Researchers identified a new pathological mechanism responsible for anaphylactic shock

Anaphylactic shock, an exacerbated allergic reaction that can prove fatal, is sometimes caused by the use of drugs during surgery.

In most of these extreme reactions, evidence can be provided that patients have anti-drug antibodies of the IgE class. In 10 to 20 percent of anaphylactic cases, evidence for the involvement of anti-drug IgE is lacking.

Anti-drug IgE enable activation of mast cells and basophils that release histamine, a potent mediator involved in anaphylaxis.

Teams from the Institut Pasteur, Inserm, the Paris Public Hospital Network (AP-HP), the CNRS, Paris-Sud University and Sorbonne University have successfully identified a new pathological mechanism responsible for these previously unexplained cases involving neutrophils activated by antibodies of the IgG class.

These findings, published on July 10 in the journal Science Translational Medicine, will help improve diagnosis and treatment for patients with this type of shock.

Anaphylaxis is a hyperacute allergic reaction caused by an inappropriate immune response following the introduction of a usually harmless antigen into the body.

When this antigen binds to antibodies already in the body, it triggers the secretion of large quantities of potent vasodilating mediators, sending the patient into a state of shock that may result in multiple organ failure and even death.

Anaphylaxis may be brought about by various substances, including drugs (antibiotics or neuromuscular blocking agents), food and insect venom.

In this study, the scientists focused on allergic reactions to neuromuscular blocking agents (NMBAs), drugs used during general anesthesia to induce muscle relaxation.

The incidence of anaphylactic shock caused by NMBAs is one case in every 10,000 to 20,000 surgeries, representing approximately three to five cases each week in the Greater Paris area.

Although it was already known that IgE antibodies could cause anaphylaxis, teams from the Institut Pasteur, Inserm, the Paris Public Hospital Network (AP-HP), the CNRS, Paris-Sud University and Sorbonne University have demonstrated in a clinical study that IgG antibodies can also be involved in drug-induced anaphylactic shocks.

This unexpected role of IgG antibodies had already been identified in mice in 2011 by some of the same authors.

This multicenter study, led by Bichat Hospital (part of the Paris Public Hospital Network), was launched in 2012 by a consortium of scientists, clinical biologists and anesthetists. The consortium monitored 86 patients with perioperative anaphylactic shock and 86 control patients in 11 hospitals in the Greater Paris area, coordinated at Bichat Hospital by immunologist Professor Sylvie Chollet-Martin (Paris-Sud University) and anesthetist Professor Dan Longrois.

Blood samples were taken as soon as an anaphylactic shock occurred in the operating room, enabling the scientists to identify the alternative IgG-dependent mechanism.

They demonstrated that IgG antibodies activate neutrophils (50-70 percent of our white blood cells), releasing high doses of harmful vasodilating mediators.

Neutrophil activation was more pronounced in cases of severe shock than in cases of moderate shock.

Interestingly, the IgG-neutrophil pathway was also identified in most cases of shock where the traditional IgE-dependent mechanism was observed, suggesting that IgGs and neutrophils may contribute to the severity of most cases of shock via an additive effect.

“These findings elucidate 10 to 20 percent of cases of anaphylactic shock that previously had no biological explanation.

They will be extremely valuable in refining diagnosis in these patients and avoiding any future exposure with the drug that triggered the allergic reaction,” explains Professor Sylvie Chollet-Martin (Paris-Sud University), joint last author of the study and Head of the Immunology laboratory on Autoimmunity and Hypersensitivity at Bichat Hospital.

“Although IgG antibodies are known to protect the body from infection and to act as aggressors in some autoimmune diseases, this study reveals that they may be involved in humans in another reaction that is harmful for the body, anaphylaxis.

We are currently carrying out experimental research to explore how we might block this new activation pathway for IgG antibodies so that we can propose a therapeutic solution,” comments Pierre Bruhns, joint last author of the study, Inserm Research Director and Head of the Institut Pasteur’s Antibodies in Therapy and Pathology Unit.

