Anaphylaxis

Epidemiology

Definitions

  • Anaphylactoid Reaction
    • Mechanism Involves Direct Mast Cell Activation (Importantly without Prior Sensitization)
    • However, Anaphylactoid Reaction is Clinically Indistinguishable from Anaphylaxis
  • Anaphylaxis
    • Mechanism Involves IgE-Mediated Mast Cell Activation (Type I Hypersensitivity Reaction)

Specific Subset of Allergens Account for 90% of Anaphylaxis Cases

  • Egg
  • Fish/Shellfish
  • Milk
  • Soy
  • Peanuts
  • Tree Nuts
  • Wheat

Risk Factors for Severe/Fatal Anaphylaxis

  • Age-Related Factors
    • Infant: inability to describe symptoms
    • Adolescent/Young Adult: increased risk-taking behaviors that may impede ability to obtain prompt medical care, etc
    • Labor/Delivery: increased risk from medications
    • Elderly: increased risk of fatality from medication or venom-associated anaphylaxis
  • Concomitant Disease-Related Factors
  • Concomitant Medications/Toxins-Related Factors
    • Angiotensin Converting Enzyme (ACE) Inhibitors (see Angiotensin Converting Enzyme Inhibitors)
    • Antidepressants: use may impair the ability to recognize anaphylaxis triggers and symptoms
    • β-Blockers (see β-Adrenergic Receptor Antagonists)
    • Ethanol (see Ethanol): use may impair the ability to recognize anaphylaxis triggers and symptoms
    • Recreational Drugs: use may impair the ability to recognize anaphylaxis triggers and symptoms
    • Sedatives: use may impair the ability to recognize anaphylaxis triggers and symptoms
  • Presence of Physiologic Defect in Mediator Degradation Pathways
    • Low Serum ACE Activity: impaired ability to degrade tryptase, histamine, bradykinin
    • Low Serum PAF Acetylhydrolase Activity: impaired ability to degrade platelet-activating factor

Risk Factors Which Amplify Anaphylaxis

  • Acute Infection
  • Disruption of Routine
    • Travel
  • Emotional Stress
  • Exercise: best characterized amplifying factor
    • Commonly Associated with Anaphylaxis Due to Concomitant Ingestion of a Specific Food Trigger
      • Celery
      • Omega-5 Gliadin
      • Shellfish
      • Wheat
    • Less Commonly Associated with Anaphylaxis Due to Concomitant Ingestion of Ethanol or NSAID Drug: these enhance intestinal permeability and allergen absorption
  • Premenstrual Status

Etiology

IgE-Mediated Mast Cell Activation (Type I Hypersensitivity) (see Immune Hypersensitivity)

Foods/Food Additives (see Food Allergy)

  • General Comments: specific food triggers vary geographically (due to different foods consumed and methods of preparation)
    • North America/Some Countries in Europe and Asia: cow milk, hen’s egg, peanut, tree nuts, shellfish, and fish are common triggers
    • European Countries: peach is a common trigger
    • Middle East: sesame is common trigger
    • Asia: buckwheat, chickpea, rice, and bird’s nest soup are common triggers
  • Annatto (see Annatto): yellow food colorant
  • Carmine (see Carmine): insect-derived red colorant
  • Eggs
  • Legumes: beans, lentils, peanuts, peas, soybeans/soy
  • Milk: cow milk, goat milk, sheep milk
  • Peach
  • Red Meat
    • Epidemiology: has also been described with lamb and some cuts of pork
    • Physiology
      • Tick Acquires the Oligosaccharide, Alpha-Gal, After Feasting on a Mammal, Retaining it in its Gastrointestinal Tract Until it Bites a Human: the bite provokes an IgE response in the human
      • Alpha-Gal is Found in Red Meats
      • Alpha-Gal is Also Found in Cetuximab (Erbitux) (see Cetuximab)
      • Alpha-Gal May Also Be Found in Porcine Products, Such as Heart Valves and Heparin
    • Clinical
      • Alpha-Gal Related Meat Allergy is Unusual in that it has a Delayed Onset, Occurring 4-6 hrs After Meat Ingestion
      • Alpha-Gal Associated Cetuximab (Erbitux) Allergy (see Cetuximab): may occur on first exposure and may be severe, resulting in anaphylaxis
      • Allergy May Recede Over Months-Years if Red Meat is Avoided
  • Seafood: crustaceans, shellfish, finned fish, shrimp
  • Sesame
  • Spices
  • Tree Nuts: almonds, cashews, walnuts
  • Vegetable Gums
  • Wheat

