ALLERGIC REACTIONS AND ANAPHYLACTIC SHOCK
Allergic reaction is an amplified multiorgan reaction to a certain protein, called allergen, normally harmless for the most part of the population. It is a form of hypersensitivity of type I, that causes evident body reaction in about 1-2 hours(we can see plain symptoms of allergic reactions even after few minutes or half an hour).
Normally certain patients who are predisposed to allergy (they are atopic), after a first contact with an allergen, become sensitive to it. This is the process:
- the dendritic cells that come into contact with the allergen, expose it or its fragments on their MHC class II;
- lymphocytes Th2 (T helper) link by their TCR the complex composed by MHC class II + antigen, and start to produce and release IL-4;
- IL-4 stimulates the activation of lymphocytes B (B cells) that turn into plasmacyte, releasing IgE against that particular allergen into the blood;
- We could find IgE moving freely into the patient’s blood or tied to the membrane of macrophages and neutrophils: in case of a new contact with the allergen these cells would recognize it through the IgE and would immediately start to produce cytokines(we would see a primary reaction) as well as IL-4 to amplify the IgE secretion and IL-5 to activate eosinophils, strictly linked to a chronic allergic reaction. The atopy would became allergy(clinical manifestation of atopic disease).
The mediators of an allergic reaction aren’t only represented by IgE: in fact these globulins enable macrophages’ and neutrophils’ recognition of the allergen and start the allergic reaction, anyhow this reaction is amplified by cytokines released by the IgE presenting cells. Those cytokines are PAF (Platelet Activating Factor), PBE, leukotrienes and histamine: they are important vasoactive molecules. These mediators are involved both in the acute(vasodilatation and augmented vessels permeability, edema ad skin urticaria; bronchospasm, bronchial asthma, rhinitis and rhinorrhea; vomiting and diarrhea) and in the chronic allergic reaction(bronchial muscles hipertrophy, bronchospasm aggravation, skin eczema and chronic rhinitis).
We can have clinical manifestation of an allergy characterised by different latency, duration and severity depending on the kind and amount of allergen the patient contacted, on the level of sensitivity to the allergen and on the body tissues involved(skin tissue, renal system, gastrointestinal system, respiratory system, cardiovascular system, nervous system) .
Frequently patients who have discovered to be allergic to some substances follow a sort of prophylaxis:
- They try to keep their distance from the allergen;
- They may undergo vaccines or immunotherapy.
In addiction they generally know what to do in case an allergic reaction appears.
On the other hand a first aid ward could admit a patient with the typical symptoms of an allergic or anaphylactic reaction, who wasn’t aware to be allergic.
The anaphylactic shock is a reversible or irreversible syndrome due to exposure to different allergens, that appears in patients who are sensitized to these allergens. It is a sort of greatly amplified allergic reaction, seriously life-threatening, that requires an immediate medical treatment. Common allergen responsible for this reaction are:
- Drugs (antibiotics, insulin, muscle relaxant drugs, vaccines, immunotherapeutic drugs, substances for skin tests or provocation tests);
- Hymenoptera venoms(0,4-8% of all the cases): bees, wasps and hornets.
What occurs during an anaphylactic shock?
We have seen it is an amplified allergic reaction: it begins like an allergic reaction but in few minutes or hours evolves in a more severe systemic reaction.
It starts as an IgE mediated reaction in a sensitized patient followed by the release of cytokines by neutrophils and macrophages. Then a systemic reaction occurs mediated by histamine, leukotrienes and quinines: the last step is the development of systemic shock.
The differences between an allergic reaction and an anaphylactic shock lie in the whole body involvement: the anaphylactic shock is a systemic reaction.
The predominant target of shock are the respiratory and cardiocirculatory systems. The reaction occurs within 30-60 minutes, even if we can see reactions occur in few minutes: the latency and the severity of the symptoms depend on the way of contact or introduction of the antigen into the body, and on the chemical structure, and then aggressiveness, of the allergen.
Prodromes: they appear only if the shock hasn’t a sudden onset. They are asthenia, malaise, anxiety, psychomotor restlessness and profuse sweating.
- Cardiocirculatory system: hypotension and tachycardia due to vasodilatation, augmented vessel permeability, loss of capillary fluids and edema vascular collapse, blood stasis and hypovolemia.
