Unusual case of recurrent hypoglycaemia in multiple bee sting envenomation

Abstract

A bee sting can result in allergic and toxin-mediated local manifestations like pain, swelling, redness and itching to serious systemic effects like acute kidney injury (AKI), pancreatitis, Kounis syndrome and stroke. Melittin and phospholipase A2, which make up 62% of honeybee venom, have vasoactive, haemolytic properties causing severe AKI. Its role in lowering blood glucose in diabetics is an interesting research topic. We report an elderly herdsman, a known diabetic on irregular oral hypoglycaemic drugs, who presented with altered mental status due to hypoglycaemia. On further prodding, a recent multiple bee sting attack 5 days ago was found which was followed by altered coloured urine for 2 days for which no medical attention was sought. Additional analyses revealed reticulocytosis, azotemia and high serum creatine phosphokinase. The patient was treated with dextrose infusion, antihistamines, fluids and haemodialysis. Renal failure resolved completely and the patient was discharged in a stable condition.

Background

Honeybees, wasps and hornets belong to the order Hymenoptera of class Insecta, phylum Arthropoda. Bee species specific to India are Apis mellifera, Apis cerana, Apis dorsata, Apis laborious and Apis florea.¹ Bee sting envenomation causes clinical manifestations either due to allergy or toxin-mediated effects. The allergic effects vary from pain, swelling, itching and redness at the bite site to systemic and fatal anaphylaxis. The venom causes toxin-mediated cellular injury, the spectrum of which ranges from local skin necrosis to rare, severe complications like rhabdomyolysis, acute kidney injury (AKI), intravascular haemolysis, acute respiratory distress syndrome (ARDS), acute pancreatitis and multiorgan dysfunction syndrome (MODS).^2–6 The cause for such serious manifestations can be due to factors like multiple stings, species like African bees, patient comorbidities, anatomical area stung and sometimes idiosyncrasy.

There are limited data on bee sting-induced AKI worldwide. A single sting may cause an allergic reaction but the prognosis depends on the number of stings and is directly proportional to it. The severe AKI that follows a massive bee attack is attributed to multiple factors, which include direct toxicity of venom to the kidney tubules, rhabdomyolysis hypotension and intravascular haemolysis. Such patients are often brought to the healthcare services critically ill because of delayed and non-specific reports. Though bee stings are common in India, reporting of such serious complications is rare.^3–5 Recurrent hypoglycaemia can be due to AKI as well as the antihyperglycaemic action of the bee venom (BV). The antihyperglycaemic action could be the result of suppression of pancreatic β-cell inflammation, promotion of insulin secretion or promotion of the uptake of glucose in adipose tissue.

Case presentation

A 75-year-old herdsman dwelling in the nearby hills was brought to the emergency department by his son with altered sensorium for 1 day. At triage, his vitals were heart rate of 80 beats/min, blood pressure of 150/80 mm Hg, respiratory rate of 22/min, oxygen saturation of 99% on room air, a temperature of 98°F and random blood sugar of 68 mg/dL. He was wheeled immediately to the red area of our emergency department and an intravenous access was taken through which 20 mL of 25% dextrose solution was administered. His pupils were sluggish in reacting to light and he also had bilateral Babinski’s reflex. The patient regained his orientation to time, place and person after a few minutes. The patient was a known case of diabetes mellitus (DM) for 4 years taking tablet metformin 500 mg, tablet glimepiride 2 mg per oral on an irregular basis and hypertensive for 4 years for which he was not taking any medication. The patient had not taken his usual oral hypoglycaemic agents for the past several days. Tetanus toxoid injection, normal saline intravenous infusion and antibiotics were given.

