Kounis Syndrome and Intracardiac Metal Devices From Bedside to Bench! Nicholas Kounis, Iatros, MD, FESC, FACC “A hypersensitivity blow up inside the heart”
Jun 16, 2015
Kounis Syndrome and Intracardiac Metal Devices
From Bedside to Bench!
Nicholas Kounis, Iatros, MD, FESC, FACC
“A hypersensitivity blow up inside the heart”
Hypersensitivity inflammation
Acute coronary syndrome+
Hypersensitivity inflammation
Acute coronary syndrome
Hypersensitivity coronary syndrome (Kounis syndrome)
+
Hypersensitivity inflammation
Acute coronary syndrome
Hypersensitivity coronary syndrome (Kounis syndrome)
Intracardiac devices Containing Nickel and Other Metals
1. Coronary Stents including Bare Metal Stents (BMS) and Drug Eluting Stents (DES)
2. Devices for Closure
Of Atrial
Septal Defects
and Patent Foramen
Ovale
3.Cardiac
Pacemakers and
defibrillators
4. Artificial Cardiac
Valves
Kounis syndrome: the hypersensitivity coronary syndrome
What is?“The concurrence of acute coronary syndromes with conditions associated with mast cell activation, involving interrelated and
interacting inflammatory cells, and including allergic or hypersensitivity and anaphylactic or anaphylactoid insults”. “It is caused by inflammatory mediators such as histamine, neutral proteases, arachidonic acid products, platelet activating factor and a variety of cytokines and chemokines released during the activation process.” “A subset of platelets bearing FCεRI and FCεRII receptors are also involved in the activation cascade”
Mast cells
Macrophages T-cells
Mast cells
The vicious cycle of inflammatory cells
Macrophages
Mast cells
Macrophages
T-cells
Macrophages
All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals:
1. Mast cells can enhance T cell activation1
2. T cells can mediate mast cell activation and proliferation2
3. Inducible macrophage protein-1α can activate mast cells3
4. mast cells can activate macrophages4
5. T cells can regulate macrophage activity5
1. Nakae S, et al. J Immunol 2006; 176: 2238 2. Mecori YA, et al. Clin Immunol 1999; 104: 517 3. Miyazaki D, et al. J Clin Invest 2005; 115: 434 4. Salari H, et al. J Immunol 1989; 142: 2821 5. Doherty TM. Curr Opin Immunol 1995; 7: 400
Kounis syndrome variants
Type I variant: includes patients with normal coronary arteries without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA, et al. Can J Cardiol 2002; 18: 508
Type II variant: includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant: includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M. Expert Rev Clin Immunol 2010; 6: 777-88
Nikolaidis LA, et al. Can J Cardiol 2002; 18: 508
Kounis syndrome: main actions of main mediators
Cardiac effects of histamine1.Coronary vasoconstriction (histamine test)2. Induces tissue factor expression and activity3. Activates platelets and potentiates the
aggregatory response of agonists e.g. adrenaline, 5-hydroxytryptamine, and thrombin
4. Intimal thickening5. Inflammatory cell modulation6. Modulates the activity of neutrophils,
monocytes, and eosinophils7. Proinflammatory cytokine production8. P-selectine upregulation9. Sensitizites nerve endings in coronary plaques
Kounis syndrome: cardiac actions of main mediators: Proteases
Tryptase
1. Activates the zymogen forms of metalloproteinases such as interstitial collagenase, gelatinase, and stromelysin and can promote plaque disruption or rupture.
2. Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides, such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3. Tryptase can degrade HDL 4. Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2, and thrombin receptors
Chymase
1. Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries. Thus, angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery. Chymase also can remove cholesterol from HDL
2. Activates MMP-1,-2,-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
3. Releases latent TGF-β1 from the extracellular matrix
4. Inhibits smooth muscle growth5. Induces apoptosis of arterial smooth
muscle cells and endothelial cellsCathepsin D
1. Angiotensin II-forming protease
2.Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes: Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane: A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor: In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators. In experimental anaphylaxis reproduces the electrical and mechanical effects observed in allergic reactions such as ST changes and arrhythmias acting either through the release of leukotrienes or as a direct
vasoconstrictor
Kounis syndrome: cardiac actions of the main mediators
How Kounis syndrome is associated with stent and other devices thrombosis? Antigens are necessary and antigens are
present not only throughout stenting process but also after implantation of devices containing nickel,
polymers and other metals
the Factsthe evidence
the mechanism
THE FACTS: First generation Drug Eluting Stents components:
1.The metal itself is made from stainless steel which contains:
nickel, chromium, manganese, titanium and molybdenum
2.The polymer coating
3.The antineoplastic Paclitaxel 3.The antiproliferative Rapamycin
All these are strong allergens andconstitute the “stent antigenic complex”
Kounis NG, et al. J Am Coll Cardiol 2006; 48: 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome (erythema in the buttocks and upper
inner thighs resembling the red bottom of baboons)
bronchial asthma dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG. Hahalis G, Theoharides TC. J Interven Cardiol 2007; 20: 314
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG. Hahalis G, Theoharides TC. J Interven Cardiol 2007; 20: 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG. Hahalis G, Theoharides TC. J Interven Cardiol 2007; 20: 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG. Hahalis G, Theoharides TC. J Interven Cardiol 2007; 20: 314
Hypersensitivity reactions of Rapamycin -acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION STENTS: they are named cobalt-chromium
stents (misleading term?)
Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55% cobalt 20% chromium, 15% tungsten, 10% nickel
Min. Max Carbon 0.05 0.15
Manganese 1.00 2.00
Silicon -- 0.40
Phosphorus -- 0.040
Sulfur -- 0.030
Chromium 19.00 21.00
Nickel 9.00 11.00
Tungsten 14.00 16.00
ron -- 3.00
Cobalt* Balance Balance•
SECOND GENERATION STENTS: they are named cobalt-chromium
stents (misleading term?)
Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55% cobalt 20% chromium, 15% tungsten, 10% nickel
Min. Max Carbon 0.05 0.15
Manganese 1.00 2.00
Silicon -- 0.40
Phosphorus -- 0.040
Sulfur -- 0.030
Chromium 19.00 21.00
Nickel 9.00 11.00
Tungsten 14.00 16.00
ron -- 3.00
Cobalt* Balance Balance•
Endeavor (zotarolimus) stent
4. Clopidogrel-induced allergic skin rash
4. Clopidogrel-induced allergic skin rash
5. Kounis NG, et al. “Myocardial infarction after aspirin treatment, and the Kounis syndrome”. J R Soc
Med 2005; 98: 296
6. Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may “join forces” with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous, persistent,
chronic and repetitive allergic irritation!
Allergic inflammation is initiated by allergens
cross-bridging their corresponding, receptor-bound, immunoglobin IgE or IgG antibodies on the surface of the mast cells or basophils. A total of 1000 bridges are necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface. It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibody
“ IgE antibodies with different specificities can have an additive effect i.e. if mast cells are sensitized with small, even subthreshold numbers of IgE antibodies of different specificities they can “join forces” and trigger the cells to release its mediators,if the patient is simultaneously exposed to corresponding allergens”
Nopp A, et al. Allergy 2006; 61: 1336
MacGlashan DW, et al. J Immunol 1997; 158: 1438
Stents, like magnet, attract inflammatory cells!
1. Stent thrombosis associated with allergic symptoms such as glottis edema, cold sweat, and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation. Int J Cardiol. 2009; 134: e45-6.
2. Acute myocardial infarction, in the stented area, coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography . Int J Cardiol 2010; 139: 206-9.
3. Intrastent thromboses have also been reported following insect and larvae sting allergic reactions. Cases J. 2009; 2: 7800
Types of PFO and ASD ocluders containing nitinol ( nickel-titanium alloy)
AMPLATZER® device - used for PFO repair GORE HELEX Septal Occluder - used for PFO repair
The generators are covered with titanium and the pacing leads are made from MP35N (an alloy of
Ni, Co, Cr, and Mo)
Artificial heart valves: Parts are made of Co-Cr-W-Ni alloy. Today nickel free-valves are available
The ASD and PFO closure device and Kounis syndrome symptoms and signs
The “Device syndrome”
Eight out of 9 patients with proven, by skin tests, allergy to nickel developed a syndrome the 2nd and 3rd posroperative day after implantation a full nitinol Aplatzer occluder and low nitinol Premere
closure system consisting of:
-exertional dyspnea -palpitations
-worsening of headache
-asthenia
-leukocytosis
-atrial fibrillation (2 patients with negative skin patch testing but with occluder system implantation)
Rigatelli G, et al. Congenit Heart Dis 2007;2:416–20
The ASD and PFO closure device and Kounis syndrome symptoms and signs
The “Device syndrome”
Eight out of 9 patients with proven, by skin tests, allergy to nickel developed a syndrome the 2nd and 3rd posroperative day after implantation a full nitinol Aplatzer occluder and low nitinol Premere
closure system consisting of:
-exertional dyspnea -palpitations
-worsening of headache
-asthenia
-leukocytosis
-atrial fibrillation (2 patients with negative skin patch testing but with occluder system implantation)
Rigatelli G, et al. Congenit Heart Dis 2007;2:416–20
The Kounis syndrome
• -Chest discomfort• -Acute chest pain• -Dyspnea• -Faintness• -Nausea• -Vomiting• -Syncope• -Pruritus• -Urticaria• -Hypotention• -Diaphoresis• -Pallor• -Palpitations• -Bradycardia• -Tachycardia Kounis NG, et al. Br J Clin Pract 1991;45:121–8
THE EVIDENCE
Kounis syndrome and intracardiac Devices
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious?- Virmani et al. Circulation 2004; 109: 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes, with a focal giant cell reaction around stent strut (*) and surrounding polymer. Marked inflammation is similarly present in intima, media, and adventitia in J (left box in E). K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
It has been stated that “eosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarity”
Zavalloni D, et al. J Cardiovasc Med 2009;10: 942
THE MECHANISM
Kounis syndrome and intracardiac device thrombosis
Platelets play a central role in pathogenesis of thrombosis
Stent thrombosis
1. Platelet adhesion
2. Platelet activation
3. Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb/ IIIa inhibitors
2. ACTIVATION
MediatorsAdhesive (vWF, fibrinogen)Prothrombotic (V,XI, PAI-1)Proinflammatory (PDGF, PF4)Aggregatory (ADP, ATP, Ca, Mg)
Mast cell
MEDATORS
1. ADHESIONVia interaction of GP IIb/II/a and vWF
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
3. AGGREGATION
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb/ IIIa receptors
Ticlopidin
2.
