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Welcome Willkommen Bienvenue Velkomen Isten hozta Zayt wilkum Merhaba Karibu Patient 1 • 10 y.o. female with a 2-week history of pruritic rash and mild loss of appetite • ROS otherwise negative; no constitutional symptoms, no recent weight loss, no diarrhea, no abdominal pain • Family came to US from Guatemala four years ago • No significant past medical history Patient 1: Clinical photographs Summary of initial laboratory values Test WBC Neutrophils Eosinophils Basophils Hemoglobin Hematocrit Platelet ALT AST ESR Rapid GpA Strep Urinalysis ANA c-ANCA p-ANCA hepatitis A and B Complement C3 Lab value *30,000/ml 2,400/ml *22,500/ml *300/ml 13.4 g/dL 39% 424,000/ml *105 U/l *64 U/l *19 mm/hr negative negative negative negative negative past resolved infection 127 U CH50/ml 110 mg/dl Reference range (4,500-13,500/ml) (1,800-7,000/ml) (0-500/ml) (0-200/ml) (11.5-15.5 g/dL) (35-45%) (200,000-450,000/ml) (8-49 U/l) (10-44 U/l) (<10 mm/hr) negative negative negative negative negative --(80-160 U CH50/ml) (87-247 mg/dl) Patient 1: Stool analysis • Trichrome stain positive for cysts of Giardia lamblia Patient 1: Histopathology Hypersensitivity tissue reaction Differential diagnosis: - urticaria/urticarial vasculitis - Well’s syndrome - hypereosinophilic syndrome - drug reaction - arthropod assault - reaction to parasitic infection Patient 1 • Initially treated with metronidazole, but unable to tolerate after two days due to nausea • Finished a one week course of furazolidone • Urticarial plaques did not improve with treatment • Bone marrow biopsy revealed acute lymphoblastic leukemia (ALL) ALL/Eo • Distinct entity first reported by Spitzer and Garson in 1973 • Eosinophilia is rare with ALL • Average age ~15 y.o., M>F • 41 patients described in literature • Good initial response to chemo, but high relapse rate • Poor prognosis; median survival time of 7.5 months ALL/Eo • Systemic symptoms common, including fever, cough, LAN, arthralgias, splenomegaly, pulmonary infiltrates • Rash common; variably described in literature with “purpura”, “petechial”, “erythematous”, even “erythroderma” Patient 2 • 51 y.o. Vietnamese female with one month history of intensely itchy rash and blisters • Also complains of blisters in the mouth • Tactile fevers (no specific temp), horrible pruritis and intermittent dysuria; remainder of ROS unremarkable • No significant past medical history or medications • Has been in US for at least five years Patient 2: Clinical photographs Patient 2: Laboratory values Test WBC Hemoglobin Hematocrit Neutrophils Eosinophils Basophils Reticulocyte (corr.) Serum iron TIBC Transferrin satur. Vitamin B12 Lab value 18,300 per uL 8.3 g/dL 27 % 8,970 per uL 4,940 per uL 180 per uL 1.2 % 9 ug/dL 213 ug/dL 4% 552 pg/mL Reference range (4,300-10,000) (11.5-15.5) (36-45%) (1,800-7000) (0-500) (0-200) --(55-155) (270-400) (15-50) (224-1132) - Urinalysis: 1+ WBCs, 1+ RBCs, positive leukocyte esterase - Basic metabolic panel revealed BUN of 4, otherwise unremarkable - LFTs showed albumin of 3.1 g/dL, otherwise unremarkable - Blood cultures negative and viral FA and culture negative - G6PD screen negative Patient 2: Histopathology Patient 2 • Started on prednisone 60 mg po qd and dapsone 100 mg po qd • After one week, added minocycline 100 mg po bid • One week later, increased prednisone to 100 mg po qd, d/c’d dapsone and minocycline, and started Cellcept 500 mg po bid plus Keflex for superinfection • One week later, increased Cellcept to 1 gm po bid Malignancy and BP • In 1990, over 600 pts described in 3 separate reports; no association of BP with increased cancer risk • 1995 (Ogawa et al.) 1113 pts with BP in Japan