Stings/Bites/Envenomations

  • Phylum Arthropoda -> Class Insecta -> Order Hymenoptera
  • Phylum Arthropoda -> Class Insecta -> Order Hemiptera
    • Bed Bug Bite (Cimex) (see Bed Bug Bite): may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
    • Kissing Bug Bite (Triatoma) (see Kissing Bug Bite)
  • Phylum Arthropoda -> Class Insecta -> Order Diptera
  • Phylum Arthropoda -> Class Insecta -> Order Lepidoptera
    • Pine Processionary Caterpillar Envenomation
    • Puss Caterpillar Envenomation (see Puss Caterpillar Envenomation): may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
  • Phylum Arthropoda -> Class Arachnida
    • Ixodes Holocyclus (Australian Paralysis Tick) Bite (see Tick Bite)
    • Argas Reflexus (Pigeon Tick) Bite (see Tick Bite)
    • Scorpion Sting (see Scorpion Sting): particularly Centruroides (common striped scorpion)
    • Ixodes Pacificus (Western Black-Legged Tick) Bite (see Tick Bite)
  • Phylum Cnidaria
    • Box Jellyfish (Carybdea Alata) Sting (see Jellyfish Sting): may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
    • Portuguese Man-of-War (Physalia Physalis) Sting: may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
    • Sea Nettle Sting
  • Phylum Chordata -> Class Reptila
    • European Viper (Vipera) Snake Bite
    • Gila Monster Bite (see Poisonous Lizard Bite): may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
    • Mexican Beaded Lizard Bite (see Poisonous Lizard Bite): may induce an anaphylaxis-like reaction (unknown if IgE-mediated)
    • Rattlesnake (Crotalus) Bite (see Rattlesnake Bite)
  • Phylum Chordata -> Class Mammalia
    • Gerbil Bite
    • Hamster Bite
    • Mouse Bite
    • Rat Bite