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Defining anaphylaxis: history and consensus

In 1839, François Magendie was the first to describe the phenomenon of anaphylaxis experimentally when he found that rabbits that were able to tolerate a single injection of egg albumin often died after the second or third injection. He assumed these reactions were “toxic” because the injected albumin in these animals acted as a poison.1 In 1902, Charles Richet and Paul Portier coined the term anaphylaxis from ana (against) and phylaxia (protection) in Greek for the “property that has a poison to lower immunity rather than reinforce it.”2 Current expert consensus has defined anaphylaxis as a serious allergic reaction that is rapid in onset and can be fatal.3,4 The diagnosis is based on three possible clinical scenarios:

1. Sudden onset of an illness (minutes to hours) with involvement of the skin, mucosal tissue (or both), and at least one of the following: a) respiratory compromise and b) reduced blood pressure or symptoms of end-organ dysfunction;
2. Two or more of the following that occur after exposure to a likely allergen or other triggers (minutes to several hours): skin/mucosal symptoms and signs, respiratory compromise, reduced blood pressure or associated symptoms, and/or gastrointestinal symptoms (crampy abdominal pain or vomiting).
3. Reduced blood pressure after exposure to a known allergen (minutes to hours).5

Critically, anaphylaxis involves at least two organ systems or sudden changes in vital signs. Skin and mucosal changes are usually but not always present, whereas hypotension and shock features are not mandatory for the diagnosis.6,7

Anaphylactoid reactions are clinically indistinguishable from anaphylaxis, with no demonstrable involvement of immunoglobulin E (IgE), and the term is no longer used, mainly to avoid unnecessary delays in diagnosis and treatment.3,8,9

Despite advances in the field of allergy, the symptoms of anaphylaxis continue to be under-recognized, diagnosis is often missed, treatment is often delayed (including the lack of epinephrine use), and the underlying causes are under-investigated worldwide.5,7,10

In 2003, to homogenize the nomenclature of allergy worldwide, the World Allergy Organization (WAO) proposed two classifications of anaphylaxis on the basis of the pathophysiological mechanism involved in the reaction. The term allergic anaphylaxis denotes reactions mediated by an immunologic mechanism – for example, IgE-, Ig, or an immune complex complement-related (corresponding to the classic hypersensitivity reactions [HSRs] described by Gell and Coombs) pathways. The term non-allergic anaphylaxis denotes reactions mediated by other mechanisms (eg, direct activation by bradykinin or complement), which are usually triggered by agents or events that induce sudden mast cell or basophil activation.11

Between 2004 and 2005, several organizations came together to update the definition and emphasize the use of epinephrine as a first-line treatment for anaphylaxis.6,12 Several studies were carried out to validate the criteria and to expand the scientific evidence with regard to the pathophysiology, triggers, and clinical management of anaphylaxis. The WAO provided a consensus document for the diagnosis and treatment of anaphylaxis. This report has been reviewed and updated to incorporate changes based on updated scientific evidence.3,4,8,9

Recently, a consensus document between the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology was published, which summarizes current knowledge in the field of allergy. They proposed a new approach based on precision medicine through phenotypes, which is associated with specific mechanisms that are defined as endotypes and the associated diagnostic biomarkers in food and drug allergies and anaphylaxis.13 This new classification encompasses the classic HSRs described by Gell and Coombs as well as reactions outside the classification.14Go to:

Phenotypes, endotypes, and biomarkers of anaphylaxis

Phenotypes are defined by clinical presentation, and endotypes refer to the cellular and molecular mechanisms of the HSRs defined by the diagnostic biomarkers (skin testing, tryptase, IgE, interleukin [IL]-6, and others).

