This blog is a way of sharing the information and resources that have helped me to recover my son Roo from an Autism Spectrum Disorder. What I have learned is to view our symptoms as the results of underlying biological cause, which can be identified and healed. I say "our symptoms" because I also have a neuro-immune disorder called Myalgic Encephalomyelitis.

And, of course, I am not a doctor (although I have been known to impersonate one while doing imaginative play with my son)- this is just our story and information that has been helpful or interesting to us. I hope it is helpful and interesting to you!

Friday, March 3, 2017

Kounis Syndrome (Allergic Heart Attack)

The correlation between allergic reactions and cardiac symptoms was first officially noted in 1950 during an allergic reaction to penicillin.  Since then, this correlation has been noted at other times, but it wasn't until 1991 when Dr Kounis brought attention to the phenomenon that it started getting more recognition.  Kounis Syndrome (KS) refers to the situation in which an allergic reaction progresses to involve significant cardiac distress that can be an actual heart attack (Myocardial Infarction) or a spasming of the coronary artery that is very similar to a heart attack   Sometimes the chest pain associated with allergic reactions is called Allergic Angina.

The majority of Kounis Syndrome cases occur in Spain, Italy, Greece, and Turkey.  In these areas Kounis Syndrome is seen in about 1 in 5 coronary events.  It seems likely that this reflects a much more widespread awareness of this disorder in these countries, so it seems likely that the rate of Kounis Syndrome in the US is probably much higher than currently thought.  Without recognition of
the relationship between allergic reactions and coronary symptoms, people prone to Kounis Syndrome will continue to have these dangerous attacks until their allergic problems are managed better. KS has been documented in both children and adults.

Medscape explains a Kounis Syndrome episode in more detail:
"The pathophysiologic characteristics of KS involve coronary artery spasm and/or atheromatous plaque erosion or rupture during an allergic reaction. Coronary spasm is the result of local
hyperreactivity of a coronary segment to a vasoconstrictor stimulus.[1] The exact mechanisms resulting in vasospastic angina have not been fully established. It has been postulated that endothelial injury and hypercontractility of vascular smooth muscle may be the result of vasoconstrictor mitogens, leukotrienes, serotonin, endothelin, angiotensin II, histamine, and higher local concentration of blood-borne vasoconstrictors in areas adjacent to neovascularized atherosclerotic plaque.[15]"

There are 3 types of Kounis Syndrome:
-the first type is when the patient does not have existing coronary artery disease, but the mediators released during a mast cell reaction induce spasms in the coronary artery.  This can feel and look like a heart attack but does not always leave behind traces of evidence such as elevated enzyme levels.
-in the second type there is pre-existing atherosclerosis, which can be loosened and freed by the coronary spasms and this can then cause an actual Myocardial Infraction.
-in the third type, the person has a stent and the stent becomes occluded due to inflammation from histamine.  Since most stent-associated occlusions occur soon after they are placed, suspect this if the occlusion occurs long after the stent is placed.

Medscape provides more detail about the first two types:
Type 1 "is the occurrence of chest pain during an acute allergic reaction in patients without predisposing factors for coronary artery disease. An acute allergic event induces coronary artery spasm, resulting in chest pain and ischemic electrocardiographic changes, and the cardiac enzymes can either be normal or reflect progression to an acute myocardial infarction.[6,11] These cases have a normal myocardial perfusion scan, normal coronary angiogram, and positive ergonovine test.[11] The explanation for this type would be endothelial dysfunction or microvascular angina.[12]"

Type 2 "is the occurrence of chest pain in patients with angiographic evidence of coronary artery disease during an acute allergic reaction.[6,11] This type includes patients with quiescent pre-existing atheromatous disease, in whom an acute allergic episode can induce plaque erosion or rupture manifesting as an acute myocardial infarction.[1,6,12]"

More from Medscape "Histamine not only constricts the coronary arteries, but also sensitizes the nerve endings adjacent to adventitial mast cells in atherosclerotic coronary arteries.[20] Cardiac histamine acts via four different histamine receptors, and each receptor can contribute to the severity of the allergic myocardial damage. The H1 receptor mediates coronary vasoconstriction, while the H2 receptor mediates a minor degree of coronary relaxation. The interaction between H1 and H2 causes a decrease in diastolic blood pressure and an increased pulse pressure. H3 inhibits the endogenous norepinephrine release (enhancing the degree of shock observed during allergic reactions), and finally the H4 receptor regulates the chemotaxis of mast cells, eosinophils, and lymphocytes, causing change in the shape of eosinophils and upregulating adhesion molecules.[6,13,20]"

"Not all patients suffering from an allergic reaction develop an acute coronary event. What determines the development of KS remains unclear; however, it has been suggested that there is a threshold level of mast cell activation and mediator release above which the coronary artery spasm and plaque erosion or rupture occurs. This threshold level would be closely linked to the body site where the antibody-antigen reaction occurs, the area of exposure, mediator release, and, of course, the severity of the allergic reaction.[19,23]"

Detecting and Diagnosing Kounis Syndrome

Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management
"Recent research has shown that Kounis-like syndromes can affect the mesenteric and cerebral arteries. The coronary arteries, the heart and the entire arterial system seem to be vulnerable to allergic, hypersensitivity, anaphylactic, and/or anaphylactoid events and physicians should be alert for its consequences."

