Death following ceftazidime-induced Kounis syndrome

Introduction

Kounis syndrome, also known as allergic myocardial infarction or allergic angina syndrome, coincides with chest pain and allergic reactions.^1,2 The condition involves the activation of interrelated inflammatory cells as a consequence of an allergic or anaphylactoid event. The condition results from released inflammatory mediators including histamines, neutral proteases, arachidonic acid products, platelet-activating factor and a variety of cytokines and chemokines, during an allergic event.

The human heart is described as the site and primary target organ of anaphylaxis. Endogenous catecholamine release, together with therapies administered during management of anaphylaxis, may have damaging myocardial consequences. These include chest pain similar to that of ischaemic origin and also ischaemic electrocardiographic changes, but without the involvement of the coronary arteries. ² Preexisting coronary artery disease is associated with a higher prevalence of Kounis syndrome. However, the condition was also observed in patients with healthy coronary vessels. It was proposed that the primary pathophysiological mechanism of Kounis syndrome is vasospasm of the coronary arteries.^3,4

Case report

A 52-year-old male outpatient, who had been treated for a nail prick on the right heel 15 days earlier, was admitted to a local hospital. He was a known diabetic and allergic to amoxicillin and ampicillin. The following afternoon, he was administered an intravenous ceftazidime injection, with no penicillin skin testing performed prior to drug administration. He developed difficulty breathing with chest pain following the injection and was immediately transferred to the nearest tertiary care hospital with a Glasgow Coma Scale score of 3/15. On admission, his pulse was weak and thready with a rate of 130 beats/min. Despite intensive care management, he died approximately 19 h after ceftazidime administration.

An autopsy examination showed a surgically altered wound over the right sole, massive laryngeal oedema and mucous plugging with collapsed lungs. We also observed an enlarged spleen and blood-stained, partially digested food in the stomach, associated with submucosal erosion. The coronary arteries showed 30%–40% atheroma.

The ImmunoCAP tryptase assay performed on an autopsy sample showed a tryptase level of 118 µg/L (normal < 11.4 µg/L). Histopathology showed myocardial cellular infiltrates primarily consisting of neutrophils, with some mast cells and eosinophils. Myocytes showed early contraction band necrosis (Figure 1). The myocardial changes were transmural. There was mucous plugging in the bronchi and associated moderate peribronchial cellular infiltration with some eosinophils (Figure 2). The liver showed moderate fatty changes. There were no hypoxic changes of the brain. OPEN IN VIEWER

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Figure 2.

Mucous plugging of the bronchi.

Discussion

Investigation into a death associated with anaphylaxis is often a challenge to forensic experts because of a lack of specific findings at autopsy. Clinical history, detailed postmortem findings and ancillary testing are important for reaching a conclusion. A postmortem study conducted on cases of fatal anaphylaxis in the United Kingdom showed that 23 of 56 deaths had no macroscopic postmortem findings. ⁵ Positive autopsy findings in fatal anaphylaxis include cutaneous erythema, upper airway oedema, mucous plugging of the bronchi, hyperinflation of the lungs, petechial haemorrhage and pulmonary oedema and congestion. Microscopic findings may also be negative. ⁵ In some individuals, microscopy shows upper airway oedema, pronounced eosinophilia of the laryngeal mucosa and oedema, inflammation with eosinophilia, and epithelial sloughing of the bronchi. ⁵

Analyses of total and specific immunoglobulin E in postmortem serum are feasible. However, these analyses can verify only the atopic nature and degree of sensitisation of the patient and not necessarily an acute anaphylactic episode. Histamine, a mediator of acute anaphylactic or anaphylactoid reactions, rapidly degrades in postmortem blood. Mast cell tryptase, a serine protease stored in the mast cell granules, is released together with histamine and is relatively stable, even postmortem. Tryptase can be detected in blood beginning a few minutes after the reaction and for up to several hours after mast cell degranulation. Therefore, tryptase levels are fairly reliable indicators in postmortem samples of suspected anaphylactic deaths. However, increased tryptase levels were also reported in a few cases of death from non-allergic causes. ⁶ When elevated levels are observed with other autopsy findings, the diagnostic value of tryptase for fatal anaphylaxis is much greater.