- Respiratory system: tachypnea, dyspnoea due to bronchospasm, bronchoconstriction and associated with augmented mucous secretion(a higher resistance to the air flow)and edema of the glottis.
- We can also find other symptoms involving nervous system(loss of consciousness, coma, convulsions), gastrointestinal system (vomit, diarrhoea and severe abdominal pain), renal system (oliguria or anuria due to hypovolemia) and skin and mucous tissues (itching, urticaria, edema of the glottis, cyanosis, paleness and cold skin).
The altered function of the cardiocirculatory system, is the main cause for organ damage and tissue necrosis: weak tissue perfusion and alteration in the microcirculation cause an important change in tissue metabolism, leading it to necrosis and loss of function.
Therapy: the more sudden is the onset of the shock, the most serious is the prognosis and the most immediate the therapeutic administration must be.
- Let the patient assume a comfortable position;
- Remove the allergen;
- Administrate adrenaline(0.5 ml of a 1:1000 solution of adrenaline), antihistamine anti H1- anti H2 (Prometazina, Ranitidina 50 mg), high doses of corticosteroids (Hydrocortisone 25-50mg/Kg), β2 agonists in case of bronchospasm (Salbutamolo 250μg), α agonists to contrast hypotension (Dopamine), high flow oxygen, 1-2 liters of liquids(plasma substitutes) .
HYMENOMPTERA VENOM ALLERGY
An hymenopter by means of a sting can inject into our skin about 5μg of venom that can determine anaphylactic shock or a less severe allergic reaction in sensitized patients(more frequently in atopic than in non-atopic patients). The same sting event may results in a skin wheal or pustule without any complication in non sensitized patients.
The allergic reaction and anaphylaxis depend on proteins, enzymes and amines contained in the venom that are capable to disrupt a wide range of cell mechanisms. Therefore after a subcutaneous injection of hymenoptera venom different symptoms may appear as a consequence of the tissue damage due to the venom components and the immune-mediated answer.
The hymenopter’s venom in composed by:
- Low molecular weight biological amines: histamine, serotonin, acetylcholine, epinephrine;
- Proteins: quinines, mellitin (vasodilatation and hemolysis), apamin (neurotoxic effect);
- High molecular weight substances: phospholipase A (hemolysis), hyaluronidase (affect the rate of absorption of venom).
The low molecular weight amines are involved in local reactions(reactions in the site of injection): they work on nervous endings and vessels causing swelling, reddening, itching and pain.
Proteins are the most toxic component of hymenoptera venom, acting on human body’s tissues cells: they cause cell membrane injury followed by the release into the extracellular fluid of cytoplasmic enzymes and granules. The enzymes can contribute to the tissue damage: histamine, serotonin and heparin released by the mast cells granules work together with the venom amines and are involved in the local reaction.
The high molecular weight substances are the most significant allergens because the most part of the allergic reactions depends on them. They have both a cytotoxic effect (phospholipase A) and participate to the tissue digestion(hyaluronidase). Hyaluronidase is an enzyme able to unpack the connective tissue, which keeps the cells held together, by the digestion of hyaluronic acid. It is a spread factor of the venom.
Hymenoptera, snakes and other insects venom: composition, action and emergency treatments
Symptoms: we can refer to Muller classification of clinical signs of allergy to hymenoptera, that includes four steps.
0) Normal local inflammation found both in allergic and non-allergic patients: it is a skin lesion of variable diameter(1-10 cm) painful, swollen and flushed. It lasts 24 hours or some days;
1) Generalized urticaria, itching and general malaise. We can easily find patients fear’s signs (headache, hyperventilation, palpitations, hot flushes and paresthesias). Patients who have repeated generalized reactions to wasp venom injection recognize pulsating feelings in the ears, tightness of the throat, substernal pain and fear of impending death;
2) Nausea, vomit and vertigo; abdominal pain; bronchoconstriction and wheezing; generalized angioedema;
3) Dyspnoea, dysphagia, dysarthria, aphonia, mental confusion and sensory system’s loss of function;
4) Cyanosis, hypotension, cardiocirculatory collapse, urinary and fecal incontinence and loss of consciousness.
