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Not All Red Snappers Are M. Tuberculosis North Carolina Tuberculosis/ Respiratory Disease Institute Raleigh, NC June 25, 2013

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Not All Red Snappers Are M. Tuberculosis North Carolina Tuberculosis/ Respiratory Disease Institute Raleigh, NC June 25, 2013 Not All Red Snappers are M. tuberculosis North Carolina Tuberculosis/ Respiratory Disease Institute Raleigh, NC June 25, 2013 David M. Scollard, M.D., Ph.D. Department of Health and Human Services Health Resources and Services Administration Healthcare Systems Bureau National Hansen’s Disease Programs Disclosures • None • No conflicts of interest Mycobacterium leprae, the 1st human bacterial pathogen 1873 LEPROSY’s Uniqueness & Confounding factors Cannot culture M. leprae Major obstacle to research Slowest growing bacteria Profound delay in No diagnostic test Clinical Dx (3-10+ yr) Only bacterium found in Disability Peripheral nerves Deformity Curse, punishment STIGMA and inordinate Hands and face involved fear of leprosy Leprosy requires long term management Hansen’s Disease (Leprosy) • Caused by M. leprae –Non-cultivable –VERY slow growing –Infects nerves • Hard to “catch” • 95% of adults have native immunity Hansen’s Disease (Leprosy) Chronic infection of Skin and Nerves Diagnosis – biopsy No ‘blood tests’, no skin tests The stain matters Standard Ziehl-Nielsen Fite stain M. leprae = S-L-O-W • Very slow growing • Doubling time = 14 days (in mouse footpad) • Long incubation • 3 - 7 yrs . may be 10 - 20 yrs • An epidemic lasts 4 human generations • 80 - 100 years • Do not underestimate the slowpoke M. leprae Genome GROSS FEATURES • 1,614 genes • 1,433 genes in common with TB • 1,500 genes “deleted” • 1,133 pseudogenes Comparative Genomic Features Organism Genome (bp) CDS Pseudogenes G+C (%) M. tuberculosis 4,411,532 4,267 6 65.6 M. bovis 4,345,492 4,336 31 65.6 M. leprae 3,268,203 1,806 1133 57.8 Comparative Genomic Features Organism Genome (bp) CDS Pseudogenes G+C (%) M. tuberculosis 4,411,532 4,267 6 65.6 M. bovis 4,345,492 4,336 31 65.6 M. marinum 6,636,827 5,426 64 65.7 M. ulcerans 5,632,000 4,160 771 65.7 M. leprae 3,268,203 1,806 1133 57.8 Origins of U.S. Cases Asian/Cuban influx Leprosy in the U.S. (2001-2010) Two “sources” • Immigrants & migrants from endemic countries • U.S. “endemic cases” • U.S. born, no travel history • Southern U.S. (Gulf Coast) • Armadillo to human transmission proven NEJM 364:1626-1633, April 28, 2011. Country of Birth Frequency Percent U.S.A 344 21.2 Mexico 238 14.6 W Pacific Islands 209 12.9 Brazil 151 9.3 India 127 7.8 National Hansen’s Disease Programs • Treatment , Management, Rehabilitation • Training and Education • Intramural Basic Biomedical Research Forced confinement Discharges Outpatients & outreach 1894 1921 1941 1982 1999 Louisiana Leper Home “Miracle at HRSA Federal Carville” oversight Program Relocation to PHS Baton Rouge NHDP Indigenous US Leprosy Human & Armadillo Leprosy Lawton < 1% Tallulah 24% Woodville 5% Kisatchie 8% Atchafalaya 16% Lacassine 19% Carville 11% St. Mark's 0% Corpus Christi 18% High prevalence areas: 15-25% of armadillos infected Do Armadillos Transmit Leprosy to Man? A 35 yr old question 34oC Yes! 88% of Armadillos 64% of US Human cases In TX & LA Gulf Coast Share the same Zoonotic strain 3I-2-v1 Do amadillos transmit leprosy to man? NEJM April 28, 2011 NHDP AMBULATORY CARE CLINICS (ACP) 13 ACP treat ~3000 patients P.R. U.S. Private Sector Physicians Managing at Least 1 Case of Hansen’s Disease CT-12 MA-7 NYC-9 NJ-7 MD-7 DC-5 LA-76 More than 500 private sector Physicians managing >500 patients Contact Indeterminate Native Immunity: Health TT BT BB BL LL (95%) Cellular Immunity M. leprae Position in the spectrum: * Treatment * Prognosis Quality Control Clinically, Hansen’s disease primarily affects: •Peripheral nerves •Skin •Eyes •Mucous membranes Cardinal Signs and Symptoms •Hypoesthetic skin lesions •Nerve enlargement •Ulcers on extremities (ENL) •Painless wounds or burns •Loss of eyebrows and eyelashes •Inflammatory eye changes Tuberculoid/ Paucibacillary Nature of lesions Asymmetrical Larger Definite edge Rough and scaly Usually anesthetic Lepromatous/ Multibacillary Nature of lesions Many - diffuse or none Small Symmetrical Vague edge Smooth surface