Our patient developed symptoms immediately after ceftazidime administration. He had positive findings at autopsy, including laryngeal oedema, mucous plugging of the bronchi and eosinophil infiltration.

The presence of abundant cellular infiltrates, consisting of neutrophils, mast cells and eosinophils, and early ischaemic changes involving the full thickness of the myocardium were striking findings in this case. There were no hypoxic changes of the brain to suggest global hypoxia that followed the cardiac arrest. Therefore, in the absence of major coronary artery disease, such findings can be explained by Kounis syndrome. Cardiac mast cells participate in development of atherosclerosis, coronary inflammation and cardiac ischaemia. ⁷ Many mediators that are released from cardiac mast cells, such as tumor necrosis factor, basic fibroblast growth factor and transforming growth factor-β, affect cardiovascular pathophysiology.

Kounis syndrome has been classified into two major types. ⁴ Patients with type I have normal coronary arteries. In these patients, an acute allergic insult can induce coronary artery spasm and symptoms of angina, resulting from endothelial dysfunction, develop without an increase in levels of cardiac enzymes or troponin. Additionally, in patients with type I, an acute allergic insult can induce coronary artery spasm, progressing to acute myocardial infarction with increased cardiac enzyme and troponin levels. Type II patients include those with coronary artery disease. These patients show an increase in cardiac enzyme and troponin levels following plaque erosion or rupture, manifesting as acute myocardial infarction resulting from an acute allergic episode. Our patient suffered from type I Kounis syndrome with no evidence of coronary artery occlusion, plaque rupture or erosion, but with abundant cellular infiltrates in the myocardium.

Another remarkable finding in our patient was that he showed early transmural contraction band necrosis, despite abundant cellular infiltrates. In myocardial infarction, neutrophils play a role in the healing process. In contrast to what is found in myocardial infarction, our observations suggested that the release of inflammatory cells preceded myocardial necrosis and injury. Inflammatory cell modulation, especially the activation of neutrophils, monocytes and eosinophils, is a cardiac effect of histamine. In acute coronary events following anaphylaxis, it is important to know whether inflammatory cells, which include mast cells and their contents, are the cause of the event or the result of it. Mast cells are known to release their contents before plaque erosion or rupture and, also, to enter the lesion before a coronary event. This can result in infiltration of the area by inflammatory cells before the actual insult or coronary event. ⁸

Researchers have suggested a common pathway between allergic and non-allergic coronary syndromes. Patients with acute coronary syndrome of non-allergic aetiologies have more than twice the blood levels of histamine, tryptase and other mediators than do healthy subjects. ⁹ However, in our patient, there was no evidence for non-allergic acute coronary syndrome followed by myocardial ischaemia and necrosis.

Our patient had a history of allergy to penicillin derivatives and developed immediate symptoms following a ceftazidime injection. Ceftazidime is a third-generation cephalosporin that has cross-reactivity with penicillin-related antibiotics. Positive skin testing to penicillin and a history of allergy to penicillin usually indicate that a patient should not receive ceftazidime. However, recent literature has indicated that the cross-reactivity of ceftazidime to penicillin is much less ¹⁰ than older literature suggested. ¹¹ Anaphylactic shock and acute myocardial infarction were reported following an intravenous injection of ceftazidime in Sri Lanka. ¹² Skin testing was not performed on our patient prior to ceftazidime administration. Positive skin testing can be important for avoiding administering an allergenic drug to a patient, even though a negative skin test does not completely exclude possible allergies. Antibiotic administration should be performed cautiously if patients have not received a skin test. Therefore, in our case, there might have been a failure to provide a reasonable degree of skill and care, in accordance with the Bolitho principle, a legal test that is applied to determine medical negligence.

Conclusion

Myocardial infarction or angina is a rare complication of anaphylactic reactions, but can occur even in people with normal coronary arteries. In our case, the myocardial microscopic observations support the concept of inflammatory cell infiltration before the actual insult or coronary event. Therefore, this cellular infiltration could have caused the myocardial injury, rather than being a consequence of an allergic myocardial infarction.