Abstract

Massive envenomation by honey bee sting is capable of causing multiorgan dysfunction as a result of direct toxic effect of venom and secondary to systemic anaphylactic reactions. Myocardial infarction (MI) due to honey bee sting is rare, so is acute renal failure (ARF). The probable mechanism is severe coronary arterial spasm with secondary in situ thrombosis as a result of systemic anaphylaxis. This is a case of Kounis syndrome, which is the concurrence of acute coronary syndromes with conditions associated with mast cell activation. We describe a case of ARF and MI in a 58-year-old man after multiple honey bee stings; clinically silent and detected on electrocardiography and by cardiac biomarkers.

Hymenoptera sting envenomation may result in a number of clinical presentations: 1) nonallergic, local reactions (pain, minor edema, redness at the sting site); 2) allergic, large local reactions (extensive swelling >10 cm persisting for >24 hours); 3) anaphylaxis (generalized urticaria, angioedema, bronchospasm, hypotension, cardiovascular collapse and loss of consciousness); 4) systemic toxic reactions (edema, vomiting, diarrhea, headache, seizures and altered sensorium) and 5) unusual reactions (cardiac ischemia, encephalomyelitis and cerebral infarctions).¹ We report a case of massive bee sting envenomation with unusual manifestations of acute myocardial infarction (AMI) and acute renal failure (ARF).

Case Presentation

A 58-year-old forest official (Fig. 1), presented to us with a history of multiple bee stings (>200). He had been immediately admitted to a local hospital with swelling of lips and face. He was given preliminary care (treatment details are not known) and was referred to our hospital with dyspnea and decreased urine output. He had dark colored urine. There was no history of chest pain, palpitations, syncope, seizure or altered sensorium. He was a chronic smoker. He was a known hypertensive on regular treatment. No past history of diabetes mellitus, ischemic heart disease or dyspnea on exertion or angina.

He was brought to our emergency department 8 hours after the bee stings. On admission, his pulse rate was 98 beats/minute, blood pressure was 90/60 mmHg, respiratory rate was 18/minute and oxygen saturation was 98% at room air. There were multiple stings on face, head, arms, chest, back and legs. There was marked edema of face and lips with diffuse urticaria over the entire body. He had rhonchi in all lung fields. Rest of the systemic examination was normal.

Hematological examination revealed total leukocyte counts (30,760 cells/mm3), and reduced platelet counts (58,000 cells/mm3). Renal parameters were elevated (urea, 62 mg/dL; creatinine, 3.3 mg/dL). Serum electrolytes were normal (sodium, 136 mmol/L; potassium, 4.2 mmol/L; chloride 106 mmol/L). Electrocardiograph showed ST segment elevation in lead II, III and aVF, reciprocal ST depression was seen in lead I, aVL (Fig. 2). Urine microscopy showed 10-12 pus cells and albuminuria 2+, troponin I was elevated (28.046 ng/mL).

ECG showed no further progression of ST elevation or poor progression of R waves. 2D-Echo showed normal cardiac chambers, normal cardiac valves, regional wall motion abnormality in inferior wall, ejaculation fraction (EF) was 55%.

He was given injection hydrocortisone 100 mg intravenously q6h, injection chlorphenaramine maleate 25 mg q12h and injection ranitidine 50 mg q8h. He was hydrated with IV fluids. Injection epinephrine 0.3 mg IM  was repeated thrice. Injection noradrenaline was given as an infusion at the rate of 1 µg/min. He was started on  anticoagulants and oral antiplatelets.

Next day renal parameters increased (urea, 101 mg/dL; creatinine, 5.1 mg/dl). Ultrasonography of abdomen showed Grade I renal parenchymal disease with normal sized kidneys. Urine output did not improve inspite of above measures. He was dialyzed on alternate days. His renal function gradually improved. ECG changes were reversed to almost normal limits.

Angioedema and urticaria also resolved completely. Injection hydrocortisone was gradually tapered and stopped. He was switched to oral pheniramine maleate and ranitidine and discharged in 10 days. Patient was referred to higher center for further evaluation, where angiogram was done and reported to be normal.

