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Anaphylaxis and Angioedema

Anaphylaxis and Angioedema

Mast Cell Disorders

Andrew M. Smith, MD, MS Division of , , and Rheumatology University of Cincinnati and Cincinnati VA Medical Centers August 10 and 11, 2012 Disclosures

• None

• The contents do not represent the view of the Department of Veterans Affairs or U.S. Government Objectives

• Identify the clinical features of disorders • Explain the immunologic mechanisms of mast cell disorders • Describe appropriate evaluation and treatment of mast cell disorders Case Presentation

• 35 year old male, previously healthy • Symptoms began in the winter of 2011 • Woke up in the middle of the night – Started with hands and feet itching – , diarrhea, and – Lip swelling, quickly progresses to tongue swelling • Presented to the Emergency Department – Received and Case Presentation

• Fall 2011 - most severe episode • Awaked in the early morning • head to toe, tongue and lip swelling

• Treated with loratidine, famotidine, and prednisone daily

Case Presentation

• Further episodes: 11 times in 12 months and 4 episodes in the past 14 days – Facial/lip swelling with every episode – Faster progression to respiratory distress and low – Most recent episodes with chest pain – Most episodes have started in the middle of the night Case Presentation

• Allergy/Immunology consulted • “What is causing the recurrent episodes of ?”

• Definitions of anaphylaxis, , and urticaria Anaphylaxis - Definition

• Difficulty in defining anaphylaxis • Traditional Definition – A systemic, immediate reaction caused by (IgE)- mediated immunologic release of mediators from mast cells and Anaphylaxis World Allergy Organization definition: • A severe, life threatening, generalized or systemic hypersensitivity reaction involving two or more organ systems

• Allergic anaphylaxis – reaction mediated by an immunologic mechanism

• Non-allergic anaphylaxis – non-immunologic reaction

WAO Journal 2011; 4:13–37 Anaphylaxis - Symptoms

Signs and Percentage Signs and Percentage Symptoms Symptoms Cutaneous >90% 30-35% • Urticaria/Angio 85-90% Abdominal 25-30% • Nausea/Vomiti • 45-55% ng Respiratory 40-60% • Diarrhea • Dyspnea/Whe 45-50% Miscellaneous ezing • 5-8% • 15-20% • Substernal 4-6% Dizziness/Synco 30-35% pain pe • Seizure 1-2%

J Allergy Clin Immunol 2010;126:477-80. Angioedema - Definition • Swelling in the deep skin tissue • Fewer sensory nerve endings • Little or no • May be described as painful or burning • Generally asymmetric and short lived • May occur in isolation, accompanied by urticaria, or as a component of anaphylaxis • Can be life-threatening

Cleveland Clinic Journal of Medicine January 2009 vol. 76 1 12-15 Angioedema - Locations

• Larynx – Can develop rapidly – Early symptoms: hoarse voice, throat tightness, and difficulty swallowing • Skin and mucous membranes – Mild pain and warmth may be present, burning sensation – Resolves without leaving residual markings on the skin • Bowel wall – Colicky abdominal pain, sometimes nausea, vomiting and/or diarrhea – Bowel wall edema often visualized by abdominal CT or ultrasound Urticaria •Hives

•Itchy, red raised lesions •Turn pale when pressed, indicating the presence of enlarged blood vessels and fluid •Last minutes to hours •Resolve without discoloration/scarring

Molecular and Cellular Immunology, 7th ed. Anaphylaxis, Angioedema, Urticaria Causes

Approximately 1% of the population is dispensed outpatient epinephrine

WAO Journal 2011; 4:13–37 Mast Cells and the Immune System Mast Cell Function Effector of the humoral immune system

Fights off worm and bacterial infections Mast Cell Dysfunction

• Anaphylaxis • Systemic • Mast cell activation syndrome (MCAS) • MCAS and postural syndrome (POTS) Anaphylaxis Mechanism

Molecular and Cellular Immunology, 7th ed. Anaphylaxis * , , prostaglandins * •Pathophysiologic activity * • spasm, mucus secretion, vasodilatation, increased vascular permeability * •Clinical correlates • , urticaria, angioedema, flush, itch, * diarrhea and abdominal pain, hypotension, and rhinorrhea

Molecular and Cellular Immunology, 7th ed. Anaphylaxis Neutral proteases:

•Pathophysiologic activity • Further activation of mast cells

•Clinical correlates • Can magnify response due to further mast cell activation • Tissue damage *

Molecular and Cellular Immunology, 7th ed. Systemic Mastocytosis

• Excess growth of mast cells and accumulation in 1 or more organs • 93% of cases due to a mutation of c-kit gene (KIT D816V) • Symptoms are due to mast cell mediator release • Rare: 1 in 20,000-40,000 – More common in Caucasians Systemic CNS: 10-90% Const: 12-56% Mastocytosis Symptoms

• GI – abdominal pain, Resp: 4-57% diarrhea, nausea/vomiting CV: 5-30% • Skin – itching/flushing, fixed skin lesions • Cardiovascular (CV) – fast GI: 5-80% heart rate, loss of consciousness, anaphylaxis • Nervous system (CNS) – headache, confusion Skin: 8-95% • Musculoskeletal (MS) – bone pain • Constitutional – weakness, MS: 9-75% fatigue, malaise • Respiratory – , nasal symptoms

Annals of allergy, & immunology. 2010 Jan;104(1):1-10. Systemic Mastocytosis

• Presence of at least 1 major and 1 minor or 3 minor criteria in bone marrow or other organ • Major – Excessive mast cells on bone marrow biopsy*** • Minor – Excessive atypical mast cells – c-KIT D816V mutation – Mast cells with surface markers (CD2, CD25, CD117) – Serum tryptase >20 ng/mL Systemic Mastocytosis