In some case other reaction have been observed:
- Serum sickness disease: fever, arthritis and lymphadenopaty;
- Glomerulonephritis and nephrotic syndrome;
- Cardiac arrhythmias especially in the elderly and in the youngest patients, myocardial infarction;
- Proteinuria, haematuria, hemolytic anemia, thrombocytopenia and CID ( Disseminated Intravascular Coagulation);
- Peripheral neuropathy, intracranial edema or haemorrage, mental changes.
All of these symptoms are strictly related to the wasp venom proteins and amines, that are powerful vasoactive molecules and to molecules derived from mast cell degranulation and immune-mediated allergic reaction. For example histamine, contained both in wasp venom and in mast cell, basophilic and eosinophilic granules has a predominant role. It induces an increase in vessels permeability that leads to extravasation and edema, reduced capillary perfusion and augmented mucous secretion especially in the airways; it mimes the adrenergic system activity by the stimulation of stomach, bronchi, intestine and uterus smooth muscles contraction and by the stimulation of large blood vessels contraction and small blood vessels distension. It works on heart with inotropic and chronotropic effect; it works on coronary stimulating their dilatation.
It also interacts with the synaptic terminals: it has a sympathomimetic or vagotonic activity.
Then its release brings to:
- Hypotension and hypovolemia;
- Tachycardia to grant tissues perfusion with a reduces blood volume;
- Bronchoconstriction and dyspnoea, asthma;
- Skin local or generalised reaction with edema and swelling, reddening, pain, itching and urticaria (we have to remember that our body activates an immune-mediated reaction that results in a local or systemic inflammation);
- Vomit and abdominal pain;
- Altered activity of neuronal synapses.
- EMERGENCY TREATMENT: non allergic people generally do not need to be treated. Allergic patients, or patients stung in the mouth or with past severe allergic reactions need a quick intervention.
First of all we have to remove the bee sting with tweezers or with nails without squeezing the venom sack, and to disinfect the site of injection putting a corticosteroid ointment or packed ice on it. We have to position the patient supine on a solid support, raising his lower limbs in order to aid the venous return. Afterward we have to ensure venous access and to apply a string near the hymenopter injury, removing it every 10-15 minutes. If a severe edema of the glottis is noticeable tracheotomy or intubation are needed.
The pharmacological intervention is needed too and consists of the administration of adrenaline or noradrenaline, antihistamine antiH1 – anti H2 (ranitidina, prometazina), corticosteroids (hydrocortisone), α and β agonists, high flow oxygen and plasma substitutes, exactly as we saw talking about anaphylactic reaction therapy.
- IMMUNOTHERAPY (prevention and prophylaxis): is a concrete prevention option. It is a sort of desensitization by the hymenoptera venom, obtained through the subcutaneous administration of venom doses. It is a recently discovered still evolving therapy very useful for people who doesn’t develop a natural type of desensitization or who have a severe reaction on being stung again.
Its aim is that of suppress established IgE reaction by central suppression of IgE answer or by peripheral interference with it. Its administration must be carefully evaluated depending on patient’s age, allergic history, and other diseases. It consists in a local, subcutaneous or oral administration of growing doses of the venom: we start with little doses of 0.1μg three times a day at 30-minutes interval on the first day. Then we give weekly improving doses trying to reach loss of sensitivity, until we reach doses of 100μg in about six weeks. Every patient has his own history and therefore has a specific reaction to this trial(more or less positive and fast). It’s important, especially for highly sensitive patients, to be treated in a hospital or in a clinic where supporting treatment ,in the event of an anaphylactic reaction, is available.
- Abnormal reaction after a sting: 1:100 individuals
- Severe systemic reaction after a sting: 1: 100.000 individuals
- Fatal event after a sting: 1:1.000.000. 33% of all fatal event occur after a single sting, frequently on head or in neck areas, of over 40-years-old individuals.
Allergy to bee stings: a review - Nov1980
HOW TO DIAGNOSE AN HYMENOPTERA VENOM’S ALLERGY
- Anamnesis: life and work environment, risk of contact with hymenoptera; identification of the stinging insect; latency and duration of the allergic reaction; organs and tissues target of the venom-mediated and immune-mediated reaction; kind of reaction(local or generalized);
- Skin tests: prick test using venoms of insect present in the country where patient lives;
- In vitro test(laboratory test): dosage of IgE (total IgE with PRIST test; IgE specific for a certain allergen with RASP-RAST, EIA-ELISA).