Drugs

  • Abacavir (see Abacavir)
  • Acetaminophen (Tylenol) (see Acetaminophen)
    • Epidemiology: cases of anaphylaxis have been reported
  • Allergen Immunotherapy (Subcutaneous) (see Allergen Immunotherapy)
  • Alpha-1 Antitrypsin (Aralast, Glassia, Prolastin, Zemaira) (see Alpha-1 Antitrypsin): occurs in <1% of cases
  • Angiotensin Converting Enzyme (ACE) Inhibitors (see Angiotensin Converting Enzyme Inhibitors)
  • Acyclovir (Zovirax) (see Acyclovir)
  • Anti-Thymocyte Globulin (ATG) (see Anti-Thymocyte Globulin)
  • Antivenoms
  • β-Lactam Antibiotics (see β-Lactam Antibiotics)
    • Cephalosporins (see Cephalosporins)
    • Imipenem (see Imipenem): cross-reactivity in 50% of patients with allergy to penicillins
    • Penicillins (see Penicillins): occurs in 0.05% of cases, fatal in 5-10% of cases
  • Demeclocycline (see Demeclocycline)
  • Gemcitabine (Gemzar) (see Gemcitabine): cases of laryngeal edema have been reported
  • Heparin (see Heparin): anaphylaxis is a manifestation of heparin-induced thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia)
  • Insulin (see Insulin)
  • Iodinated Drugs
    • See Also Radiographic Contrast Below
  • Local Anesthetics
  • Monoclonal Antibodies/Biologics
    • Cetuximab (Erbitux) (see Cetuximab)
      • Physiology: tick bite-associated alpha-galactosidase sensitization has been found to be a mechanism of allergic sensitization to cetuximab and read meats (J Allergy Clin Immunol, 2015) [MEDLINE]
    • Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin)
    • Omalizumab (Xolair) (see Omalizumab): rare etiology of anaphylaxis
    • Rituximab (Rituxan) (see Anti-CD20 Therapy)
  • N-Acetylcysteine (Mucomyst, Acetadote, Fluimucil, Parvolex) (see N-Acetylcysteine)
    • Epidemiology: associated with intravenous administration
    • Physiology: histamine release has been implicated
  • Non-Dextran Intravenous Iron
    • Ferumoxytol (Feraheme) (see Ferumoxytol)
    • Iron Gluconate (Ferrous Gluconate, Fergon, Ferralet, Simron) (see Iron Gluconate)
    • Iron Sucrose (Venofer) (see Iron Sucrose)
      • Risk of First-Exposure Anaphylaxis (see Anaphylaxis) [MEDLINE]: 24 per 100k patients
      • Cumulative Risk of Anaphylaxis (Over 12 wk Period) [MEDLINE]: iron sucrose has lowest risk of all of the intravenous iron agents
  • Nonsteroidal Anti-Inflammatory Drugs (NSAID’s) (see Nonsteroidal Anti-Inflammatory Drug)
    • Epidemiology: NSAID’s rarely cause allergic reactions via this mechanism
  • Platins
  • Progesterone (see Progesterone)
  • Protamine (see Protamine)
  • Radiographic Contrast (see Radiographic Contrast)
    • Epidemiology: although contrast-associated IgE-mediated anaphylaxis was once considered rare, contrast-specific IgE antibodies have been demonstrated in some cases (Am J Roentgenol, 2008) [MEDLINE] (Allerg Immunol, 1993; Paris) [MEDLINE]
    • Physiology
      • IgE-Mediated: some cases
      • Non-IgE-Mediated: most cases
        • Activation of Coagulation/Kinin/Complement Cascades
        • Direct Mast Cell Activation
        • Inhibition of Cholinesterase
        • Inhibition of Platelet Aggregation with Increased Serotonin Release
  • Sorafenib (Nexavar) (see Sorafenib)
  • Streptomycin (see Streptomycin)
  • Succinylcholine (see Succinylcholine)
  • Sulfobromophthalein
  • Taxanes (see Taxanes)
  • Vaccines: may be due to either egg or gelatin components of the vaccine
  • Vitamin K (see Vitamin K)

Other

  • Aeroallergens: rarely involved in angioedema/anaphylaxis
    • Cat Dander
    • Grass Pollen
    • Horse Dander
  • Allergen Immunotherapy (see Allergen Immunotherapy)
  • Blood Products
  • Fluorescein (see Fluorescein)
  • Hemodialysis (see Hemodialysis): due to reaction to dialysis membranes
    • Cellulose Membranes: predominant type of membrane associated with anaphylaxis
      • Membranes are ethylene oxide sterilized
      • Membranes can activate complement
    • Polyacrylonitrile AN69 High Flux Membranes: fewer reported cases of anaphylaxis
  • Human Seminal Fluid
    • Epidemiology: rare etiology of anaphylaxis in females
  • Intradermal Allergen Skin Testing
  • Natural Rubber Latex (see Latex)
  • Occupational Allergens
  • Vaccines

Immunologic Non-IgE-Mediated Mast Cell Activation

  • Heparin Contaminated with Oversulfated Chondroitin Sulfate (see Heparin)
    • Physiology: mediated by coagulation system activation
  • Dextrans
    • Dextran (see Dextran)
    • Iron Dextran (Dexferrum, INFeD) (see Iron Dextran)
      • Risk of First-Exposure Anaphylaxis [MEDLINE]): 68 per 100k patients
      • Cumulative Risk of Anaphylaxis (Over 12 wk Period) [MEDLINE]: iron dextrose has highest risk of all of the intravenous iron agents
  • Idiopathic Histaminergic Angioedema
    • Clinical: recurrent angioedema often associated with chronic spontaneous urticaria or inducible (physical) urticaria
  • Infliximab (Remicade) (see Infliximab)
    • Physiology: IgG-mediated
  • Packed Red Blood Cells (PRBC) (see Packed Red Blood Cells)
    • Epidemiology: rare cases of patients with very low levels of IgA and anti-IgA Ab’s, may develop anaphylaxis upon receiving blood with IgA present (these patients need IgA-deficient blood products)
  • Radiographic Contrast (see Radiographic Contrast)
    • Epidemiology: although contrast-associated IgE-mediated anaphylaxis was once considered rare, contrast-specific IgE antibodies have been demonstrated in some cases (Am J Roentgenol, 2008) [MEDLINE] (Allerg Immunol, 1993; Paris) [MEDLINE]
    • Physiology
      • IgE-Mediated: some cases
      • Non-IgE-Mediated: most cases
        • Activation of Coagulation/Kinin/Complement Cascades
        • Direct Mast Cell Activation
        • Inhibition of Cholinesterase
        • Inhibition of Platelet Aggregation with Increased Serotonin Release

