Pathophysiology and Organ Damage in Anaphylaxis



Anaphylaxis is an acute, potentially life-threatening multisystem syndrome resulting from the sudden release of mast cell- and basophil-derived mediators into the systemic circulation. Foods, medications, and insect stings cause most anaphylaxis for which a cause can be identified, but virtually any agent capable of directly or indirectly activating mast cells or basophils can cause it. This syndrome can consist of some or all the following signs and symptoms: diffuse pruritus, erythema, urticaria, and/or angioedema; bronchospasm; laryngeal edema; hypotension; and/or cardiac arrhythmias. Some of the other symptoms that can occur include nausea, vomiting, diarrhea, lightheadedness, headache, feeling of impending doom, and unconsciousness. Regardless of the presenting signs or symptoms, which usually present within 5–30 min following the administration of the offending agent, this reaction can progress to respiratory compromise and cardiovascular collapse resulting in human fatalities. Usually, the more rapid the onset of clinical manifestations, the more likely the anaphylaxis will be life threatening. Immediate and appropriate therapy, especially with epinephrine, is mandatory to reverse the reactions. While most reactions are uniphasic, some can be biphasic or protracted. This chapter discusses the immunopathologic mechanisms and effects of anaphylaxis.


Anaphylaxis Pathophysiology Severe allergic reactions Systemic allergic reactions 


  1. 1.
    Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol 2006;117:391–397.PubMedCrossRefGoogle Scholar
  2. 2.
    Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341–348.PubMedCrossRefGoogle Scholar
  3. 3.
    Simons FER, Sampson HA. Anaphylaxis epidemic: fact or fiction? J Allergy Clin Immunol 2008;122:1166–1168.PubMedCrossRefGoogle Scholar
  4. 4.
    Pumphrey, RS. Fatal anaphylaxis in the UK, 1992–2001. Novartis Found Symp 2004;257:116–128.PubMedCrossRefGoogle Scholar
  5. 5.
    Johansson SGO, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 2004;113:832–836.PubMedCrossRefGoogle Scholar
  6. 6.
    Coombs RRA, Gell PGH. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Gell PGH, Coombs RRA, Lachmann PJ, eds. Clinical Aspects of Immunology, 3rd ed. Oxford, England: Blackwell; 1975:761–781.Google Scholar
  7. 7.
    Sell S. Immunopathology. In: Rich RR, Fleisher TA, Schwartz BD, et al., eds. Clinical Immunology: Principles and Practice. St. Louis, Mo.: Mosby; 1996:449–477.Google Scholar
  8. 8.
    Finkelman FD. Anaphylaxis: lessons from mouse models. J Allergy Clin Immunol 2007;120:506–515.PubMedCrossRefGoogle Scholar
  9. 9.
    Strait RT, Morris SC, Finkelman FD. IgG blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interruption and Fcγ(gamma)RIIb cross-linking. J Clin Invest 2006;116:833–841.PubMedCrossRefGoogle Scholar
  10. 10.
    Shibamoto T, Liu W, Cui S, et al. PAF, rather than histamine, participates in mouse anaphylactic hypotension. Pharmacology 2008;82:114–120.PubMedCrossRefGoogle Scholar
  11. 11.
    Yokoi H, Myers A, Matsumoto K, et al. Alteration and acquisition of Siglecs during in vitro maturation of CD34+ progenitors into human mast cells. Allergy 2006;61:769–776.PubMedCrossRefGoogle Scholar
  12. 12.
    Olivera A, Mizugishi K, Tikhonova A, et al. The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis. Immunity 2007;26:287–297.PubMedCrossRefGoogle Scholar
  13. 13.
    Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003;98:1315–1324.PubMedCrossRefGoogle Scholar
  14. 14.
    Stallmach A, Giese T, Schmidt C, et al. Severe anaphylactic reaction to infliximab: successful treatment with adalimumab—report of a case. Eur J Gastroenterol Hepatol 2004;16:627–630.PubMedCrossRefGoogle Scholar
  15. 15.
    Hod EA, Sokol SA, Zimring JC, Spitalnik SL. Hypothesis: hemolytic transfusion reactions represent an alternative type of anaphylaxis. Int J Clin Exp Pathol 2009;2:71–82.PubMedGoogle Scholar
  16. 16.