We are going to see two cases of myocardial infarction after a wasp sting.
The first one is that of a 72 –years-old man with pre-existent anatomical coronary impairment and recidivous ischemic heart disease occurred during a wasp sting related anaphylactic reaction.
This 72-years-old man was brought to the emergency department. He complained of a severe and prolonged precordial pain. He was suffering from an anaphylactic shock due to a wasp sting on his right foot, characterized by urticaria, itching, vomit and profuse sweating. He was hypotensive, his blood systolic pressure (PAS) was 80 mmHg: he was given 500ml of Haemaccel to normalise blood pressure.
- History of inferior Acute Myocardial Infarction: one year before the patient underwent an exercise test, that pointed out a residual ischemia. He was suggested to undergo a coronary angiogram, but he didn’t accomplished it;
- Risk factors for ischemic cardiopathy: anatomical coronary impairment;
- Current therapy with β blocker, nitro-derivatives, ACE-inhibitors, ASA and Statin(endogenous cholesterol synthesis’ blocker).
CLINICAL EXAMINATION: when he was admitted to the Intensive Care Unit he was asymptomatic and the physical examination showed valid and rhythmic heart sounds with baseline ejection murmur; symmetric pulses and blood arterial pressure 120/70 mmHg; absence of moist sounds on thorax auscultation. The cutaneous manifestation secondary to allergy had disappeared.
ECG realised during chest pain showed ischemic abnormalities of cardiac apex ventricular repolarisation.
Echocardiogram showed mild dilatation of the left ventricle(FE 60% = ejection fraction), middle-lower, mid-basal postero-lateral hypokinesia and basal inferior akinesia.
The chest X-ray showed central interstitial involvement with apico-basal flow equalization.
- CBC: normal levels of hemoglobin and hematocrit; WBC = 17.900/mm³ (82% neutrophils; 2% eosinophils), high levels.
- VES: in standard;
- PCR =1,61mg/dl, high levels;
- Cardiac Marker: augmented levels - with peak reached twelve hours after the heart failure- of Troponin(Tn-T)= 46,9 ng/ml, CK= 308 U/L, CK-MB= 38,3ng/dl;
- Prick test: confirmed allergic reaction to wasp venom.
During the hospital stay the patient revealed neither sign of cardiovascular decompensation nor symptoms of angina. Repeated ECG showed an ischemic evolution at the cardiac apex, but neither hypo-hyperkinetc arrhythmias nor silent ischemia were evident.
One month later the patient underwent a Coronary Angiogram at another hospital that allowed to document Multivessel Coronary Artery Disease (occlusion of the right coronary artery[CDx], severe stenosis of the circumflex first segment with occlusion of a branch of the obtuse margin[MO], no significant stenosis of the anterior interventricolar artery and septal and epicardial collateral circulation due to CDx and MO); bilateral renal artery stenosis with aneurysm of the sub-renal abdominal aorta.
- We have leukocytosis and high levels of PCR: inflammation?
- The Prick Test confirmed the patients allergy to wasp’s venom;
- The altered ECG and levels of Cardiac Markers together with the results of the Echocargiogram and of the Chest X-Ray confirmed the ventricular apex ischemia;
- The Coronary Angiogram confirmed the Croronary Artery Disease.
The simultaneous accomplishment of those events creates a link between Coronary Artery Disease, anaphylactic reaction and Acute Myocardial Infarction. In 5% of autopsies carried out after the death of the patient for anaphylactic shock there is evidence of Acute Myocardial Infarction: it is then reasonable in this case to link the past history of the patient and his predisposition to heart diseases, due to his Multivessel Coronary Artery Disease, to his wasp’s venom allergy.
We can say that after the wasp’s sting the patient developed an anaphylactic reaction that through coronary vasospasm, arterial hypotension and thrombogenesis in an already compromised tissue (Multivessels Coronary Artery Disease) caused a secondary Acute Myocardial Infarction.
1)Coronary vasospasm: vasoactive amines contained in the insect venom and vasoactive amines release from damaged or activated mast cells (Histamine, Serotonin, Epinephrine, Leukotrienes, Bradykinin) bring to systemic vasodilatation and coronary vascontriction.
