Cardiology

Hymenoptera heartaches -cardiac manifestation with hymenoptera stings, a retrospective study from a tertiary care hospital in South India

a b s t r a c t

Introduction: Hymenoptera stings usually have a multitude of presentations from very subtle to life-threatening conditions. Various Cardiac manifestations including Kounis syndrome often get missed due to lack of suspicion. The aim of the study was to describe the clinical profile of the cardiac etiologies associated with hymenoptera stings and review literature with focus on diagnosis and treatment strategies.

Methodology: A retrospective chart analysis was performed including all adult patients who had a hymenoptera sting during a two-year window (October 2018 – October 2020). Of these, patients with cardiac features were enrolled. A structured case record form was used to capture information like basic demography, clinical profile, and outcomes.

Results: Thirteen cases presented with hymenoptera stings of which six cases had cardiac presentation and were considered. The most common presentations were breathlessness and generalised itching with only one patient complaining of chest pain. All patients(with available data) had ECG changes suggestive of ischemia and associ- ated raised troponin levels with 2D echo changes. The diagnoses considered included Kounis syndrome, hyper- sensitivity myocarditis, and Takotsubo cardiomyopathy. Patients were managed conservatively with one patient undergoing a coronary angiography. All patients were stable at discharge.

Conclusion: Cardiac manifestations with hymenoptera stings although rare may complicate diagnosis and treat- ment.It should be borne in mind during assessment and standardised guidelines should be developed for ED treatment such as the one recommended in this study. Keywords:Hymenoptera, Kounis syndrome, Acute Coro- nary Syndrome, emergency medicine.

(C) 2021

  1. Introduction

Hymenoptera stings are commonly seen in rural parts of India and are usually associated with local symptoms such as pain, swelling and edema. Occasionally, systemic manifestations such as vasculitis, serum sickness, neuritis, and encephalitis have been reported [1]. One such complication which is reported in medical literature but can get missed and is underreported is acute myocardial infarction [2]. “Acute coronary syndrome associated with mast-cell and platelet activation in the set- ting of hypersensitivity and allergic or anaphylactic insults” is defined as Kounis Syndrome(KS) or allergic angina first described by Kounis and Zavras in 1991 [3-5]. KS is acknowledged as a “not rare but

Abbreviations: KS, Kounis Syndrome; ACS, Acute Coronary Syndrome; ED, Emergency Department; ECG, Electrocardiography; 2D, 2-Dimensional; STEMI, ST Elevation Myocardial Infarction; ECHO, Echocardiogram; BSACI, British Society for Allergy & Clinical Immunology.

* Corresponding author at: Department of Emergency Medicine, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.

E-mail address: [email protected] (W. Wilson).

underdiagnosed” condition both due to little awareness of its existence among physicians as well as due to the shared pathogenesis and clinical manifestations with acute coronary events of ischemic etiology that shift focus away from a synchronous allergic response [6]. Other cardiac manifestations that may mirror KS are hypersensitivity myocarditis and even Takotsubo cardiomyopathy. By the means of this retrospective study, we hope to add to the existing pool of knowledge and do a com- prehensive review of literature focussing on pathophysiology, clinical picture, and treatment of cardiac complications associated with Hyme- noptera stings.

  1. Methodology

After procuring IEC consent (854/2020) we conducted a record re- view of all cases ofhymenoptera stings that presented to our Emergency Medicine Department (ED) between October 2018-October 2020 using the emergency department registers, ICD code- T63.441A for medical record review and data from the VENOMS registry from December 2019 to October 2020. The VENOMS Registry is a CTRI registered single centric hospital based registry that includes all cases of envenomation

https://doi.org/10.1016/j.ajem.2021.08.003

0735-6757/(C) 2021

presenting at the ED (CTRI/2019/10/021828). The diagnosis of hyme- noptera sting was based on history, clinical presentation and evidence which included bee, wasp, hornet, and insect sting. 13 cases of hymenopterastings presented to the ED during that time. These patient records were scrutinized for features suggestive of cardiac etiologies, in- cluding history, ECG, laboratory findings, and 2D echo as well as a diag- nosis at the time of discharge. We found 6 cases that fit this criterion, and have discussed them in detail.