compared to 1987 gov’t figures (393 hosp.) – 5.8% of pts had malignancy (M=6.6%, F=5.0%) – BP association with malignancy was higher among younger patients – No difference in mucous involvement or annular erythema; ? Lower rate of negative BMZ Ab’s Age-group associations of BP and malignancy from Ogawa et al. Age group BP patients General population* 45-54 9.2% 0.13% 55-64 5.7% 0.39% 65-69 5.9% 0.44% 70+ 5.5% 0.61% *rates for medical care for malignancy among Japanese in 1987 Malignancies seen with BP by Ogawa et al. • • • • • • • GI = 32/64 Urinary/genital = 10/64 Pulmonary = 7/64 Heme = 5/64 Breast = 6/64 Skin = 3/64 Sinus = 1/64 Patient 3 • 39 y.o. Hispanic male with one day history of pruritic rash after release from incarceration • Admitted to isolation for diagnosis of chickenpox • ROS unremarkable; no current fevers but had viral symptoms 2-3 weeks ago that resolved • Patient purports a history of chickenpox as a child at age 13, describing his illness in convincing vivid detail • PMH includes schizophrenia, stable on Seroquel (has been on this drug for many months), and an abdominal gunshot wound • Unusual story about childhood hospitalization lasting one month for workup of diarrhea; discharged with no diagnosis Patient 3: Clinical photographs Patient 3: Laboratory findings • Basic metabolic panel, LFTs, and CBC unremarkable • RPR and HIV negative • No VZV DNA detected in serum by PCR • Serologies consistent with past VZV infection • FA and viral culture negative for Herpes group infection • Anti-endomysial and anti-tissueTG antibodies negative Patient 3: Tzanck preparation Patient 3: Histopathology Patient 3 • Minimal response to topical triamcinolone ointment • Initiated on prednisone 40 mg po qd • Did well on prednisone, added dapsone 100 mg po qd • Tapered prednisone • Stopped dapsone secondary to difficulty with refill • Rash recurred during taper at prednisone 5 mg • Restarted dapsone and slightly bumped prednisone to 10 mg to re-taper Eosinophilic folliculitis • Rare inflammatory dermatosis of unclear etiology • Described by Ofuji in 1965 • Predominantly seen in adults; childhood variant described as distinct entity • Gender predominance unclear • Most cases reported from Japan Ofuji’s disease HIV-associated EPF Infantile/neonatal EPF Adults with average age of 30 Adults with HIV and CD4 < 300 cells/mm3 Infants < 1 year old, M>F Pruritis common Pruritis common Pruritis common Follicular papules coalesce to form figurate plaques Follicular papules without figurate lesions, looks like folliculitis Follicular papules and pustules, usually with erythematous base and secondary crusting Face, upper extremeties, trunk and also non-follicular areas (fingers, palms) Face, scalp, upper trunk Primarily scalp, but can be seen on face and trunk, less often on extremeties Recurrent crops that involute over 1-2 weeks, relapse q 3-4 weeks Chronic condition Self-limiting condition, resolves after cyclical 3 month to 5 year course - Other folliculitides - ? Heme malignancies - ? Parasitic infections -Demodex folliculitis -Drug-induced folliculitis -Other common folliculitides -Erythema toxicum neonatorum -Transient neonatal pustular melanosis -Infantile acropustulosis -LCH The biology of eosinophils and their role in skin disease Andy J. Chien, M.D., Ph.D. University of Washington Division of Dermatology (Photo from Nobel e-museum online) Paul Ehrlich (1854-1915) • Born in Strehlan in 1854 • 1878 doctorate in medicine – thesis on staining of animal tissues, differentiates mast cells from plasma cells • 1879 – defines and names the eosinophil • Establishes criteria based on cell morphology, physiology and pathology to classify hematolgic malignancies (Photo from