Sensation variable Tend to coalesce Nodular Lesions in LL Courtesy of Dr. C. Chun Cardinal Signs and Symptoms •Hypoesthetic skin lesions •Nerve enlargement •Painless wounds or burns •Loss of eyebrows and eyelashes •Inflammatory eye changes Places Where Nerves Can Be Felt Great Auricular Median Nerve Nerve Radial Cutaneous Nerve Ulnar Nerve Posterior Tibial Nerve Peroneal Nerve Cardinal Signs and Symptoms •Hypoesthetic skin lesions •Nerve enlargement •Ulcers on extremities (ENL) •Painless wounds or burns •Loss of eyebrows and eyelashes •Inflammatory eye changes Diagnosis Skin biopsy/ punch, 3-4 mm deep to reach subcutaneous nerves, preferably from cool region of the body (elbows, knees, ears) or from leading edge of the lesion. Chemotherapy of Leprosy is VERY Early Dx Effective Early Rx GOAL: MDT Prevent or arrest the Trajectory of Disability Deformity Disability NERVE DAMAGE NERVE Damage 0 1941, Promin, the Dr. Guy Faget “Miracle at Carville” Standard Treatment Regimen in U.S. HD medicines provided by NHDP at no charge Tuberculoid(PB) Lepromatous (MB) • Dapsone 100 mg/d • Dapsone 100 mg/d • Rifampin 600 mg/d • Rifampin 600 mg/d • Clofazimine 50 mg/d 1 Year 2 Years Resolution of Skin Lesion during Treatment August, 2011 April, 2012 8 months later 2009 2010 First visit 1 year 2 year 3 year 4 year 5 year Risk of Infection of Children from Parent with HD One or more Parents had Lepromatous HD, Treated with Dapsone only (1950’s) Children born Children born before after treatment treatment Cases of HD started Cases of HD started 98 11 68 0 Worth & Wong, Int J Lepr. 39: 745-49, 1971 Uncomplicated Leprosy • Insidious onset • Indolent infection • Little or no malaise Even when • No fever infected with billions of bacilli ! • Only ‘rash’ ( sensation) • Infection responds well, but slowly, to MDT • Cure Majority of Disabilities from Leprosy Are the Result of Nerve Damage Feet Fissures and Deformities Chemotherapy of Leprosy is VERY Early Dx Effective Early Rx GOAL: MDT Prevent or arrest the Trajectory of Disability Deformity Disability NERVE DAMAGE NERVE Damage 0 complications = Reactions Type 1 vs Type 2 Reactions Type 1 (“Reversal”) Type 2 (“ENL”) Onset Gradual Sudden Initial symptoms Vague malaise Fever, Malaise Gradual increase in New red, tender tenderness of lesions; lesions; Neuritis Neuritis Natural course Months 1-2 weeks NOT a drug reaction May occur before, during, or after Rx Reactions at Diagnosis Increasing risk of reactions 100 during treatment Reaction 90 80 No Tuberculoid Reaction Lepromatous 70 60 50 40 30 20 10 0 Percent of Patients Diagnosis of Reversal Reactions • Worsening of existing skin lesions with increased edema and erythema • Pain and/or swelling of hands and feet • Tender peripheral nerves Swelling in the feet Type 1 Reaction: A clinical diagnosis Mechanism(s) of Type 1 Reaction • Borderline Leprosy • Enhanced Cellular Immunity BT • Spontaneous Local Increases: – CD4+ T cells – CD1+ Dendritic cells BB – TH1 cytokines – Increased CXCL10 BL • Initiation of Type 1 Reactions? – (Leprosy + AIDS) + HAART T1R as Immune Reconstitution Inflammatory Syndrome (IRIS) – TNFa inhibition/ restoration T1R as IRIS Erythema Nodosum Leprosum (ENL) Mild symptoms Severe symptoms • Non tender • Painful subcutaneous lesions nodules • Ulcerating skin lesions • Fever >102o • WBC > 20,000 • Anemia • Organ involvement (orchitis, iritis) Pathogenesis of ENL • ???? • Immune-complexes • Tissue/ fixed IC • T-cell participation? • Elevated pro-inflammatory cytokines … Treatment of Reactions • Type 1 (Reversal Reaction) – Corticosteroids • Type 2 (ENL) – Corticosteroids (Oral and IV) – Thalidomide – High Dose Clofazimine – Immunosuppressives (Methotrexate, Azathioprine, Cyclosporine) Summary • Leprosy remains at a constant, low level in the USA • Consider this diagnosis when: – Chronic, non-healing skin lesions – Travel history – Loss of sensation in lesions • M. leprae infection is curable • Most of the problems in leprosy result from nerve damage • For information, Free Medication, and consultation contact the NHDP: www.hrsa.gov/hansens Contact Information David M. Scollard, M.D., Ph.D. Acting Director National Hansen’s Disease Programs Tel: 225-756-3713 Toll-free: 800-642-2477 e-mail: [email protected] Web: www.hrsa.gov/hansensdisease .
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