"The diagnosis of Kounis syndrome is based on clinical symptoms and signs as well as on laboratory, electrocardiographic, echocardiographic and angiographic evidence. A variety of these findings might accompany allergic symptomatology that helps in putting the correct diagnosis. Recently, modern tools such as cardiac magnetic resonance imaging and myocardial scintigraphy have helped to confirm the diagnosis. A high index of suspicion is of paramount importance. Therefore, patients with systemic allergic reactions associated with clinical, electrocardiographic and laboratory findings of acute myocardial ischemia should be suspected as having Kounis syndrome."

In patients with type I variant, treatment of the allergic event alone can abolish symptoms. The use of intravenous corticosteroids such as hydrocortisone at a dose of 1–2 mg/kg/day and H1 and H2 antihistamines such as diphenhydramine at a dose of 1–2 mg/kg and ranitidine at a dose of 1 mg/kg are adequate. The administration of vasodilators such as calcium channel blockers and nitrates can abolish hypersensitivity induced vasospasm. Calcium channel blockers can induce minor skin rash and angioedema is extremely uncommon. However, nitroglycerin can causes hypotension and tachycardia that may further complicate anaphylactic reaction. In addition, although uncommon, allergic reactions to nitroglycerin such as urticaria and contact dermatitis can occur especially with the transdermal use of nitroglycerin. Most patients with these reactions have tolerated oral and sublingual nitroglycerin. Therefore, the use of intravenous or sublingual nitroglycerin seems reasonable and safe in patients with Kounis syndrome if the blood pressure is satisfactory. Bolus administration of antihistamines can precipitate hypotension and compromise coronary flow; therefore, these drugs should be given slowly."

"In patients with type II variant, treatment should be initiated with an acute coronary event protocol together with corticosteroids and antihistamines. Vasodilators such as nitrates and calcium blockers are given when these are necessary. The use of b-blockers can exaggerate coronary spasm due to unopposed action of a-adrenergic receptors. Epinephrine which is the drug of choice and can save lives in anaphylaxis, but in Kounis syndrome can aggravate ischemia and worsen coronary vasospasm. In severe cases sulfite free epinephrine is preferable to be given intramuscularly because it has faster onset of action and more sustained levels as compared with the subcutaneous route (recommended intramuscular doses 0.2–0.5 mg [1:1000]). Aqueous solution is preferable. In patients with previous history of coronary heart disease, who receive b-blockers, epinephrine may be ineffective. It may also induce more vasospasm due to unopposed a-adrenergic effect. In this case glucagon infusion (1–5 mg, intravenously over 5 min, followed by infusion 5–15 μg/min) can be used for patients who are already on beta-blockers or received them during the management of the acute coronary syndrome. Methoxamine, a potent alpha agonist, can also be considered in patients who do not respond to epinephrine. Opiates such as morphine, codeine and meperidine given to relieve acute chest pain should be administered with extreme caution in patients with Kounis syndrome, since they can induce massive mast cell degranulation and aggravate allergic reaction. Acetaminophen (paracetamol) is not recommended, especially its intravenous administration, because it might cause severe hypotension due to reduction of cardiac output. Fentanyl and its derivatives show slight mast cell activation and are preferable."

The utility of cardiac magnetic resonance imaging in Kounis syndrome.
"Dynamic cardiac MR imaging is a reliable tool for assessing cardiac involvement in Kounis syndrome. Delayed contrast-enhanced images show normal washout in the subendocardial lesion area in patients with Kounis syndrome type 1."

Two questions for Kounis syndrome: can we use magnetic resonance imaging in the diagnosis and does ST elevation correlates with troponin levels?
"These cases showed that there seems to be no correlation with ECG and troponin levels in KS. In addition, for patients in whom KS type 1 is expected without troponin elevation, noninvasive cardiac magnetic resonance imaging study seems to be appropriate for the diagnosis of KS."

Prevention and Treatment

As with any mast cell disease, identifying and avoiding triggers is essential, but this may not be easy since there are so many things that can trigger a Kounis Syndrome episode.

Coronary Hypersensitivity Disorder: The Kounis Syndrome
This article has a relatively long section about treatment for each type of Kounis Syndrome.