  1. Results

Six cases presented with hymenoptera stings that had concomitant cardiac manifestations. Of these, four were male and two female. All pa- tients were elderly with a mean age of 71.7 years. All the cases reported multiple Bee stings, involving predominantly the face and upper limbs. One patient was riding a two-wheeler and subsequently suffered a head injury. Most patients did not have any comorbidities, barring two who were hypertensive on treatment. The Presenting complaints of the pa- tients had features such as breathlessness, itching, and facial swelling. Only one patient complained of cardiac symptoms of Chest tightness. Three patients of the six presented with altered sensorium of which one had a road traffic accident. On local examination, all patients had local edema, redness with stingers present. Systemic examination re- vealed two patients had rhonchi otherwise cardio-pulmonary examina- tion for the remaining atients was normal.Concerning vital signs, four patients had tachycardia which responded to initial management how- ever two patients presented with hypotension and tachycardia, which required inotropic IV Norepinephrinesupport. The cause of shock was attributed to distributive or cardiogenic in nature. Investigations re- vealed 4 patients had increased total white blood cell count and two had deranged renal function tests (increased creatinine and increased blood urea.) With respect to specific cardiac workup, ECG of all the pa- tients was suggestive of ST-T changes with ST segment depression and T wave inversions. No patients developed a STEMI following envenom- ation. Troponin -T was elevated confirming cardiac etiology. (details in Table 1) 2D transthoracic ECHO done in the ED showed regional Wall motion abnormality in four cases confirming our suspicion of NSTEMI or possible KS. The remaining two cases with normal ECHO but elevated troponin were considered as possible myocarditis. Treat- ment strategy for these patients involved initial airway, breathing and circulation stabilization. The patients were treated with a varietyof drugs including adrenaline, steroids, H1 and H2 antihistamines and

antiplatelets (see Table 2). The cardiac etiologies that were considered, included KS type 2 (patient 3), hypersensitivity myocarditis and possi- ble KS type 1 (patient 1 and 6) and possible type 2 (patient 2, 4 and 5). There were no mortalities with all patients stable at discharge.

  1. Discussion
    1. Hymenoptera species and distribution in the region

The identification of the culprit species in envenomation is of utmost importance in the emergency department. It will help direct initial diag- nostics and the level of observation required. A concerted effort must be carried out in all cases.Hymenoptera is a large order of insects that in- clude ants, wasps, sawflies, and bees. Of medical significance are the bees, wasps, hornets and some species of stinging ants. Of these, the bees and hornets are the most medically significant, responsible for a large number of attacks on humans and associated anaphylaxsis linked morbidity and mortality from hymenoptera envenomation. The species found in the regions of the western ghats are A. dorsata– Rock bee,

A. cerana indica-Indian hive bee, Apis florea-Dwarf bee, Apis mellifera– European or Italian bee, Tetragonula iridipennis-Dammer or Stingless bee, Asian giant hornet- Vespa mandarinia and the greater banded hornet-Vespa Tropica [7] (see Fig 1), of these it is the rock bee that is of greatest concern due to its aggressive nature and large swarms during attacks on humans. One postulation is that these bees build their hives in the open on tree branches and rock overhangs as compared to others which do so inside tree cavities and rock caves and is the reason for their defensive aggressive behavior. In urban areas, these bees build their hives on concrete sunshades of windows and balconies which is another risk factor for an increase in attacks due to the proximity to humans. But why these bees randomly attack humans has not yet been identified. All six cases in our study were likely A. dorsata envenomations. One confirmatory finding is the presence of stingers on the patients who are absent with hornet and wasp attacks (Fig. 1 B).

    1. Risk factors for hymenoptera stings

Sara Oppenheim et al. in their analysis of the genome of A. dorsata at- tributed the defensive aggression of the A. dorsata to a genetic trait. They identified four 5-HT2A receptors in A. dorsata of which one was suffi- ciently divergent and because serotonin has an effect on aggression may be the genetic basis of aggression in A. dorsata [8]. Beekeeping,

Table 1

Clinical and laboratory profile.