• Neuroendocrine evaluation – Rule out pheochomocytoma, VIPoma,

• Multispecialty approach likely necessary Systemic Mastocytosis

• Avoid triggers • Block mast cell – Alcohol related symptoms – Spicy – H1 – NSAIDs – H2 Antihistamines – Narcotics – Epinephrine – Intense exercise – Cromolyn – Stinging insects – LTRA – Stress – Steroids • only if severe

MCAS

• Newly recognized disorder • No excessive growth of mast cells • Symptoms are due to mast cell mediator release • Demographics – Females: 89% of cases in one series – Can happen in any age group – On average, 4.6 years before referral

CNS: 83% MCAS Symptoms

• Abdominal pain (94%) Resp: 39% • Dermatographism (89%) CV: 17% • Flushing (89%) • Headache (83%) • Poor concentration and GI: 94% memory (67%) • Diarrhea (67%) • Nose and eye symptoms Skin: 89% (39%) • Asthma (39%) • Anaphylaxis (17%)

The Journal of allergy and clinical immunology. 2011 Jul;128(1):147-52 e2. MCAS

• Clinical history • Laboratory evaluation – Serum total tryptase, 24-hour urine for histamine, N-methylhistamine, prostaglandin D2 • Rule out other causes, including systemic mastocytosis (bone marrow biopsy) – Neuroendocrine evaluation MCAS

• Avoid triggers • Block mast cell – Alcohol related symptoms – Spicy foods – H1 Antihistamines – NSAIDs – H2 Antihistamines – Narcotics – Epinephrine – Intense exercise – Cromolyn – Stinging insects – LTRA – Stress – Steroids

MCAS and POTS

• Postural tachycardia syndrome (POTS) – Rare, disabling condition – High heart rate with standing – More common in young females – Unclear cause • Poor nerve signaling (neuropathic) • Excessive adrenal activation (hyperadrenergic) – Some patients with flushing, suggesting mast cells might be involved CNS: 63% Const: 88% MCAS and POTS Symptoms

• GI – nausea/vomiting, Resp: 38% diarrhea CV: 100% • Skin – flushing • Cardiovascular (CV) – fast heart rate, lightheadedness, GI: 38% loss of consciousness • Nervous system (CNS) – headache, confusion • Constitutional – weakness, Skin: 100% fatigue, dizziness, malaise, • Respiratory – shortness of breath, nasal symptoms

Hypertension. 2005 Mar;45(3):385-90. MCAS and POTS

• Tilt table testing • Evaluation and treatment as with MCAS • Trigger avoidance – Exercise – Prolonged standing – After meals – Premenstrual – Heat intolerance – Emotional stress Case Presentation Mast Cell Neuroendocrine Evaluation Evaluation •Tryptase with episode – 26.7 •Urine/serum metanephrines – NL (elevated) •Urine/serum catecholamines – •Urine histamine with episode – NL elevated •GI scope for carcinoid – NL •Urine 5’-HIAA – NL •Baseline tryptase – NL •VIP – NL •Cortisol – NL •Bone marrow – NL •Neurokinin A – NL •CT scan of chest and abdomen – NL

Case Presentation

• Best diagnosis: MCAS

• The patient was transitioned to more appropriate treatment Epinephrine Treatment

• H1-Antihistamines – Decrease itch, flush, urticaria, sneezing, and rhinorrhea – Do not prevent or relieve obstruction to airflow or hypotension/ – Cetirizine, doxepin, cyproheptadine • H2-Antihistamines –

Ann Emerg Med 2000;36:462-8. Treatment

• Glucocorticoids • Pharmacologic effects – Switch off transcription of activated genes that encode pro-inflammatory proteins • Clinical relevance – Onset of action takes several hours – Used to prevent and relieve mast cell related symptoms

Ann Allergy Asthma Immunol 2005;95:217-26. Treatment

• modifying agents (LTMA) – , zafirlukast, zileuton

• Cromones (mast cell stabilizer) – Cromolyn – GI symptoms only

• Dosing very important Case Presentation

• Changed to: – Cetirizine 20mg twice a day (H1) – Ranitidine 300mg twice a day (H2) • Start slow prednisone wean • Reviewed use and indications Case Presentation

• He has had only one mild episode including facial flushing, nausea and stomach pain – No Emergency Department visit • Added zafirlukast 20mg twice a day (LTMA) • No episodes since then Resources

• Bains SN, Hsieh FH. Current approaches to the diagnosis and treatment of systemic mastocytosis. Annals of allergy, asthma & immunology. 2010 Jan;104(1):1-10. • Hamilton MJ, Hornick JL, Akin C, et al. Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. The Journal of allergy and clinical immunology. 2011 Jul;128(1):147-52 e2. • Shibao C, Arzubiaga C, Roberts LJ, 2nd, et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005 Mar;45(3):385-90. • Pardanani A. Systemic mastocytosis in adults: 2012 Update on diagnosis, risk stratification, and management. American journal of hematology. 2012 Apr;87(4):401-11.

Resources

• American Academy of Allergy, Asthma, and Immunology – http://www.aaaai.org • The Mastocytosis Society – http://www.tmsforacure.org • The Elephant Project – Dr. Peter Vadas and Sarah Leach • [email protected] Conclusions

• Mast cell disorders are relatively rare but severe • Patient history is extremely important • Extensive evaluation and a multispecialty approach may be necessary to rule out all probable causes • Good outcomes with appropriate treatment Questions

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