Discussion

Massive honey bee envenomation is defined as more than 50 stings at a time. Individuals who are highly allergic to the venom may develop severe systemic anaphylaxis (type I hypersensitivity) from a single sting. Massive bee attacks can result in toxic reactions, regardless of pre-existing allergic conditions, by virtue of a high venom load potentially causing multiorgan dysfunction.¹

The clinical and pathophysiological background of AMI after a bee sting is generally related to different mechanisms. Hymenoptera venom can cause acute myocardial injury by several mechanisms: a) AMI occurring in subjects without significant coronary artery disease because of coronary thrombosis and vasospasm enhanced by intoxication.² Release of allergenic proteins, vasoactive (epinephrine, dopamine), inflammatory (leukotrienes), thrombogenic peptides and amine constituents (histamine, serotonin, bradykinin, leukotrienes, thromboxane); which act on the coronary vasculature and induce coronary artery vasospasm and facilitate platelet aggregation as well as thrombosis. Paradoxical vasoconstriction could be an underlying mechanism. Severe coronary arterial spasm or secondary in situ thrombosis may also play a role in such a case;3 b) direct cardiotoxic effect of the venom and c) anaphylactic reaction. Anaphylactic reactions which result in acute coronary syndromes is also known as Kounis syndrome.⁴

Hymenoptera sting can lead to an AMI by different pathogenetic mechanisms depending on the presence of pre-existent coronary atherosclerosis, the development of shock or the therapeutic use of epinephrine. Vasoactive amines, including histamine, dopamine and noradrenaline can provoke ischemia and even MI through profound hypotension and arrhythmia, or by increasing oxygen demands through direct inotropic and chronotropic effects in the presence of pre-existing ischemic heart disease.⁵ In patients with AMI after multiple bee stings as reported in literature, the coronary arteries were normal or insignificantly stenosed. Electrocardiographic changes consistent with acute myocardial ischemia or infarction, including ST depression or elevation and even the appearance of pathologic Q-waves, are seen in these patients. Rhythm abnormalities such as supra-ventricular arrhythmias, VPC’s, junctional rhythm and right bundle branch block may occur.⁴

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. In 1991, Kounis and Zavras ⁶ described the ‘syndrome of allergic angina’ as the coincidental occurrence of chest pain and allergic reactions accompanied by clinical and laboratory findings of classical angina pectoris caused by inflammatory mediators released during the allergic insult.

Allergic angina can progress to AMI, which was named ‘allergic myocardial infarction’.⁷ In 1998, Braunwald, ⁸ in an editorial, noted that vasospastic angina can be induced by ‘allergic reactions with mediators such as histamine or leukotrienes acting on coronary vascular smooth muscle’.

There are two variants of this syndrome that have been described recently.⁹ Type Ι 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 leading to unstable angina or coronary vasospasm progressing to AMI. This variant might represent a manifestation of endothelial dysfunction. Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom acute allergic episode can induce plaque erosion or rupture manifesting as an AMI. 

If the clinical judgment favors the use of aspirin in these patients, it seems reasonable to give it after the initial treatment for Kounis syndrome has been started. Use of IV or sublingual nitroglycerin seems reasonable and safe if the blood pressure is satisfactory.

-blockers may offset some of the beneficial effects of epinephrine. Heparin bolus should be avoided. Heparin should be used at low dose at a slow infusion rate. Calcium channel blockers may be considered the initial anti-ischemic drug of choice in patients with Kounis syndrome.¹⁰

Bee venom exposure may be associated with albuminuria.¹¹ ARF following bee stings is a rare complication. Following bee stings, biphasic renal failure has been documented with early renal failure due to hemolysis and a second episode of azotemia about 10 days later occurring in conjunction with depressed serum complement C3 level and nephritic changes on renal biopsy. The major causes of renal failure are acute tubular necrosis (ATN) due to hypotension or pigment nephropathy resulting from rhabdomyolysis and intravascular hemolysis, and acute interstitial nephritis.¹² Renal failure has resulted from stings ranging from 22 to 1,000 in number. The exact mechanism of rhabdomyolysis is not known but a direct toxic effect of venom on muscle is believed to be the main cause.¹³ However, other mechanisms postulated for renal damage due to bee stings are: 1) Direct nephrotoxicity due to toxin; 2) hypotension leading to ischemic tubular necrosis and 3) nephropathy due to hemoglobinuria and myoglobinuria.¹⁴