S

no.

Age Sex Presenting

complaints

Local examination Troponin ECG ECHO CAG Possible cardiac

manifestation

      1. 65 M Fall from cycle,

Transient LOC Breathlessness

Left eye redness,swelling of lips and bilateral multiple swelling over the extremities

0.134

ng/ml

ST-T depression chest leads

EF – 62% No RWMA

No diastolic dysfunction

-na- hypersensitivity myocarditis/type 1KS

      1. 70 M Generalised

itching

Generalised rashes 0.722

ng/ml

ST, T inversion in precordial leads.

EF 47%

apical trabeculation present, mild LV systolic dysfunction.

Did not consent Type 1KS/type

2KS/hypersensitivity myocarditis

      1. 66 F Breathlessness

Sweating Chest tightness

Swelling of left arm 0.065

ng/ml

T wave depression V1-V6

EF 69%,

LV diastolic dysfunction.

CAD- LMCA

+double vessel + branch vessel disease

Type 2 KS

      1. 82 M

altered sensorium

Redness and swelling of face, eyes, lips

0.60

ng/ml

T wave inversion in V3-6

EF 55%

distal IVS and apex mildly hypokinetic

-na- Type

2KS/hypersensitivity myocarditis

      1. 68 F Facial swelling

breathlessness

periorbital edema and swelling over lips.

-na- T wave inversions in chest leads with poor R wave progression

EF-42%

Globally hypokinetic LV

-na- Type 1KS/type 2KS/hypersensitivity myocarditis

      1. 79 M Breathlessness

altered sensorium

Redness and swelling of face, eyes, and lips

0.473

ng/ml

ST-T depression chest leads

EF-68% No RWMA

No diastolic dysfunction

-na- Type

1KS/hypersensitivity myocarditis

Table 2

Treatment regimens used

Drug/Dose

Case 1

Case 2

Case 3

Case 4

Case 5

Case 6

Rajha et al

Ranitidine

?

?

?

?

?

?

?

Diphenhydramine

?

?

?

?

?

?

?

Hydrocortisone

?

?

?

?

?

?

?

Dexamethasone

?

?

?

?

?

?

?

Adrenaline

?

?

?

?

?

?

?

Heparin

?

?

?

?

?

?

?

Aspirin

?

?

?

?

?

?

?

Ticagrelor

?

?

?

?

?

?

?

Clopidogrel

?

?

?

?

?

?

?

Atorvastatin

?

?

?

?

?

?

?

Pantoprazole

?

?

?

?

?

?

?

Ondansetron

?

?

?

?

?

?

?

Cetirizine

?

?

?

?

?

?

?

honey hunting and forestry practices predispose individuals to hyme- noptera envenomation. Plantation work, gardening and traveling out- doors were other risk factors for hymenoptera envenomation in a study done by Witharana et al. in Sri Lanka [9]. All of our cases were from rural/ village areas with tree cover (see Fig. 2) and none of the

victims were involved in forestry or agricultural work at the time of being attacked.

    1. Venom components

Hymenoptera venoms are composed of biogenic amines, peptides, small proteins and enzymes which compose of histamine, serotonin, acetylcholine, apamin, melittin, mast cell degranulating peptide, wasp or hornet kinin, phospholipase A and/or phospholipase B.Mastoparan and mandaratoxin are peptides found in wasp and hornet venom whose action depends on the cell type. Mandaratoxin is a potent neuro- toxin found in the asian giant hornet [10,11]. All 6 cases in our study presented with similar findings and were consistent with hymenoptera envenomation causing a hypersensitivity like reaction.

    1. Initial assessment and resuscitation

It is clear from our study that the 6 cases were treated based on pre- sentation and not by protocol. It is evident that early diagnosis and pro- phylactic treatment strategies will reduce morbidity and complications such as KS. Specific ED guidelines and protocols have not yet been

Image of Fig. 1

Fig. 1. A. Apis dorsata- Rock bee, B. Stings retrieved from the victims. C & D. Greater banded hornet-Vespa Tropica.