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb/ IIIa inhibitors
2. ACTIVATION
MediatorsAdhesive (vWF, fibrinogen)Prothrombotic (V,XI, PAI-1)Proinflammatory (PDGF, PF4)Aggregatory (ADP, ATP, Ca, Mg)
Mast cell
MEDATORS
1. ADHESIONVia interaction of GP IIb/II/a and vWF
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
3. AGGREGATION
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb/ IIIa receptors
PAF
Ticlopidin
2.
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb/ IIIa inhibitors
2. ACTIVATION
MediatorsAdhesive (vWF, fibrinogen)Prothrombotic (V,XI, PAI-1)Proinflammatory (PDGF, PF4)Aggregatory (ADP, ATP, Ca, Mg)
Mast cell
MEDATORS
1. ADHESIONVia interaction of GP IIb/II/a and vWF
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
3. AGGREGATION
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb/ IIIa receptors
PAF histamine
Ticlopidin
2.
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb/ IIIa inhibitors
2. ACTIVATION
MediatorsAdhesive (vWF, fibrinogen)Prothrombotic (V,XI, PAI-1)Proinflammatory (PDGF, PF4)Aggregatory (ADP, ATP, Ca, Mg)
Mast cell
MEDATORS
1. ADHESIONVia interaction of GP IIb/II/a and vWF
EosinophilAspirin
Mast cell
serotonin
Pl change from discoid to spiculated form
Degranulation
3. AGGREGATION
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb/ IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
2.
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb/ IIIa inhibitors
2. ACTIVATION
MediatorsAdhesive (vWF, fibrinogen)Prothrombotic (V,XI, PAI-1)Proinflammatory (PDGF, PF4)Aggregatory (ADP, ATP, Ca, Mg)
Mast cell
MEDATORS
1. ADHESIONVia interaction of GP IIb/II/a and vWF
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
3. AGGREGATION
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb/ IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
“allergic unit”
Petrikova M, et al. H1 antihistamines and activated blood platelets. Inflammation
Res 2006; 55 Suppl 1: S51-S52.
Antihistamines Dithiaden, Loratadine and Bromadyl inhibited platelet activation-aggregation in 3 experimental systems: 1. Whole human blood from healthy male donors 2. Platelets in plasma 3. Isolated plateletsDespite their stimulation with adenosine-5`-diphosphate (ADP)
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors (!)
In patients with cardiac pacemakers and defibrillators who died: Thrombi were found at autopsy in 33% of ventricular
and 48% on atrial leadsNovak M, et al. Europace. 2009; 11: 1510-6
Krumsdorf U, et al. JACC 2004;43; 302-9
Thrombus after ASD and PFO Device closure
Mid esophageal 2 (chamber view, 90 degrees).