Phenotypes of anaphylaxis are classified, by their clinical presentation, into Type I reactions, cytokine-release reactions (CRRs), mixed reactions, and, finally, bradykinin- and complement-like reactions. The corresponding endotypes underlying these phenotypes include IgE- and non–IgE-mediated mechanisms, cytokine-mediated mechanisms, mixed processes, and direct activation of immune cells by either complement or bradykinin14 (Figure 1).

Type I

IgE-mediated anaphylaxis is the major mechanism underlying allergic anaphylaxis.1 After exposure to the allergen, a series of signals trigger the production of allergen-specific IgE by B cells (sensitization phenomenon).

In subsequent exposures, the antigen–allergen-specific IgE complex binds to the Fc-epsilon-RI receptor on mast cells and/or basophils and, with adequate signaling, activates and degranulates these cells, thereby releasing preformed mediators, enzymes, and cytokines and facilitating the synthesis of de novo inflammatory mediators (eg, tryptase, histamine, leukotrienes, prostaglandins, platelet-activating factor [PAF], cytokines).15,16

The mediators cause allergic symptoms by directly acting on tissues.

The reaction is propagated by recruiting and activating additional inflammatory cells – particularly eosinophils, which release more mediators, including lipid-derived mediators such as prostaglandin D2 and cysteinyl leukotrienes.16

In addition to the classical pathway mediated by IgE, other possible pathways have been described in animal models that are difficult to explore in humans.17 

One of these alternative pathways is similar to the IgE-mediated pathway, but involves IgG antibodies. IgG-mediated reactions are mediated by IgG complexes that cross-link to the macrophage low-affinity receptor (FcgRIII) thus stimulating PAF (rather than histamine) release.18

PAF causes platelet aggregation and release of the potent vasoconstrictor thromboxane A2 and serotonin; acts directly on vascular endothelial cells to increase vascular permeability; decreases cardiac output, which can produce hypotension and cardiac dysfunctions; and increases smooth muscle contraction in the airways, gut, and uterus, among other effects.19,20

Although IgG-dependent anaphylaxis has not been demonstrated in humans, it has been hypothesized that IgG antibodies can mediate systemic anaphylaxis if there are large numbers of both IgG and antigen present.21 

IgG receptors are capable of activating macrophages and neutrophils to secrete PAF and activate mast cells in vitro, which may contribute to human anaphylaxis.20–23 

Chimeric IgG monoclonal antibodies (mAbs), such as rituximab, have been shown to induce anaphylaxis even in the absence of IgE, suggesting IgG-dependent anaphylaxis.24,25

Recent reports with regard to the direct activation of mast cells, independent of those mediated by IgE, indicate that the human G-protein–coupled receptor – MRGPRX2 – may be the receptor for many drugs and cationic proteins, such as quinolone antibiotics (eg, ciprofloxacin, levofloxacin), general anesthetics such as atracuronium and rocuronium, icatibant, and other drugs with tetrahydroisoquinoline (THIQ) motifs.26–29

The endotype for IgE-mediated reactions is mast cell and basophil mediator release that causes flushing, pruritus, hives, angioedema, shortness of breath, wheezing, nausea, vomiting, diarrhea, hypotension, oxygen desaturation, and cardiovascular collapse along with other symptoms.16,30

The common triggers for these reactions include foods, drugs, latex, Hymenoptera venoms, and environmental allergens.3,8–10,31,32 

There are important geographic and age-related variations between countries; however, the most common food allergens are peanut, milk, eggs, nuts, shellfish, fruits and vegetables;33 antibiotics such as β-lactams, nonsteroidal anti-inflammatory drugs (NSAIDs), chemotherapeutic agents such as platins and taxanes, chimeric humanized human mAbs, general anesthetics, and immunotherapy allergens are other common allergens both in children and adults.34,35

CRRs

The CRR phenotype is caused by the release of proinflammatory mediators such as tumor necrosis factor alpha (TNF-α), IL-1B, and IL-6, and their target cells (endotype) include monocytes, macrophages, mast cells, and other immune cells with the Fc gamma receptor (FcgR) – an essential participant in many immune system effector functions, including the release of inflammatory mediators and antibody-dependent cellular cytotoxicity.