Five days before arrival to our hospital, the patient had a history of attack by a swarm of honeybees while grazing his cattle in the nearby forest, following which he developed pain and swelling over sting sites all over the body. Stings were removed in a clinic and some injections were given (details not available). The patient had a history of passing red-coloured urine for the next 2 days and dark brown colour on the third and fourth day, which normalised on the day of arrival. The patient developed sudden onset slurring of speech associated with a deviation of the angle of the mouth around 21 hours before arrival. There was no history of loss of consciousness, vomiting, headache, fever and decreased urine output.

On re-examination, his vitals were stable and blood sugar was found to be 156 mg/dL. The power in all the four limbs also improved to 4+/5. On complete exposure, we noted over 50 hyperpigmented, discrete, maculopapular lesions with central puncture on his face, trunk and bilateral upper limbs. Pallor was present but icterus was absent. His face was symmetrical. His pupils were bilaterally equal and normally reacting to light. His plantar reflexes were still extensors bilaterally. Rest of the systemic examination was within normal limits. The patient’s arterial blood gas on arrival is shown in table 1. Tables 2 and 3 show other laboratory parameters on arrival. After 4 hours, while the patient was returning from non-contrast CT (NCCT) of the head, he was found to have altered sensorium, slurred speech and weakness of all limbs. His blood sugar levels were 72 mg/dL. He was again given a bolus of 20 mL of 25% dextrose solution intravenously and simultaneously dextrose maintenance fluid was initiated. The patient symptoms improved after a few minutes. His urine was clear and straw coloured with an output of 25 mL/hour. Table 4 shows the urinalysis of the patient on arrival.

Table 1.

ABG at presentation

pH	7.326
pO2	102 mm Hg
pCO2	31.6 mm Hg
HCO3	16.6 mEq/L

ABG, arterial blood gas; HCO₃, bicarbonate; pCO₂, partial pressure of carbon dioxide; pO₂, partial pressure of oxygen.

Table 2.

Timeline of the laboratory profile

	Day 1	Day 2	Day 5
Haemoglobin	76 g/L	42 g/L	77 g/L
Total leucocyte count	10 000/mm3	11 360/mm3	12 970/mm3
Platelet count	1.00×105/mm3	0.58×105/mm3	2.14×105/mm3
Serum glutamic pyruvic transaminase	296 U/L
Serum glutamic oxaloacetic transaminase	348 U/L
Serum bilirubin total	2.71 mg/dL
Direct bilirubin	1.34 mg/dL
Serum creatinine	6.4 mg/dL	4.83 mg/dL	6.57 mg/dL
Blood urea	343 mg/ dL	170.8 mg/dL	222 mg/dL
Calcium	8.4 mg/dL	9.1 mg/dL	7.3 mg/dL
Serum phosphate	5.6 mEq/L	5.9 mEq/L	7.1 mEq/L
Serum potassium	5.5 mEq/L	5.4 mEq/L	4.64 mEq/L
Serum sodium	143 mEq/L	127 mEq/L	138 mEq/L
Serum chloride	112 mEq/L	91.6 mEq/L	104 mEq/L

Table 3.

Other laboratory parameters on arrival

Serum lactate dehydrogenase level	754 IU/L
Serum creatine phosphokinase level	7328 IU/L
Iron level	81.5 µg/dL
Folic acid	6.7 nmol/L
Vitamin B12: cyanocobalamine	674 pg/mL
Reticulocyte count	5.15%
Serum ferritin	>1650 ng/mL

Table 4.

Urinalysis on arrival

Urine colour	Straw
Urinary pH	6.8
Urinary sugar	0
Urinary protein	1+
Red cell count	2–5/high-power field
White cell count	5–6/high-power field

Investigations

He was non-reactive for HIV I and II, anti-hepatitis C virus and hepatitis B surface antigen.

Peripheral blood smear

Red blood cells (RBCs) show normocytic normochromic population of cells with a fair number of hypochromic cells.

White blood cells—mild shift to left seen.

Platelets are reduced.

No hemoparasite seen.

Impression—anaemia, normocytic type.