Nobel e-museum online) Paul Ehrlich (1854-1915) • 1882 – washes aniline dye with acidified alcohol and becomes first to visualize Koch’s bacillus as “acid-fast bacilli” • 1885 – uses stains to recognize that different tissues have different oxygen demands • 1886 – describes use of methylene blue as a dye for neural structures, malaria parasites (Photo from Nobel e-museum online) Paul Ehrlich (1854-1915) • 1885 – “sidechain theory” and lock-and-key mechanism of antibody recognition; bunnies survive 5000-fold lethal dose of toxin with slow, increased exposures • 1889 – contracts TB • 1896 – heads institute to standardize diptheria and other anti-toxins (Photo from Nobel e-museum online) Paul Ehrlich (1854-1915) • 1901 – induces immunity against transplanted tumors in mice via injections of tumor cells • 1906 – prophesizes chemical “magic bullets” to target intracellular parasites • 1908 – wins Nobel prize for theory of immunity (Photo from Nobel e-museum online) Paul Ehrlich (1854-1915) • 1910 – discovers antitreponemal effects of arsenical compound Salvarsan (arsphenamine in the U.S.) • 1915 – dies of stroke at age 61 • 1945 – genus Ehrlichia established to honor Ehrlich’s work as a microbiologist (Photo from Nobel e-museum online) Paul Ehrlich (1854-1915) • Pioneer in cell staining • Father of hematology • Pioneer in microbiology • Father of immunology • First successful chemotherapy Eosinophilia • • • • • P arasitic infection A llergic response N eoplasm I diopathic hypereosinophilic syndrome C onnective tissue disease The eosinophil • Life cycle consists of marrow, blood and tissue phases • Tissue:blood eosinophils ~100:1 (rat) • Typically reside in tissues exposed to external environment (lung and gut) • Half-life of 8 to 18 hours in bloodstream • Tissue life span estimated at 2-5 days, but may be longer (in vitro up to 14 days with cytokines) The eosinophil • In injected rats, 2 day delay before detection of peripheral eosinophilia • Maximum peripheral eosinophilia at 6-7 days • Increased bone marrow eosinophils at 5 days • Possible demargination may result in more rapid response Eosinophil structure Eosinophil structure Primary granule • Charcot-Leyden crystal protein • 7-10% of eosinophil protein • Round with uniform electron density • A.k.a. lipophospholipase • Found in eosinophilic promyelocytes • Also a major product of basophils • ? Protection from lytic phospholipids • ? Degradation of pulmonary surfactant Eosinophil structure Small granule • Aryl sulfatase B and acid phosphatase Eosinophil structure Secondary granule • Dense core surrounded by less dense matrix • Major basic protein (MBP) located in the core • Eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), eosinophil-derived neurotoxin (EDN) and betaglucuronidase in matrix • Matrix:core protein ration approximately 2:1 Major Basic Protein (MBP) • • • • Produced as proMBP, cleaved with maturation Cytotoxic, bactericidal and helminthotoxic Disrupts lipid bilayers Causes histamine release from basophils and mast cells • Activates neutrophils and platelets • Neutralizes heparin effects on clotting • Promotes bronchospasm Eosinophil Cationic Protein (ECP) • Helminthotoxic, neurotoxic and bactericidal • Causes histamine release from mast cells • Inhibits peripheral blood lymphs in vitro • Neutralizes heparin effects on clotting • Weak RNase activity Eosinophil-Derived Neurotoxin (EDN) • • • • • Severely damages myelinated neurons Inhibits peripheral blood lymphs in vitro Weak helminthotoxin Potent RNase activity 60% sequence identity to ECP Eosinophil Peroxidase (EPO) • Distinct absorption spectra and heme group from neutrophil myeloperoxidase • In the presence of halide and H2O2, EPO kills tumor