    Cox L, Platts-Mills TAE, Finegold I, et al. American academy of allergy, asthma & immunology/American college of allergy, asthma and immunology joint task force report on omalizumab-associated anaphylaxis. J Allergy Clin Immunol 2007;120:1373–1377.PubMedCrossRefGoogle Scholar
  17. 17.
    Dreyfus DH, Randolph CC. Characterization of an anaphylactoid reaction to omalizumab. Ann Allergy Asthma Immunol 2006;96:624–627.PubMedCrossRefGoogle Scholar
  18. 18.
    Akin C, Scott LM, Kocabas CN, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood 2007;110:2331–2333.PubMedCrossRefGoogle Scholar
  19. 19.
    Lieberman P. Anaphylaxis and anaphylactoid reactions. In: Adkinson NF Jr, Yunginger JW, Busse WW, et al., eds. Middleton’s Allergy: Principles and Practice, 6th ed. St. Louis, Mo.: Mosby Year Book; 2003:1497–1522.Google Scholar
  20. 20.
    Ono E, Taniguchi M, Mita H, et al. Increased production of cysteinyl leukotrienes and prostaglandin D2 during human anaphylaxis. Clin Exp Allergy 2009;39:72–80.PubMedCrossRefGoogle Scholar
  21. 21.
    Kinn JW, Bache RJ. Effect of platelet activation on coronary collateral blood flow. Circulation 1998;98:1431–1437.PubMedCrossRefGoogle Scholar
  22. 22.
    Choi IH, Ha TY, Lee DG, et al. Occurrence of disseminated intravascular coagulation (DIC) in active systemic anaphylaxis: role of platelet-activating factor. Clin Exp Immunol 1995;100:390–394.PubMedCrossRefGoogle Scholar
  23. 23.
    Vadas P, Gold M, Perelman B, Liss GM, Lack G, Blyth T, et al. Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis. N Engl J Med 2008;358:28–35.PubMedCrossRefGoogle Scholar
  24. 24.
    Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005;95:217–228.PubMedCrossRefGoogle Scholar
  25. 25.
    Pushparaj PN, Tay HK, H’ng SC, et al. The cytokine interleukin-33 mediates anaphylactic shock. Proc Natl Acad Sci USA 2009;106:9773–9778.PubMedCrossRefGoogle Scholar
  26. 26.
    Goetzl EJ, Wasserman SI, Austin KF. Eosinophil polymorphonuclear leukocyte function in immediate hypersensitivity. Arch Pathol 1975;99:1–4.PubMedGoogle Scholar
  27. 27.
    Erjefält JS, Korsgren M, Malm-Erjefält M, et al. Acute allergic responses induce a prompt luminal entry of ­airway tissue eosinophils. Am J Respir Cell Mol Biol 2003;29:439–448.PubMedCrossRefGoogle Scholar
  28. 28.
    Kaliner M, Sigler R, Summers R, Shelhamer JH. Effects of infused histamine: analysis of the effects of H-1 and H-2 receptor antagonists on cardiovascular and pulmonary responses. J Allergy Clin Immunol 1981;68:365–371.PubMedCrossRefGoogle Scholar
  29. 29.
    Chrusch C, Sharma S, Unruh H, et al. Histamine H3 receptor blockade improves cardiac function in canine anaphylaxis. Am J Respir Crit Care Med 1999;160:142–149.Google Scholar
  30. 30.
    Schwartz LB. Effector cells of anaphylaxis: mast cells and basophils. Novartis Found Symp 2004;257:65–74.PubMedCrossRefGoogle Scholar
  31. 31.
    Yunginger JW, Nelson DR, Squillace DL, et al. Laboratory investigations of death due to anaphylaxis. J Forensic Sci 1991;36:857–865.PubMedGoogle Scholar
  32. 32.
    Lin RY, Schwartz LB, Curry A, et al. Histamine and tryptase levels in patients with acute allergic reactions: an emergency department-based study. J Allergy Clin Immunol 2000;106:65–71.PubMedCrossRefGoogle Scholar
  33. 33.
    Smith PL, Kagey-Sobotka A, Bleecker ER, et al. Physiologic manifestations of human anaphylaxis. J Clin Invest 1980;66:1072–1080.PubMedCrossRefGoogle Scholar
  34. 34.