Cardona L et al. Circulation 2011;124:1595-159695-1596
Prevention of thrombosis
Fighting against stent thrombosis1.Taking careful history of
adverse drug reactions and allergies
2.Monitoring of inflammatory mediators after stent or device insertion
3.Performing antibody and skin testing when and where appropriate
4.Performing macrophage and T-cell activation studies
5.Considering desensitization strategies
6.Considering the use of mast cell stabilizers and steroids
Kounis NG, et al. J Am Coll Cardiol 2006; 48: 592Kounis NG, et al N Engl J Med 2006; 354: 2076
7.Measuring of acute phase reactans8.Periprocedural antiinflammatory therapyGaspardone A, Versaci F. Am J Med 2005; 96: 65L
Fighting against stent thrombosis1.Taking careful history of
adverse drug reactions and allergies
2.Monitoring of inflammatory mediators after stent or device insertion
3.Performing antibody and skin testing when and where appropriate
4.Performing macrophage and T-cell activation studies
5.Considering desensitization strategies
6.Considering the use of mast cell stabilizers and steroids
Kounis NG, et al. J Am Coll Cardiol 2006; 48: 592Kounis NG, et al N Engl J Med 2006; 354: 2076
7.Measuring of acute phase reactans8.Periprocedural antiinflammatory therapyGaspardone A, Versaci F. Am J Med 2005; 96: 65L
Fighting against stent thrombosis1.Taking careful history of
adverse drug reactions and allergies
2.Monitoring of inflammatory mediators after stent or device insertion
3.Performing antibody and skin testing when and where appropriate
4.Performing macrophage and T-cell activation studies
5.Considering desensitization strategies
6.Considering the use of mast cell stabilizers and steroids
Kounis NG, et al. J Am Coll Cardiol 2006; 48: 592Kounis NG, et al N Engl J Med 2006; 354: 2076
7.Measuring of acute phase reactans8.Periprocedural antiinflammatory therapyGaspardone A, Versaci F. Am J Med 2005; 96: 65L
Which means that allergicpredispositionmay help in prediction of the risk for stentthrombosis
Future directions for
stents and other devices
1.Nickel free stainless steel with number of blood platelets attached to and 316L stainless steel
after dipping in fresh human blood plasma for 25 min and 3 hours
Yang K, Ren Y. Sci Technol Adv Mater 2010; 11: 1-13
Nickel sensitization (patch test)in North-Eastern Italy(Belluno, Bolzano, Padova, Pordedone, Rovereto,Rovigo, Trento, Trieste)
31.6% in women (9771)10.0% in men (4693)The overall prevalence 24.6%
Bioabsorbable Stents• …At 2 years after
implantation the stent was bioabsorbed, had vasomotion restored, restenosis
prevented and was clinically safe, suggesting freedom from late thrombosis
Serruys PW, et al. Lancet; 2009; 373: 897
Bioabsorbable Stents• …At 2 years after
implantation the stent was bioabsorbed, had vasomotion restored, restenosis
prevented and was clinically safe, suggesting freedom from late thrombosis
Serruys PW, et al. Lancet; 2009; 373: 897
• ..However, three “mores” are needed: more patients, more follow-up, and more experience in complex lesions
Colombo A, Sharp A. Lancet. 2009; 3 73: 869
3. Bioabsorbable Stents: A
self expanding drug-eluting non allergic poly-lactic acid stent
Medronic’s Official safety information
Contraindications
The Endeavor Sprint Zotarolimus-Eluting Coronary Stent System is contraindicated for use in:
1. Patients with a known hypersensitivity to zotarolimus or structurally-related compounds.
2. Patients with a known hypersensitivity to the cobalt-based alloy (cobalt, nickel, chromium, and molybdenum).
3. Patients with a known hypersensitivity to Phosphorylcholine polymer or its individual Components and in
4.patients with a known hypersensitivity or allergies to aspirin, heparin, clopidogrel or
ticlopidine
Warnings
Please ensure that the inner package has not been opened or damaged, as this indicates the
sterile barrier has been breached.
The use of this product carries the risks associated with coronary artery stenting, including
subacute thrombosis, vascular complications, and/or bleeding events.
This product should not be used in patients who are not likely to comply with the
recommended antiplatelet therapy
My euharisties to all of you
Σας Ευχαριστώ όλους σας
Nicholas Kounis
Nickel: a ubiquitous metalNickel allergy is most commonly associated with earrings and other jewelry for body piercings that contain some nickel. Common sources of nickel exposure include: Jewelry for body piercingsOther jewelry, including rings, bracelets, necklaces and jewelry claspsWatchbandsClothing fasteners, such as zippers, snaps and bra hooksBelt bucklesHairpinsEyeglass framesCoinsKitchen utensilsPaper clipsPensKeysTools, such as hammers and screwdriversDental fillingsArtificial body parts (prostheses), such as artificial heart valvesDrinking waterAlkaline batteriesCell phonesNickel is also found in some foods, such as oatmeal, chocolate, nuts, beans and dried fruit. Nickel may also be found in canned foods
Nickel allergy
Allergic to Nickel? Eat a Nickel Free Diet
People who are severely allergic to nickel as from earrings or belt buckles, can actually develop a rash from eating foods high in
nickel.In particular, chronic hand dermatitis has been associated with
eating foods high in nickel in patients with a known allergy. If you are allergic to nickel and have a chronic rash, especially of your
hands, then consider a nickel-free diet. Try to avoid:
-Chocolate
-Potatoes
-Salmon
-Nuts and Legumes (beans, lentils)
-Any canned food or canned fruit
-Hot water from the tap
-Anything acidic (like tomatoes) cooked in a stainless steel pan
-Leafy green vegetables