Non-Immunologic Direct Mast Cell/Basophil Activation

  • Ethanol (see Ethanol): rarely induces anaphylaxis by itself, but may augment mast cell activation
  • Foods: these “pseudoallergens” may cause urticaria (or contact urticaria) via IgE-mediated or via non-immunologic mechanisms, especially in children
    • Strawberries
    • Tomatoes
  • Neuromuscular Junction Antagonists (see Neuromuscular Junction Antagonists)
    • Relative Incidence (in Australian Study from 2002-2011): Rocuronium (56% of cases) > Succinylcholine (21% of cases) > Vecuronium (11% of cases) (Br J Anaesth, 2013) [MEDLINE])
      • Cisatracurium Had the Lowest Prevalence of Cross-Reactivity in Patients with Known Anaphylaxis to Either Rocuronium or Vecuronium
    • Atracurium (see Atracurium)
    • Cisatracurium (Nimbex) (see Cisatracurium
    • Curare (see Curare)
    • Rocuronium (Zemuron) (see Rocuronium)
    • Succinylcholine (see Succinylcholine)
    • Vecuronium (see Vecuronium)
  • Non-Steroidal Anti-Inflammatory Drugs (NSAID) (see Non-Steroidal Anti-Inflammatory Drug)
  • Opiates (see Opiates)
  • Physical Factors
    • Cold
    • Heat
    • Exercise: usually associated with a co-trigger (such as a food, NSAID, or exposure to cold air or water)
    • Sunlight/Ultraviolet Radiation
  • Radiographic Contrast (see Radiographic Contrast)
    • Epidemiology: although contrast-associated IgE-mediated anaphylaxis was once considered rare, contrast-specific IgE antibodies have been demonstrated in some cases (Am J Roentgenol, 2008) [MEDLINE] (Allerg Immunol, 1993; Paris) [MEDLINE]
    • Physiology
      • IgE-Mediated: some cases
      • Non-IgE-Mediated: most cases
        • Activation of Coagulation/Kinin/Complement Cascades
        • Direct Mast Cell Activation
        • Inhibition of Cholinesterase
        • Inhibition of Platelet Aggregation with Increased Serotonin Release
  • Stinging Nettle (Urtica Dioica) (see Stinging Nettle): urticaria was named after this weed (which is commonly found in North America, South Americam Europe, and parts of Africa
    • Physiology: histamine (and pain-causing mediators) contained in the plant
  • Vancomycin (see Vancomycin)

Other

  • Clonal Mast Cell Disorder
  • Systemic Mastocytosis (see Systemic Mastocytosis)
  • Previously Unrecognized Allergen

Physiology

Molecular Mechanism of Anaphylaxis

  • Mast Cell/Basophil Activation with Release of Multiple Mediators
    • Histamine
    • IL-4
    • IL-13
    • Leukotrienes
    • Platelet Activating Factor
    • Prostaglandin D2 (PGD2)
    • TNFα
    • Tryptase

Distributive Shock (Similar to Sepsis) (see Hypotension)

  • Variable Cardiac Output (CO)
    • Early (Before Volume Resuscitation): hypovolemia predominates -> decreased preload -> normal or decreased CO
    • Later (After Volume Resuscitation): high CO with low SVR state
    • Myocardial depression (decreased ejection fraction observed on echocardiogram) is frequent, despite increased CO
  • Venous and Arterial Vasodilation
  • Capillary Leak: due to endothelial cell dysfunction
    • Interstitial edema
  • Tachycardia: due to hypotension-induced reflexive increase in heart rate
  • Hypovolemia (early in course): due to capillary leak and venous/arterial vasodilation

