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Welcome Willkommen Bienvenue Velkomen Isten hozta Zayt wilkum Merhaba Karibu

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

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Welcome Willkommen Bienvenue Velkomen Isten hozta Zayt wilkum Merhaba Karibu

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  1. WelcomeWillkommenBienvenueVelkomenIsten hoztaZayt wilkumMerhabaKaribu

  2. 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

  3. Patient 1: Clinical photographs

  4. Summary of initial laboratory values Test Lab value Reference range WBC *30,000/ml (4,500-13,500/ml) Neutrophils 2,400/ml (1,800-7,000/ml) Eosinophils *22,500/ml (0-500/ml) Basophils *300/ml (0-200/ml) Hemoglobin 13.4 g/dL (11.5-15.5 g/dL) Hematocrit 39% (35-45%) Platelet 424,000/ml (200,000-450,000/ml) ALT *105 U/l (8-49 U/l) AST *64 U/l (10-44 U/l) ESR *19 mm/hr (<10 mm/hr) Rapid GpA Strep negative negative Urinalysis negative negative ANA negative negative c-ANCA negative negative p-ANCA negative negative hepatitis A and B past resolved infection --- Complement 127 U CH50/ml (80-160 U CH50/ml) C3 110 mg/dl (87-247 mg/dl)

  5. Patient 1: Stool analysis • Trichrome stain positive for cysts of Giardia lamblia

  6. Patient 1: Histopathology

  7. Hypersensitivity tissue reaction Differential diagnosis: - urticaria/urticarial vasculitis - Well’s syndrome - hypereosinophilic syndrome - drug reaction - arthropod assault - reaction to parasitic infection

  8. 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)

  9. 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

  10. 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”

  11. 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

  12. Patient 2: Clinical photographs

  13. Patient 2: Laboratory values Test Lab value Reference range WBC 18,300 per uL (4,300-10,000) Hemoglobin 8.3 g/dL (11.5-15.5) Hematocrit 27 % (36-45%) Neutrophils 8,970 per uL (1,800-7000) Eosinophils 4,940 per uL (0-500) Basophils 180 per uL (0-200) Reticulocyte (corr.) 1.2 % --- Serum iron 9 ug/dL (55-155) TIBC 213 ug/dL (270-400) Transferrin satur. 4 % (15-50) Vitamin B12 552 pg/mL (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

  14. Patient 2: Histopathology

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. Patient 3: Clinical photographs

  21. 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

  22. Patient 3: Tzanck preparation

  23. Patient 3: Histopathology

  24. 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

  25. 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

  26. Infantile/neonatal EPF HIV-associated EPF Ofuji’s disease Adults with average age of 30 Pruritis common Follicular papules coalesce to form figurate plaques Face, upper extremeties, trunk and also non-follicular areas (fingers, palms) Recurrent crops that involute over 1-2 weeks, relapse q 3-4 weeks - Other folliculitides - ? Heme malignancies - ? Parasitic infections • Adults with HIV and CD4 < 300 • cells/mm3 • Pruritis common • Follicular papules without figurate • lesions, looks like folliculitis • Face, scalp, upper trunk • Chronic condition • Demodex folliculitis • Drug-induced folliculitis • Other common folliculitides • Infants < 1 year old, M>F • Pruritis common • Follicular papules and pustules, • usually with erythematous base • and secondary crusting • Primarily scalp, but can be seen • on face and trunk, less often on • extremeties • Self-limiting condition, resolves • after cyclical 3 month to 5 year • course • -Erythema toxicum neonatorum • -Transient neonatal pustular • melanosis • Infantile acropustulosis • LCH

  27. The biology of eosinophils and their role in skin disease Andy J. Chien, M.D., Ph.D. University of Washington Division of Dermatology

  28. 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)

  29. 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)

  30. 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)

  31. 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)

  32. 1910 – discovers anti-treponemal 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)

  33. Pioneer in cell staining • Father of hematology • Pioneer in microbiology • Father of immunology • First successful chemotherapy (Photo from Nobel e-museum online) Paul Ehrlich (1854-1915)

  34. Eosinophilia • P arasitic infection • A llergic response • N eoplasm • I diopathic hypereosinophilic syndrome • C onnective tissue disease

  35. 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)

  36. 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

  37. Eosinophil structure

  38. 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

  39. Eosinophil structure Small granule • Aryl sulfatase B and acid phosphatase

  40. 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 beta-glucuronidase in matrix • Matrix:core protein ration approximately 2:1

  41. 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

  42. 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

  43. Eosinophil-Derived Neurotoxin (EDN) • Severely damages myelinated neurons • Inhibits peripheral blood lymphs in vitro • Weak helminthotoxin • Potent RNase activity • 60% sequence identity to ECP

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