Image of Fig. 2

Fig. 2. Geotagging of all the cases – suggestive that the cases are from rural/tree covered area belonging to Western Ghat region.

defined. The Association of Physicians of India recommended initial air- way, breathing, circulation stabilization and removal of stings where as the British Society for allergy and clinical immunology (BSACI) guide- lines describe in a schematic representation based on mild, moderate and severe systemic reactions, diagnostics and indications for venom immunotherapy [11]. Initial therapeutics must include H1 and H2 antihistamines which are important therapeutics that prevent H1 and H2 receptor-mediated anaphylaxis. H1 receptors mediate coronary artery vasoconstriction, cutaneous vascular permeability and wheezing while H2 receptors mediate atrial and ventricular inotropy, arterial chronotropic and coronary vasodilation. Lieberman concluded in a review that based on the knowledge of the physiology of histamine re- lease, preferential use of H1 and H2 antagonists as opposed to H1 antag- onists alone is recommended in the treatment of anaphylaxis [12]. Case 4 received IM adrenaline and case 5 received IV norepinephrine infu- sion, both responded well. Patients may also benefit froma fluid bolus and must receive IMepinephrine for confirmed anaphylactic shock, however, IV epinehrineinfusions may be considered in cases that are re- fractory to IM doses. But this may precipitate or worsen cardiac dysfunc- tion due to vasoconstriction or arrythmias and must be given with caution in cases suspected to have KS or at high risk of it. IM delivery of adrenaline is safer than IV infusions. Patients reporting with hyper- sensitivity reactions but no shock should have peripheral IV access se- cured early for the delivery of IV therapeutics and also in case of severe edema, urticaria or shock which prevent easy IV access and delay time to definitive treatment when mild to moderate cases turn severe.

    1. Diagnostics and complications

Anaphylaxis largely remains a clinical diagnosis,circumstantial history and examination usually clinches it.However at times

complications of anaphylaxis may mask the initial presentation and lab- oratory investigations are indicated. Diagnostics revolve around detect- able markers of anaphylaxis such as tryptase, Serum IgE, histamine and platelet activating factor [11,13]. Cardiac biomarkers need to be serially monitored as acute coronary syndromes may get missedin hymenop- tera envenomation. Elevated serum IgE levels have been reported to be associated with an increased chance of a cardiac event in patients with anaphylaxis and also found to be elevated in patients with coro- nary events [14,15]. Complete blood counts, renal function tests, liver function tests, coagulation profiles and Urine analysis are needed in order to monitor Organ function and associated complications. Krishna et al. in the BSACI guidelines reported complications that involved the central nervous system, haematological, muscle, renal, respiratory and ophthalmic systems which included Guillain Barre syndrome, periph- eral neuritis, myasthenia gravis, coagulopathy, hemolysis, Henoch- schonlein purpura, acute renal failure and rhabdomyolysis [11]. Other complications such as ischemic stroke, myocardial infarction(Kounis syndrome), encephalitis and polyradiculoneuropathy have also been re- ported. A major differential diagnosis of KS is Takutsubo’s cardiomyop- athy but both can coexist in a patient. Imaging such as contrast enhanced cardiac MRI and single photon emission computed tomogra- phy have been suggested but our patients did not undergo the same as they were diagnosed based on the available investigations and the clinical syndrome.

    1. Acute coronary syndrome in hymenoptera envenomation

The etiology of kounis syndrome is wide ranging from various drugs, insects bites, food, latex and plastics. Kounis syndrome following hyme- noptera envenomation is a rare but well documented entity, however the pathophysiology is not entirely understood and is confounded by comorbid conditions. Three types of KS have been explained- type I –

Image of Fig. 3

Fig. 3. Thromboelastography of A. Case 2 – showing severe hypocoagulable state. B. Case 4 – appearing normal. C. Case 6 – showing the features of mild primary fibrinolysis.