Stress triggers coronary mast cells leading to cardiac events.
"Stress can precipitate allergies and ACS. Stress stimulates MCs through the activation of high-affinity surface receptors for CRH, leading to a CRH-dependent increase in serum IL-6. Moreover, neurotensin secreted with CRH from peripheral nerves augments the effect of CRH and stimulates cardiac MCs to release IL-6, which is elevated in ACS and is an independent risk factor for myocardial ischemia. MCs also secrete CRH and uroctortin, which induces IL-6 release from cardiomyocytes. The presence of atherosclerosis increases the risk of cardiac MC activation owing to the stimulatory effect of lipoproteins and adipocytokines. Conditions such as Kounis syndrome, mastocytosis, and myalgic encephalopathy/chronic fatigue syndrome are particularly prone to coronary hypersensitivity reactions. Inhibition of cardiac MCs may be a novel treatment approach."

Drugs that may provoke Kounis Syndrome
"KS has been increasingly reported in the literature and has been linked with several conditions, environmental exposures and a variety of drugs, leading many experts to believe that KS is not rare, only "rarely diagnosed". Also:

"Treatment may be challenging because it needs to consider both cardiac and allergic symptoms simultaneously, and the drugs administered for these manifestations can aggravate an allergic reaction and heart function. Cevik et al. have summarized recommendations concerning the treatment of KS from available data, since most information about KS comes from case reports. The authors argue that:

1) Aspirin has the potential risk of aggravating an ongoing anaphylactic reaction since it might shunt arachidonic acid into the leukotriene pathway with overproduction of leukotrienes. Therefore, the utility of aspirin in patients with KS is unknown.

2) Nitroglycerin causes hypotension and tachycardia, which may further complicate anaphylactic reaction, but seems safe in KS if blood pressure is satisfactory.

3) Beta-blockers may induce more vasospasm due to unopposed α-adrenergic effect and may offset some of the beneficial effects of epinephrine.

4) Coronary spasm is very responsive to calcium channel blockers, so they may be considered the initial anti-ischemic drug of choice in patients with KS.

5) Morphine and meperidine should be used cautiously since these opiates can induce mast cell degranulation and aggravate the allergic reaction. Fentanyl and its derivatives show only a slight activation of mast cells and may be the drugs of choice when narcotic analgesia is necessary.

6) Corticosteroids have a major role in the treatment of allergic reactions, and may prevent recurrent or protracted anaphylaxis. A meta-analysis of the studies of corticosteroid treatment in acute MI reported no harm and possible mortality benefit with these drugs in this setting. Therefore, their use is probably safe and appropriate.

7) Epinephrine is the drug of choice in anaphylaxis, but in KS the risks may outweigh the benefits. Epinephrine can aggravate the ischemia as well as induce coronary vasospasm and arrhythmias. The majority of epinephrine preparations contain sulfite which itself may trigger anaphylaxis in sensitive individuals. It may also promote more vasospasm secondary to unopposed alpha-adrenergic effect in patients who have received beta-blocking agents. More case studies are needed to establish the appropriate use of epinephrine in patients with KS.

8) Mast cell membrane stabilizers may be considered in KS."

The more allergens an atopic patient is exposed to, the easier and quicker anaphylactic shock and Kounis syndrome appear: Clinical and therapeutic paradoxes.
"Clinical and therapeutic paradoxes concerning Kounis syndrome therapy, pathophysiology, clinical course and causality have been encountered during its clinical course. Drugs that counteract allergy, such as H2-antihistamines, can induce allergy and Kounis syndrome. The more drugs an atopic patient is exposed to, the easier and quicker anaphylaxis and Kounis syndrome can occur. Every anesthetized patient is under the risk of multiple drugs and substances that can induce anaphylactic reaction and Kounis syndrome. The heart and the coronary arteries seem to be the primary target in severe anaphylaxis manifesting as Kounis syndrome. Commercially available adrenaline saves lives in anaphylaxis but it contains as preservative sodium metabisulfite and should be avoided in the sulfite allergic patients."

Kounis Syndrome (MedScape)

Kounis syndrome; South Med J. 2010 Nov;103(11):1148-55.

Current understanding of Kounis syndrome
"Inflammatory mediators, adhesion molecules of neutrophils and monocytes, have been shown to be increased in the plasma of patients presenting with acute coronary syndromes. Anaphylaxis is a systemic, immediate hypersensitivity reaction caused by rapid IgE-mediated release of mediators from mast cells and basophils. Kounis syndrome is the coincidental occurrence of these two distinct conditions accompanied by clinical and laboratory findings of angina pectoris caused by inflammatory mediators released during an allergic insult. Allergic angina can progress to acute myocardial infarction, which is termed 'allergic myocardial infarction'. There are several causes reported to be capable of inducing Kounis syndrome. These include a number of conditions, several drugs, foods and insect stings, among others. In this article, the clinical aspects, diagnosis, pathogenesis, incidence and epidemiology, related conditions and therapeutic management of this important syndrome are discussed."

"We present three cases of anaphylactic acute coronary syndrome that display different clinical variants of this phenomenon. The main pathophysiological mechanism of the allergic anginal syndromes is the inflammatory mediators released during a hypersensitivity reaction triggered by food, insect bites, or drugs. It is important to appropriately recognize and treat Kounis syndrome in patients with exposure to a documented allergen."