2)Arterial hypotension: the same substances just mentioned causes hypotension because of systemic vasodilatation and growing vessels permeability linked to angioedema and consequent hypovolemia.
3)Thrombogenesis: procoagulant factors activation and genesis of thrombi.
Since some myocardial areas are less perfused due to coronary disease, the vasoconstriction, the activation of procoagulant factors and the hypovolemia further reduce the tissue perfusion determining hypoxia and ischemia, with following myocardial damage. In addition, since hypovolemia causes tachycardia, the patient’s heart has to improve his work: anyhow he can’t afford to improve it, because of reduced myocardial perfusion.
TERAPHY: during the hospital stay 500 ml of Haemaccel was administrated to the patient, and following was resumed the usual patient’s therapy. The suggested Coronary Angiogram was achieved and allowed to give an indication for timing of surgery.
If the anaphylactic reaction hadn’t disappeared it would have been necessary to administrate antihistamines or adrenaline to the patient, keeping him under strict control in case of an aggravation due to adrenaline.
It is important in this case to monitor the patient’s coronary artery disease in order to avoid other cases of IMA disconnected from a wasp injury, and to reduce the risk of contact with hymenopters.
"Infarto miocardico acuto dopo puntura di vespa - 2005": http://www.arcacardio.eu/upload/documenti/giornale/PDF200773_466363.pdf
The second one is that of a 65-year-old woman who, during an initially undiagnosed anaphylactic reaction, had ECG changes suggesting acute myocardial ischemia . An angiography showed normal coronary artery anatomy.
When this woman was brought to the emergency department by the paramedics she was nonresponsive, diaphoretic, pale and hypotermic(35°C). She was hypotensive too (PAS=60mmHg), radial pulse couldn’t be felt and she was tachicardic(BPM=126). Her respirations were shallow and no wheezing or rales were heard. When she regained consciousness she reminded she had been stung by a bee and she immediately collapsed while walking down the street.
- Family history for coronary artery disease in her mother and sister;
- She hadn’t previous history of allergy to bee stings.
- Pale, diaphoretic, non responsive, no spontaneous eye opening, ;
- Pulse regular but not detectable radial and dorsalis pedis pulses. Hypotension (PAS=60mmHg) and tachycardia(BPM=126);
- Skin without rush or lesions, no edema or cyanosis of the extremities, no evidence of trauma to the head;
- Shallow respiration without rales or wheezing.
- ECG: sinus tachycardia without ectopy. ECG changes typical of an acute posterior myocardial infarction.
A second ECG after treatment showed a return to normality.
Coronary angiography showed a normal coronary artery anatomy. No vasospasm was seen.
- CBC: a little reduced hematocrit and levels of haemoglobin;
- Not remarkable hypokalemia and hyperglycemia;
- Not remarkable changes in CK and CK-MB levels;
- Prick test: showed the woman bee’s venom allergy.
As in the previous case we see a patient that after a wasp sting develops an anaphylactic reaction that brings to Acute Myocardial Infarction. Nevertheless in the first case we see a patient with coronary artery disease exposed to a significant risk of myocardial infarction; in the second case we see a woman without coronary artery disease. In both circumstances we can diagnose a wasp sting allergy responsible for the anaphylactic shock, and an acute myocardial infarction resulting from the cardiocirculatory system’s alteration brought by the shock.
We can conclude that the anaphylactic shock may cause a myocardial infarction both in patients with anatomical coronary impairment than in patients without any anatomical coronary alteration.
The hypothesis formulated in the review to clear up this second case events include:
- A reaction mediated by the administered epinephrine;
The first and the second have been excluded since those event developed after the ECG changes, than the more reasonable interpretation is again an anaphylactic shock mediated myocardial infarction.
She was given boluses of saline solution(250ml) to a total of 2 liters and Dobutamide Hydrocloride after the first ECG evaluation: her mental state improved slightly and her PAS upgraded from 60mmHg to 70mmHg.
After the angiogram she was given Solu-Medrol(methylprednisolone sodium succinate), Benadryl(diphenhydramine hydrochloride) intravenously.
Electrocardiographic changes associated with anaphylaxis in a patient with normal coronary arteries - 1994Dec