    Pumphrey RS, Roberts IS. Postmortem findings after fatal anaphylactic reactions. J Clin Pathol 2000;53:273–276.PubMedCrossRefGoogle Scholar
  35. 35.
    Ansari MQ, Zamora JL, Lipscomb MF. Postmortem diagnosis of acute anaphylaxis by serum tryptase analysis. A case report. Am J Clin Pathol 1993;99:101–103PubMedGoogle Scholar
  36. 36.
    Schwartz HJ, Yunginger JW, Schwartz LB. Is unrecognized anaphylaxis a cause of sudden unexpected death? Clin Exp Allergy 1995;25:866–870.PubMedCrossRefGoogle Scholar
  37. 37.
    Platt MS, Yunginger JW, Sekula-Perlman A, et al. Involvement of mast cells in sudden infant death syndrome. J Allergy Clin Immunol 1994;94:250–256.PubMedCrossRefGoogle Scholar
  38. 38.
    Randall B, Butts J, Halsey JF. Elevated postmortem tryptase in the absence of anaphylaxis. J Forensic Sci 1995;40:208–211.PubMedGoogle Scholar
  39. 39.
    Edston E, van Hage-Hamsten M. β(beta)-Tryptase measurements post-mortem in anaphylactic deaths and in controls. Forensic Sci Int 1998;93:135–142.PubMedCrossRefGoogle Scholar
  40. 40.
    Edston E, Gidlund E, Wickman M, et al. Increased mast cell tryptase in sudden infant death—anaphylaxis, hypoxemia or artifact? Clin Exp Allergy 1999;29:1648–1654.PubMedCrossRefGoogle Scholar
  41. 41.
    Edston E, Eriksson O, van Hage M. Mast cell tryptase in postmortem serum—reference values and confounders. Int J Legal Med 2007;121:275–280.PubMedCrossRefGoogle Scholar
  42. 42.
    Flower RJ, Harvey EA, Kingston WP. Inflammatory effects of prostaglandin D2 in rat and human skin. Br J Pharmacol 1976;56:229–233.PubMedCrossRefGoogle Scholar
  43. 43.
    Hardy CC, Robinson C, Tattersfield AE, Holgate ST. The bronchoconstrictor effect of inhaled prostaglandin D2 in normal and asthmatic men. N Engl J Med 1984;311:209–213.PubMedCrossRefGoogle Scholar
  44. 44.
    Pugliese G, Spokas EG, Marcinkiewicz E, Wong PY. Hepatic transformation of prostaglandin D2 to a new prostanoid, 9 alpha,11 beta-prostaglandin F2, that inhibits platelet aggregation and constricts blood vessels. J Biol Chem 1985;260:14621–14625.PubMedGoogle Scholar
  45. 45.
    Goetzl EJ. Oxygenation products of arachidonic acid as mediators of hypersensitivity and inflammation. Med Clin NA 1981; 65:809–828.Google Scholar
  46. 46.
    Raible DG, Schulman ES, DiMuzio J, et al. Mast cell mediators prostaglandin-D2 and histamine activate human eosinophils. J Immunol 1992;148:3536–3542.PubMedGoogle Scholar
  47. 47.
    Juhlin L, Hammarström S. Effects of intradermally injected leukotriene C4 and histamine in patients with ­urticaria, psoriasis and atopic dermatitis. Br J Dermatol 1982;107 Suppl 23:106–110.PubMedCrossRefGoogle Scholar
  48. 48.
    Arm JP, Lee TH. Sulphidopeptide leukotrienes in asthma. Clin Sci 1993;84:501–510.PubMedGoogle Scholar
  49. 49.
    Austen KF. The Paul Kallós Memorial Lecture. From slow reacting substance of anaphylaxis to leukotriene C4 synthase. Int Arch Allergy Immunol 1995;107:19–24.PubMedCrossRefGoogle Scholar
  50. 50.
    Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium derived relaxing factor. Nature 1987;327:524–526.PubMedCrossRefGoogle Scholar
  51. 51.
    Coleman JW. Nitric oxide: a regulator of mast cell activation and mast cell-mediated inflammation. Clin Exp Immunol 2002;129:4–10.PubMedCrossRefGoogle Scholar
  52. 52.