Coronary spasm manifested by endothelial dysfunction in patients with Normal coronary arteries in whom an acute release of inflammatory me- diators induce coronary artery vasospasm without an increase in car- diacs enzymes and troponins which may progress to a myocardial infarction with elevated enzymes and troponins. Type II-Coronary thrombosis due to plaque erosion caused by coronary artery spasm induced by an acute release of Inflammatory mediators.Type III-Murat Betiker in his review proposed this third variant which would include those with Stent thrombosis and a harvested thrombus showing the presence of eosinophils and mast cells after staining with hematoxylin-eosin and giemsa stains [16,17]. Pre-existing cardiac dis- ease and interventions such as coronary stenting may determine the classification of the type of Kounis syndrome identified in each patient. In the six patients we studied, Cases 1 and 6 may have been venom in- duced myocarditis or Type 1 KS based on the clinical picture, while cases 2, 4 and 5 a Coronary angiography and cardiac MRI would have helped confirm the diagnosis. Concerning the diagnosis, one patient (patient 3) with elevated troponin, relevant ECG findings, relevant echo findings

Table 3

Recommendations for clinical management of hymenoptera envenomation in the ED.

Recommendations for clinical management of hymenoptera envenomation in the ED [18,19]

  1. INITIAL EVALUATION

AIRWAY: assessment and management -Observation? for deterioration till local and systemic signs are absent [20].

Red flags– Stridor, change of voice (Oropharyngeal and Laryngeal edema) BREATHING: assessment and observation till local and systemic signs of envenomation are absent.

Red flags- tachypnea, bronchospasm, and hypoxia CIRCULATION: assessment and monitoring

Red flags-hypotension, anasarca, decreased urine output, unresponsiveness DISABILITY: assessment and monitoring till local and systemic signs of envenomation are absent.

Red flags-altered mental status, seizures, agitation, headache- signs of stroke

  1. DIAGNOSTICS

Investigation Rationale

Complete Blood count Concomitant infection, baseline

and positive coronary angiogram(CAG) (Video 1) findings was diagnosed as KS type-2. Two patients (patient 1 and 6) with elevated

Renal function tests with electrolytes

Renal failure, baseline

troponin levels but normal echo findings were considered to be hyper- sensitivity myocarditis. As the patients did not undergo a (CAG) a defi- nite diagnosis of KS cannot be made, but the normal ECHO findings rule out KS Type 2 and 3, however a brief coronary spasm, namely KS type-1 could have explained these findings. The remaining three patients (pa- tient 2,4 and 5) with raised troponin, ECG changes and supportive echo findings raise the suspicion of KS type-2 however it was limited to a pos- sibility as CAG was not done due to consent and financial constraints, an often faced problem in our setting. However hypersensitivity myocardi- tis also overlaps with the same presentation and should also deserve attention.

    1. Treatment strategies

The treatment of KS is complex and challenging and guidelienes are a work in progress. Cevik et al. have summarized a treatment strategy which could be vital for clinicans [18]. As mentioned above, the cases studied were managedby the clinical presentation and physician’s pref- erences for therapeutics.(refer Table 2)The prognosis of KS is good, however, we suspect that it remains under diagnosed. The treatment is challenging since it involves treatment of the allergic reaction itself and anticoagulation with revascularization interventions when indicated. H1 and H2 blockers may be continued till the resolution of local and systemic symptoms including elevated biomarkers. Myocarditis or a type 1 KS may resolve in a majority of cases with anit-histaminics, steroids, and other supportive measures without the need for percutaneous intervention, similar to case 1 and 6. Anticoagulation therapies are based on standard guidelines for the management of acute coronary syndromes such as the American Heart Association and can be guided using coagulation profiles includ- ing thromboelastography analysis, particularly in patients in whom Drug history is not available at the time of presentation in the Emer- gency room as was done in cases two, four and six (Fig. 3). Drug ther- apies include unfractionated heparin, Low Molecular Weight Heparin, ticagrelor, clopidogrel and atorvastatin. Patients allergic to heparin may be given bivalirudin instead. Based on the likely classification of the type of kounis patients may undergo urgent coronary angiography and emergent coronary stenting with thrombectomy or maybe man- aged conservatively with a plan for a check angiography once the pa- tient is stable. calcium channel blockers and nitrates can reduce hypersensitivity induced vasospasm. Calcium channel blockers are rarely associated with hypersensitivity reactions whereas nitroglycerin can confound hypotension and is associated with hypersensitivity reac- tions and hence should be avoided. Epinephrine, while the drug of choice for anaphylactic shock can actually worsen myocardial ischemia and precipitate arrhythmias and so should be used with caution in