Triggers for these reactions include chimeric, humanized, and human mAbs and chemotherapeutic agents, including oxaliplatin.

These drugs have not only been used to treat neoplastic, autoimmune, and inflammatory diseases but also to treat allergic disorders including allergic asthma, eosinophilic asthma, and chronic urticaria.36,37 

HSRs to biologic agents are less common than standard infusion reactions, and they vary based on the biological agents involved.25 

Phenotypic symptoms include chills, fever, and pain; these respond to ibuprofen and fluids and have been clinically correlated with IL-6.38 CRRs are typically not as severe as cytokine storm reactions.

Cytokine storm reactions are acute, severe, and potentially lethal systemic complications due to the production of large quantities of cytokines and chemokines, which play a pathological role in the development of systemic symptoms.39,40 IL-6 and other inflammatory cytokines such as IL-8, TNF-α, interferon gamma (IFN-γ), and IL-1β induce the inactivation of cadherin, which mediate cell adhesion, leading to vascular leakage by increased capillary permeability; moreover, this induces the formation of tissue factor (thromboplastin) on the cell surface of monocytes, with subsequent activation of the extrinsic coagulation pathway.41,42 

The effects of inflammatory cytokines play a pathological role in the development of pain, tissue hypoxia, hypotension, myocardial dysfunction, and, eventually, disseminated intravascular coagulation (DIC) and multiorgan dysfunction.

IL-6 is an excellent biomarker of cytokine storm reactions because of its correlation with the severity of the reaction and its longevity in blood serum.40

This phenotype is characterized by chills, fever, and generalized malaise followed by hypotension, desaturation, and cardiovascular collapse.14,25,37 

Premedication with anti-inflammatory COX-1 inhibitors and corticosteroids can decrease the intensity of these symptoms but does not protect from severe reactions.14

Mixed reactions (Type I/CRRs)

Mixed reactions occur as a mixture of Type I and CRR phenotypes and, typically, are observed during chemotherapy and/or mAbs HSR, wherein symptoms of IgE-mediated reactions such as redness, pruritus, urticaria, angioedema, difficulty breathing, wheezing, nausea, vomiting, diarrhea, hypotension, desaturation, cardiovascular collapse, and life-threatening anaphylaxis – occurring secondary to the release of mast cell/basophil mediators (tryptase, histamine, leukotrienes, and prostaglandins) – overlap with symptoms secondary to the release of proinflammatory cytokines and chemokines (IL-1β, IL-6, and TNF-α) such as chills, fever, malaise, hypotension, desaturation, and cardiovascular collapse, thereby making it impossible to differentiate between mechanisms.

Complement/bradykinin-like reactions

Complement reactions involve direct activation of mast cells and other immune cells through complement activation as well as direct and indirect activation of the intrinsic coagulation pathway.16,22,43 

Immune complexes can activate the complement system, generating anaphylatoxins such as C3a and C5a, which can bind to complement receptors resulting in release of histamine, leukotrienes, and prostaglandins that can induce flushing, hives, hypoxia, vasodilation, and hypotension.43,44 

This mechanism has been described with drugs such as vancomycin,45 contrast media,46 dialysis membranes, and infusions of drugs that are suspended in certain lipid vehicles such as Cremophor EL, polysorbate 80, and polyethylene glycol.17,47

Notably, reports have also suggested that complement can have an important role in vespid-induced anaphylaxis, exacerbating the reaction due to the activation of complement by proteases present in the venom and adding to the IgE-mediated reaction.44,48

The molecular pathway of bradykinin reactions has been elucidated in animal models and involves an increase in heparin and Factor XII-driven contact system that results in the production of bradykinin and ultimately accounts for the increased vascular permeability (clinically, hypotension and desaturation).22 

These symptoms have been associated with contamination of heparin with oversulfated chondroitin sulfate.49

Emergency Treatment of Anaphylaxis

A = Airway

Ensure and establish a patent airway, if necessary, by repositioning the head and neck, endotracheal intubation or emergency cricothyroidotomy.