    Mitsuhata H, Shimizu R, Yokoyama MM. Role of nitric oxide in anaphylactic shock. J Clin Immunol 1995;15:277–283.PubMedCrossRefGoogle Scholar
  53. 53.
    Rolla G, Nebiolo F, Guida G, et al. Level of exhaled nitric oxide during human anaphylaxis. Ann Allergy Asthma Immunol 2006;97:264–265.PubMedCrossRefGoogle Scholar
  54. 54.
    Lowenstein CJ, Michel T. What’s in a name? eNOS and anaphylactic shock. J Clin Invest 2006;116:2075–2078.PubMedCrossRefGoogle Scholar
  55. 55.
    Cauwels A, Janssen B, Buys E, et al. Anaphylactic shock depends on PI3K and eNOS-derived NO. J Clin Invest 2006;116:2244–2251.PubMedCrossRefGoogle Scholar
  56. 56.
    De Souza RL, Short T, Warman GR, et al. Anaphylaxis with associated fibrinolysis, reversed with tranexamic acid and demonstrated by thrombelastography. Anaesth Intensive Care 2004;32:580–587.PubMedGoogle Scholar
  57. 57.
    van der Linden P-WG, Struyvenberg A, Kraaijenhagen RJ, et al. Anaphylactic shock after insect-sting challenge in 138 persons with a previous insect-sting reaction. Ann Intern Med 1993;118:161–168.PubMedGoogle Scholar
  58. 58.
    Kaplan AP, Joseph K, Silverberg M. Pathways for bradykinin formation and inflammatory disease. J Allergy Clin Immunol 2002;109:195–209.PubMedCrossRefGoogle Scholar
  59. 59.
    James LP Jr, Austen KF. Fatal and systemic anaphylaxis in man. N Engl J Med 1964;270:597–603.PubMedCrossRefGoogle Scholar
  60. 60.
    Warren S, Dixon FJ. Antigen tracer studies and histologic observations in anaphylactic shock in the guinea pig. Part 1. Amer J Med Sci 1948;216:136–145.PubMedCrossRefGoogle Scholar
  61. 61.
    Lockey RF, Bukantz SC. Allergic emergencies. Med Clin North Am 1974;58:147–156.PubMedGoogle Scholar
  62. 62.
    Munoz J, Bergman RK. Mechanism of anaphylactic death in the mouse. Nature 1965;205:199–200.PubMedCrossRefGoogle Scholar
  63. 63.
    Coca AF. The mechanism of the anaphylaxis reaction in the rabbit. J Immunol 1919;4:219–231.Google Scholar
  64. 64.
    McCusker HB, Aitken ID. Anaphylaxis in the cat. J Pathol Bacteriol 1966;91:282–285.PubMedCrossRefGoogle Scholar
  65. 65.
    Greenberger PA, Rotskoff BD, Lifschultz B. Fatal anaphylaxis: postmortem findings and associated comorbid diseases. Ann Allergy Asthma Immunol 2007;98:252–257.PubMedCrossRefGoogle Scholar
  66. 66.
    Trani N, Bonetti LR, Gualandri G, Barbolini G. Immediate anaphylactic death following antibiotics injection: splenic eosinophilia easily revealed by pagoda red stain. Forensic Sci Int 2008;181:21–25.PubMedCrossRefGoogle Scholar
  67. 67.
    Raper RF, Fisher MM. Profound reversible myocardial depression after anaphylaxis. Lancet 1988;1:386–388.PubMedCrossRefGoogle Scholar
  68. 68.
    Bristow MR, Ginsburg R, Harrison DC. Histamine and the human heart: the other receptor system. Am J Cardiol 1982;49:249–251.PubMedCrossRefGoogle Scholar
  69. 69.
    Marone G, Bova M, Detoraki A, et al. The human heart as a shock organ in anaphylaxis. Novartis Found Symp 2004;257:133–149.PubMedCrossRefGoogle Scholar
  70. 70.
    Wittstein IS, Thiemann DR, Lima JAC, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352:539–548.PubMedCrossRefGoogle Scholar
  71. 71.
    Pumphrey RS. Fatal posture in anaphylactic shock. J Allergy Clin Immunol 2003;112: 451–452.PubMedCrossRefGoogle Scholar
  72. 72.