cells and microorganisms • Causes histamine release from mast cells • Provokes bronchospasm • Damages respiratory epithelium Eosinophil cytokines • IL-3 • IL-5 • GM-CSF • • • • • • • • • • IL-1 IL-2 IL-4 IL-6 IL-8 IL-10 IL-16 TNFa TGFa and b1 RANTES IgE receptors complement receptors IgA receptors IgG receptors LT receptors C-C receptors 3. priming and activation fibronectin, laminin E and P selectin ICAM/ VCAM 2. transmigration 1. “rolling” and adhesion sialyl-diLewis X CD11/CD18 (binds ICAM) CD29/CD49 (binds VCAM) Reference: Acta Anatomica, 134:341-345, 1989. Eosinophils in skin disease • • • • • • • • • • • Atopic dermatitis Bullous pemphigoid Urticaria Parasitic infection Arthropod assaults Wells’ syndrome/eosinophilic cellulitis Eosinophilic fasciitis Eosinophilic folliculitis Angiolymphoid hyperplasia with eosinophilia Incontinentia pigmenti Id reactions Atopic dermatitis • Wassom et al. (JCI 1981): – Atopic dermatitis subjects: >50% with elevated MBP +/- increased eosinophils • Leiferman et al. (NEJM 1985): – MBP is deposited in the upper dermis with near absence of eosinophils in atopic skin; normal skin shows less extracellular MBP • Ott et al. (J Allergy Clin Immunol 1994): – Eosinophil granule proteins deposited in dermis with few infiltrating cells seen – 4/19 had serum eosinophilia; 10-15/19 had elevated serum MBP, EDN, ECP Atopic dermatitis • Peripheral blood eosinophilia roughly correlates with disease activity – Pts with respiratory allergies more likely to have eosinophilia • Serum levels of ECP correlate with disease activity (adults and children) • Variable relationship between eosinophilia and ECP levels • TH2 activity associated with IL-5, leads to eosinophil synthesis, activation, recruitment Atopic dermatitis • Wedi et al. (J Allergy Clin Immunol 1996): – Blood eosinophils of pts with atopic derm exhibit delayed apoptosis in vitro (ELISA, DNA and flow cytometry) – Increased autocrine production of IL-5, GMCSF • Cheng et al. (J Allergy Clin Immunol 1997): – 9/10 with increased extracellular MBP – No normal eosinophils seen; all in various stages of cytolysis (EM) Atopic dermatitis • Matsukura et al. (J Clin Lab Immunol 1996): – Blood eosinophil apoptosis induced by corticosteroids (dose-dependent) in AD pts • Alam et al. (J Exp Med 1994): – TGFb induces eosinophil apoptosis • Wedi et al. (J Allergy Clin Immunol 1998): – IL-4 induces apoptosis in eosinophils (peripheral blood) Bullous pemphigoid • Insert histo slide here Bullous pemphigoid • • • • • • • • Autoantibodies to BP230 and BP180 Antibody binding Complement activation Mast cell degranulation Neutrophil infiltration and activation Increased MPO and ECP in blister fluid Release of neutrophil proteolytic enzymes Role of the eosinophil? Bullous pemphigoid • Borrego et al. (Am J Path 1996) – In BP prior to blister formation (erythema, wheals) extracellular granule protein deposition > eosinophil number in dermis of involved skin – Neutrophil protein depsition less prominent than eosinophil protein deposition – Protein deposition especially prominent near areas of epidermal separation – EM: eosinophils degranulate onto basal layer – Blister fluid contains IL-3, IL-5 and GM-CSF (blocked by Abs), enhances survival in vitro – Neutrophil infiltration and degranulation variable Bullous pemphigoid • Stahle-Backdahl et al. (JCI 1994) – Eosinophil-derived 92 kDa gelatinase (MMP9) is prominent in BP blister fluid – In vitro, 92 kDa gelantinase cleaves the extracellular domain of BP180 – Minimal gelatinase seen in suction-derived blisters and therapy-derived blisters (cryo, bleomycin) Acknowledgments • Dr. Zsolt “Hungarian Idol” Argenyi • Dr. Roy “Hot-legs” Colven • Dr. Phil “The ZenMaster” Kirby