Place the patient in a supine position and elevate the lower extremities. Patients in severe respiratory distress may be more comfortable in the sitting position.

B = Breathing

Assess adequacy of ventilation and provide the patient with sufficient oxygen to maintain adequate mentation and an oxygen saturation of at least 91% as determined by pulse oximetry. Treat bronchospasm as necessary.

Equipment for endotracheal intubation should be available for immediate use in event of respiratory failure and is indicated for poor mentation, respiratory failure, or stridor not responding immediately to supplemental oxygen and epinephrine.

C = Circulation 

Minimize or eliminate continued exposure to causative agent by discontinuing the infusion, as with radio-contrast media, or by placing a venous tourniquet proximal to the site of the injection or insect sting.

Assess adequacy of perfusion by taking the pulse rate, blood pressure, mentation and capillary refill time.

Establish I.V. access with large bore (16- to 18-gauge) catheter and administer an isotonic solution such as normal saline. A second I.V. may be established as necessary. If a vasopressor, such as dopamine becomes necessary, the patient requires immediate transfer to an intensive care setting.

The same ABC mnemonic can be used for the pharmacologic management of anaphylaxis:

A = Adrenalin = epinephrine

Epinephrine is the drug of choice for anaphylaxis.

It stimulates both the beta-and alpha-adrenergic receptors and inhibits further mediator release from mast cells and basophils. Animal and human data indicate that platelet activating factor (PAF) mediates life-threatening manifestations of anaphylaxis.

The early use of epinephrine in vitro inhibits the release of PAF in a time-dependent manner, giving support to the use of this medication with the first signs and symptoms of anaphylaxis.

The usual dosage of epinephrine for adults is 0.3-0.5 mg of a 1:1000 w/v solution given intramuscularly, preferably in the anterolateral thigh, every 10-20 minutes or as necessary. The dose for children is 0.01 mg/kg to a maximum of 0.3 mg intramuscularly, preferably in the anterolateral thigh, every 5-30 minutes as necessary.

Lower doses, e.g., 0.1 mg to 0.2 mg administered intramuscularly, preferably in the anterolateral thigh, as necessary, are usually adequate to treat mild anaphylaxis, often associated with skin testing or allergen immunotherapy.

Epinephrine should be given early in the course of the reaction and the dose titrated to the clinical response. For severe hypotension, 1 cc of a 1:10,000 w/v dilution of epinephrine given slowly intravenously is indicated. The patient’s response determines the rate of infusion.

B = Benadryl (diphenhydramine) 

Antihistamines are not useful for the initial management of anaphylaxis but may be helpful once the patient stabilizes.

Diphenhydramine may be administered intravenously, intramuscularly or orally.

Cimetidine offers the theoretical benefit of reducing both histamine-induced cardiac arrhythmias, which are mediated via H2 receptors, and anaphylaxis-associated vasodilation, mediated by H1 and H2 receptors. Cimetidine, up to 300 mg every 6 to 8 hours, may be administered orally or slowly I.V. Doses must be adjusted for children.

C = Corticosteroids

Corticosteroids do not benefit acute anaphylaxis but may prevent relapse or protracted anaphylaxis. Hydrocortisone (100 to 200 mg) or its equivalent can be administered every 6 to 8 hours for the first 24 hours. Doses must be adjusted for children.

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More information: Friederike Jönsson et al. Mouse and human neutrophils induce anaphylaxis, Journal of Clinical Investigation (2011). DOI: 10.1172/JCI45232

F. Jönsson el al., “An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis,” Science Translational Medicine (2019). stm.sciencemag.org/lookup/doi/ … scitranslmed.aat1479

Journal information: Science Translational Medicine , Journal of Clinical Investigation
Provided by Institut National de la Sante et de la Recherche Medicale