 mg for adults ≥ 35 kgo 450 mg for adults < 35 kg and children > 9 years oldo 300 mg for children aged 5-9 years

index patients classified according to World Health Organization criteriao paucibacillary leprosy with single lesion in 389 patientso paucibacillary leprosy with 2-5 lesions in 353 patientso multibacillary leprosy in 295 patients

21,711 (77%) contacts completed study requirements, of which 18,869 (87%) available for 4-year follow-up

leprosy cases in contacts with rifampicin vs. placeboo 59 (0.59%) vs. 91 (0.91%) over 4 years (p < 0.05)o 29 (0.29%) vs. 67 (0.67%) during years 1-2 (p = 0.0002)o 30 (0.32%) vs. 24 (0.26%) during years 3-4 (not significant)

to prevent 1 case of leprosy among contactso NNT 265 (95% CI 176-537) after 2 yearso NNT 297 (95% CI 170-1,206) after 4 years

Reference - BMJ 2008 Apr 5;336(7647):761   EBSCOhost Full Text full-text, editorial

can be found in BMJ 2008 Apr 5;336(7647):730   EBSCOhost Full Text, commentary

can be found in BMJ 2008 Apr 19;336(7649):847   EBSCOhost Full Text

Screening:o delayed diagnosis of leprosy associated with increased nerve damage and disability - consider

leprosy diagnosis in patients with peripheral neuropathy or persistent skin lesions even if not from leprosy-endemic country(1)