Reported systemic complications following multiple bee stings include ARF, myocarditis, MI, centrilobular necrosis of liver, acute encephalopathy, Guillain-Barre syndrome, vasculitis, disseminated intravascular coagulation and thrombocytopenia.¹⁵

Conclusion 

Of particular interest in the present case report is the silent presentation of MI. Clinical presentation may be quite different in AMI patients after bee stings. It may be completely silent, or ECG changes such as ST wave elevation may occur several hours after admission. Therefore, a higher clinical suspicion is absolutely necessary to make a correct diagnosis. It follows that in any case of hymenoptera envenomation a standard ECG is advisable. Also, serial ECG recordings are recommended in every patient who complains of chest pain, regardless of the severity of the patient’s reaction to a bee sting. Maintaining adequate urine output should be instituted with aggressive hydration to reduce the likelihood of rhabdomyolysis-induced renal insufficiency. In conclusion, massive bee envenomation can cause life-threatening complications like acute myocardial injury, rhabdomyolysis, hemolysis with ARF and systemic anaphylaxis.

References

1. Betten DP, Richardson WH, Tong TC, Clark RF. Massive honey bee envenomation-induced rhabdomyolysis in an adolescent. Pediatrics. 2006;117(1):231-5.
2. Ceyhan C, Ercan E, Tekten T, Kirilmaz B, Onder R. Myocardial infarction following a bee sting. Int J Cardiol. 2001;80(2-3):251-3.
3. Massing JL, Bentz MH, Schlesser P, Dumitru C, Louis JP. Myocardial infarction following a bee sting. Apropos of a case and review of the literature. Ann Cardiol Angeiol (Paris). 1997;46(5-6):311-5. 
4. Yang HP, Chen FC, Chen CC, Shen TY, Wu SP, Tseng YZ. Manifestations mimicking acute myocardial infarction after Honeybee Sting. Acta Cardiol Sin. 2009;25:31-5.
5. Riches KJ, Gillis D, James RA. An autopsy approach to bee sting-related deaths. Pathology. 2002;34(3):257-62.
6. Kounis NG, Zavras GM. Histamine-induced coronary artery spasm: the concept of allergic angina. Br J Clin Pract. 1999;45(2):121-8. 
7. Kounis NG, Zavras GM. Allergic angina and allergic myocardial infarction. Circulation. 1996;94(7):1789. 
8. Braunwald E. Unstable angina: an etiologic approach to management. Circulation. 1998;98(21):2219-22.
9. Nikolaidis LA, Kounis NG, Gradman AH. Allergic angina and allergic myocardial infarction: a new twist on an old syndrome. Can J Cardiol. 2002;18(5):508-11.
10. Cevik C, Nugent K, Shome GP, Kounis NG. Treatment of Kounis syndrome. Int J Cardiol. 2010;143(3):223-6. 
11. Elming H, Sølling K. Urine protein excretion after Hymenoptera sting. Scand J Urol Nephrol. 1994;28(1):13-5.
12. Patil PL, Salkar HR. Wasp sting induced acute renal failure. Indian J Nephrol. 2004;14:30-1.
13. Kim YO, Yoon SA, Kim KJ, Lee BO, Kim BS, Chang YS, et al. Severe rhabdomyolysis and acute renal failure due to multiple wasp stings. Nephrol Dial Transplant. 2003;18(6):1235. 
14. Dos Reis MA, Costa RS, Coimbra TM, Dantas M, Gomes UA. Renal changes induced by envenomation with Africanized bee venom in female Wistar rats. Kidney Blood Press Res. 1997;20(4):271-7.
15. Daher Ede F, da Silva Júnior GB, Bezerra GP, Pontes LB, Martins AM, Guimarães JA. Acute renal failure after massive honeybee stings. Rev Inst Med Trop Sao Paulo. 2003;45(1):45-50.