Diagnosis

Mast Cell Serum Tryptase Level (see Serum Tryptase)

  • Draw within hours of event to diagnose anaphylaxis
  • May not be elevated in some cases

RAST Testing

  • Useful for Allergy Testing: detects allergen-specific IgE

Chest X-Ray (CXR) (see Chest X-Ray)

  • Normal CXR: most common pattern
  • Hyperinflation: may indicate the presence of bronchospasm
  • Pulmonary Edema: may occur in severe cases

Diagnostic Criteria (One of Three Following Criteria) (J Allergy Clin Immunol, 2006) [MEDLINE]

Acute Onset of Illness (Within Min-Several Hours) with Skin/Mucosal Tissue Involvement (Flushing/Generalized Erythema, Hives, Pruritus, Swollen Lips/Tongue/Uvula) and At Least One of the Following

Two or More of the Following Occurring Rapidly After Exposure to a Likely Antigen

Hypotension After Exposure to a Known Allergen for a Specific Patient Within Min-Several Hours (see Hypotension)

  • Adult: systolic blood pressure 90 mm Hg or >30% in systolic blood pressure from patient’s baseline
  • Infant/Children: age-specific hypotension or >30% decrease in systolic blood pressure

Clinical Manifestations

General Comments

  • Onset: within min-4 hrs
  • Biphasic Reaction: symptoms can recur 10 hrs later -> due to this clinical characteristic, prolonged observation may be required (and corticosteroids are often useful to blunt the development of the second phase)

Cardiovascular Manifestations

Dermatologic Manifestations

Gastrointestinal Manifestations

Neurologic Manifestations

  • Dizziness (see Dizziness)
  • Lightheadedness
  • Sense of Impending Doom

Otolaryngologic Manifestations

  • Conjunctival Injection
  • Lacrimation
  • Metallic Taste
  • Nasal Congestion
  • Ocular Pruritus
  • Oropharyngeal Edema/Upper Airway Obstruction (see Obstructive Lung Disease)
  • Peri-Orbital Edema
  • Rhinorrhea (see Rhinorrhea)
  • Sneezing

Pulmonary Manifestations

Other Manifestations

  • Uterine Contractions: in females

Anaphylactoid Reactions to Contrast Medium

Cutaneous and Mucosal

  • Angioedema
  • Edema
  • Flushing
  • Laryngeal Edema
  • Pruritus

Smooth Muscle

  • Arrhythmia
  • Bronchospasm
  • Cardiovascular
  • GI Spasm
  • Uterine Contraction
  • Vasodilation/Hypotension/Anaphylactic Shock

Types of Contrast Reactions

Minor

  • Flushing
  • Nausea
  • Pruritus
  • Rash
  • Urticaria

Major

  • Cough
  • Dyspnea
  • Seizures
  • Shock
  • Stridor
  • Syncope
  • Wheezing

Treatment

General Treatment

Epinephrine (see Epinephrine)

  • Indications
    • Systemic Symptoms (Hypotension, etc)
  • Pharmacology
    • Bronchodilation
    • Vasoconstriction
  • Adverse Effects
  • Dose: 0.3 mg IM (1:1000) for adults
    • Repeat Dosing: may repeat q5-10 min
    • Max Single Dose: 1 mg
    • Max Total Dose: none
  • Preferred Route of Administration
    • Non-Code Blue Situation: IM into thigh is preferred over SQ route
    • Code Blue Situation: IV route (with 1:10,000 solution) is preferred

Preloaded Epinephrine Injectable Devices

  • Advantages
    • Patient Can Keep Nearby at Home for Emergency Use: do not store in warm/hot places (such as a car), due to drug stability
      • Shelf-Life: 1 year (when stored properly)
  • Adult Dose: 0.3 mg IM (1:1000) for adults
  • Brands
    • Epipen
      • Hold like a pen, not like a knife (to avoid inadvertent injection into the thumb)
      • Remove blue safety cap -> firmly push orange tip against lateral thigh (don’t need to remove clothes to use), until it clicks -> hold in place for 5-10 sec
    • Auvi-Q: provides verbal instructions
    • Adrenaclick: pen-like device