Urine analysis with myoglobin If considering rhabdomyolysis ECG To rule out cardiac ailments

Serial Troponins Abnormal ECG, suspicion of NSTEMI, Myocarditis

2D cardiac echo Abnormal ECG, suspicion of NSTEMI, Myocarditis

NT-ProBNP If considering cardiac failure as a complication

IgE In Diagnostic dilemmas of etiology of shock

CPK If considering rhabdomyolysis

Chest X-ray Pulmonary edema secondary to cardiac failure

CT-Brain/MRI Brain If features of Cerebrovascular accident present

PT/INR, Thromboelastography For suspected coagulation disorders

  1. THERAPEUTICS

ACUTE THERAPY

    1. IM epinephrine (1 mg/ml preparation): Give epinephrine 0.3 ml to 0.5 ml IM, mid-outer thigh. Repeat every 5 to 15 min, as required.

If symptoms are not resolving, consider IV epinephrine for infusion.

    1. Oxygen: Start 5 to 10 l via face mask, upto 100%. Prepare crash cart if Red flag signs present. (detailed above).
    2. Fluid bolus: Treat hypotension with rapid infusion of normal saline bolus of 1 to 2 l IV. Repeat, as needed.
    3. Albuterol (salbutamol): For bronchospasm resistant to IM epinephrine, con- sider 2.5 to 5 mg in 3 ml saline via nebulizer, or 2 to 3 puffs by metered dose inhaler. Repeat, as required.

ADJUNCTS TO THERAPY

  1. Glucocorticoid: Consider giving methylprednisolone 125 mg IV.
  2. H1 antihistamine: Consider giving diphenhydramine 25 to 50 mg IV (given over 5-10 min) – for relief of urticaria and itching.
  3. H2 antihistamine: Consider giving Ranitidine 50 mg IV.
  4. Monitoring: Continuous noninvasive hemodynamic monitoring and Pulse oximetry monitoring should be done.

REFRACTORY THERAPY

  1. Epinephrine infusion: Patients not responding to IM epinephrine and IV saline, consider epinephrine continuous infusion, starting at 0.1 ug/kg/min. Titrate the dose according to haemodynamics.
  2. Glucagon: Patients on beta-blockers treatment might not respond to epineph- rine and can be given glucagon 1 to 5 mg IV over 5 min, followed by infusion of 5 to 15 ug/min.
  3. Vasopressors: An additional vasopressor (in addition to epinephrine) may be required for some patients. Titrate the dose according to haemodynamics.

* Observation period may vary depending on clinical presentation. We recommend a window between 24 and 72 h, as this is the most common time during which complica- tions may arise [20].

patients with a suspicion of kounis syndrome. Patients on Beta blockers may not benefit from adrenaline and in fact may suffer from worsening Coronary vasospasm due to unopposed alpha adrenergic receptors.In

such cases patients may be treated with glucagon and methoxamine when refractory to epinephrine.Morphine, codeine and meperidine should be avoided as they can cause Mast cell degranulation and aggra- vate allergic reaction [5,18].

  1. Conclusions/recommendations

Hymenoptera envenomation is globally significant, particularly in the tropics and temperate regions. Hymenoptera envenomation and Kounis syndrome must be considered for inclusion in academic medical curriculums even at the undergraduate level. At emergency depart- ments initial evaluation and therapeutics for consideration but not lim- ited to are mentioned in Table 3.

Credit author statement

Freston Marc Sirur – Conceptualization, Reviewing and Editing. William Wilson – Methodology, Writing- Original draft preparation. Vivek Gopinathan – Reviewing and Editing, Supervision.

Chethana AS – Data collection and analysis, images formatting. Nymisha Lekha – Data collection and analysis, video formatting. No funding/grants to declare.

Not presented at any organisations/seminar.

Declaration of Competing Interest

No conflicts to declare.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2021.08.003.

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