    Fisher MM. Clinical observations on the pathophysiology and treatment of anaphylactic cardiovascular collapse. Anaesth Intensive Care 1986;14:17–21.PubMedGoogle Scholar
  73. 73.
    Hermann K, Rittweger R, Ring J. Urinary excretion of angiotensin I, II, arginine vasopressin and oxytocin in patients with anaphylactoid reactions. Clin Exp Allergy 1992;22:845–853.PubMedCrossRefGoogle Scholar
  74. 74.
    von Tschirschnitz M, von Eschenbach CE, Hermann K, Ring J. Plasma angiotensin II in patients with Hymenoptera venom allergy during hyposensitization [abstract]. J Allergy Clin Immunol 1993;91:283.Google Scholar
  75. 75.
    Hanashiro PK, Weil MH. Anaphylactic shock in man: report of two cases with detailed hemodynamics and metabolic studies. Arch Intern Med 1967;119:129–140.PubMedCrossRefGoogle Scholar
  76. 76.
    Fahmy NR. Hemodynamics, plasma histamine and catecholamine concentrations during an anaphylactoid reaction to morphine. Anesthesiology 1981;55:329–331.PubMedCrossRefGoogle Scholar
  77. 77.
    Summers CW, Pumphrey RS, Woods WN, et al. Factors predicting anaphylaxis to peanuts and tree nuts in patients referred to a specialist center. J Allergy Clin Immunol 2008;121:632–638.PubMedCrossRefGoogle Scholar
  78. 78.
    Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995;92:1084–1088.PubMedCrossRefGoogle Scholar
  79. 79.
    Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol 2006;110:7–14.PubMedCrossRefGoogle Scholar
  80. 80.
    Abela GS, Picon PD, Friedl SE, et al. Triggering of plaque disruption and arterial thrombosis in an atherosclerotic rabbit model. Circulation 1995;91:776–784.PubMedCrossRefGoogle Scholar
  81. 81.
    Steffel J, Akhmedov A, Greutert H, et al. Histamine induces tissue factor expression: implications for acute coronary syndromes. Circulation 2005;112:341–349.PubMedCrossRefGoogle Scholar
  82. 82.
    Rubin LE, Levi R. Protective role of bradykinin in cardiac anaphylaxis: coronary-vasodilating and antiarrhythmic activities mediated by autocrine/paracrine mechanisms. Circ Res1995;76:434–440.PubMedCrossRefGoogle Scholar
  83. 83.
    Schuligoi R, Amann R, Donnerer J, Peskar BA. Release of calcitonin gene-related peptide in cardiac anaphylaxis. N-S Arch Pharmacol 1997;355:224–229.CrossRefGoogle Scholar
  84. 84.
    Rang WQ, Du YH, Hu CP, et al. Protective effects of calcitonin gene-related peptide-mediated evodiamine on guinea-pig cardiac anaphylaxis. N-S Arch Pharmacol 2003;367:306–311.CrossRefGoogle Scholar
  85. 85.
    Brown SGA, Blackman KE, Stenlake V, Heddle RJ. Insect sting anaphylaxis: prospective evaluation of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004;21:149–154.PubMedCrossRefGoogle Scholar
  86. 86.
    Schadt JC, Ludbrook J. Hemodynamic and neurohumoral responses to acute hypovolemia in conscious ­mammals. Am J Physiol 1991;260:H305–318.PubMedGoogle Scholar
  87. 87.
    Demetriades D, Chan LS, Bhasin P, et al. Relative bradycardia in patients with traumatic hypotension. J Trauma 1998;45:534–539.PubMedCrossRefGoogle Scholar
  88. 88.
    Szebeni J, Baranyi L, Sávay S, et al. Complement activation-related cardiac anaphylaxis in pigs: role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function. Am J Physiol Heart Circ Physiol 2006;290:H1050–1058.PubMedCrossRefGoogle Scholar
  89. 89.
    Fink MP. Bench-to-bedside review: cytopathic hypoxia. Crit Care 2002;6:491–499.PubMedCrossRefGoogle Scholar
  90. 90.
    Dewachter P, Jouan-Hureaux V, Franck P, et al. Anaphylactic shock: a form of distributive shock without inhibition of oxygen consumption. Anesthesiology 2005;103:40–49.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.University of Mississippi Medical CenterJacksonUSA

Personalised recommendations