Corticosteroids (see Corticosteroids)

  • Pharmacology
  • Administration
    • PO: Prednisone (see Prednisone)
      • Dose: 40-50 mg qday PO with taper
    • IV: Methylprednisolone (Solumedrol) (see Methylprednisolone)
      • Dose: 125 mg IV x1, then 60 mg IV q6hrs with taper

H1-Histamine Receptor Antagonists (see (see H1-Histamine Receptor Antagonists)

  • Indications
    • Skin Symptoms
  • Pharmacology: H1-Histamine Receptor Antagonist
  • Agents

H2-Histamine Receptor Antagonists (see H2-Histamine Receptor Antagonists)

  • Pharmacology: H2-Histamine Receptor Antagonist
  • Agents

References

  • Physiologic manifestations of human anaphylaxis. J Clin Invest 1980; 66:1072-1080 [MEDLINE]
  • Hemodynamic changes in human anaphylaxis. Am J Med 1984; 77:341-344 [MEDLINE]
  • Profound reversible myocardial depression after anaphylaxis. Lancet 1988; 1:386-388 [MEDLINE]
  • Anaphylactic shock induced by paracetamol. Eur J Clin Pharmacol. 1990;38(4):389 [MEDLINE]
  • Anaphylaxis-induced myocardial depression treated with amrinone. Lancet 1991; 337:682-683 [MEDLINE]
  • Anaphylaxis. N Engl J Med 1991; 324:1785-1786 [MEDLINE]
  • Histamine decreases left ventricular contractility in normal human subjects. J Appl Physiol 1992; 73:2530-2537 [MEDLINE]
  • Paracetamol anaphylaxis. Clin Exp Allergy. 1992;22(9):831 [MEDLINE]
  • Case report: recurrent anaphylactic shock to radiographic contrast media. Evidence supporting an exceptional IgE-mediated reaction. Allerg Immunol (Paris). 1993;25(10):425 [MEDLINE]
  • Anaphylaxis induced by horsefly bites: identification of a 69 kd IgE-binding salivary gland protein from Chrysops spp. (Diptera, Tabanidae) by western blot analysis. J Allergy Clin Immunol. 1998;101(1 Pt 1):134. [MEDLINE]
  • Second symposium on the definition and management of anaphylaxis: summary report–Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006 Feb;117(2):391-7 [MEDLINE]
  • Anaphylaxis to iodinated contrast material: nonallergic hypersensitivity or IgE-mediated allergy? AJR Am J Roentgenol. 2008;190(3):666 [MEDLINE]
  • Anaphylaxis. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S161 [MEDLINE]
  • World allergy organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J. 2011 Feb;4(2):13-37. doi: 10.1097/WOX.0b013e318211496c [MEDLINE]
  • The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose. J Allergy Clin Immunol. 2011;127(5):1286. Epub 2011 Mar 31 [MEDLINE]
  • Anaphylaxis to neuromuscular blocking drugs: incidence and cross-reactivity in Western Australia from 2002 to 2011. Br J Anaesth. 2013 Jun;110(6):981-7. doi: 10.1093/bja/aes506. Epub 2013 Jan 18 [MEDLINE]
  • Tick bites and red meat allergy. Curr Opin Allergy Clin Immunol. 2013 Aug;13(4):354-9. doi: 10.1097/ACI.0b013e3283624560 [MEDLINE]
  • International consensus on (ICON) anaphylaxis. World Allergy Organ J. 2014; 7(1): 9 [MEDLINE]
  • The alpha-gal story: lessons learned from connecting the dots. J Allergy Clin Immunol. 2015;135(3):58 [MEDLINE]
  • Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products. JAMA. 2015 Nov 17;314(19):2062-2068. doi: 10.1001/jama.2015.15572 [MEDLINE]
  • Red meat allergy induced by tick bites: A Norwegian case report. Eur Ann Allergy Clin Immunol. 2017 Jul;49(4):186-188 [MEDLINE]