NCCT of the head was suggestive of chronic lacunar infarcts in right corona radiata and bilateral gangliocapsular regions.

Bedside ultrasound of the abdomen was suggestive of normal-sized kidneys with bilateral increased renal cortical echogenicity with intact corticomedullary differentiation.

Treatment

The patient underwent three sessions of dialysis for persistent hyperkalaemia. His blood sugar levels were monitored. He was transfused two units of packed RBCs for severe anaemia during his stay. His urine output improved and creatinine on discharge was 2.8 mg/dL. The timeline of his laboratory parameters during hospital stay is shown in table 2. Table 5 shows the timeline of his blood glucose values during hospital stay.

Table 5.

Timeline of laboratory blood glucose values

	Day 1	Day 8
Random blood sugar	64 mg/dL
Fasting plasma glucose		139 mg/dL

Outcome and follow-up

The patient was finally discharged on the 10th day of admission with a definitive diagnosis of multiple bee stings with recurrent hypoglycaemia, resolving AKI, acute liver injury, DM, hypertension, prostatomegaly and anaemia.

The patient did not follow up citing socioeconomic reason.

Discussion

Bees attack usually when provoked or threatened. Single bee sting usually releases pheromone isoamyl acetate which attracts other bees resulting in multiple stings.^{3 7} BV is a biotoxin. Each sting releases about 140 µg of venom into circulation.⁷ Peptides (melittin, apamin), enzymes, amine and some other proteins are the primary constituents of BV. Melittin, the major component (50% of dry weight), along with phospholipase A2 (PLA2), has both vasoactive and haemolytic properties. Manifestations are local or systemic and acute or delayed based on factors related to bee sting like the number of stings, bee species, amount of venom released and patient factors like anatomical area, premorbid conditions, susceptibility to allergy and time of seeking treatment. Local manifestations vary from an allergic effect like immediate pain, swelling, itching and angioedema to toxin-mediated skin necrosis and delayed cellulitis.^{3 8} Systemic manifestations vary from immediate severe anaphylaxis manifested as shock, laryngospasm, respiratory failure to toxin-mediated rare effects like ARDS, AKI, intravascular haemolysis, pancreatitis and stroke.2–7 9 10 The direct toxic effect of BV can prove fatal in a person with multiple honey bee sting attack with a 15%–25% reported mortality rate.

Bee sting causes kidney injury by various mechanisms like direct toxin-induced nephropathy, acute tubular necrosis (ATN), pigment-induced nephropathy (myoglobin and haemoglobin) released by haemolysis and rhabdomyolysis, and systemic shock in MODS and anaphylactic shock.3 5–7 10 It is a well-known but a rare phenomenon. The mortality rate of patients with AKI is reported to be as high as 25%.¹¹ Our patient had AKI resulting from both intravascular haemolysis and rhabdomyolysis following multiple bee stings.

The hypoglycaemic manifestation of bee stings is very rarely documented. Our patient developed recurrent hypoglycaemia which may be contributed by one or both of the following reasons—toxin effect or AKI. The kidneys play an important role in the metabolism of glucose (15%–30% of total body gluconeogenesis)¹² and degradation of insulin. Many oral antidiabetic agents, including insulin and sulfonylureas, are partially excreted by the kidneys.

In a large national cohort of patients with diabetes on insulin or sulfonylurea monotherapy or in combination therapy, which could have included metformin, Hung et al in 2018 demonstrated that patients with AKI have a significant risk of developing hypoglycaemia in the post-discharge period (∼7% in 90 days), with a relative increase in risk of 27% as compared with similarly ill patients with no AKI.¹³ Our patient was a diabetic on irregular medications with AKI induced due to multiple bee stings. Hence, hypoglycaemia can be explained. In a retrospective study conducted by Vikrant and Parashar in the 35 patients who presented with AKI with hymenoptera stings in a span of 13 years (2003–2016), the peak values of serum urea and creatinine were 238±117 and 10.2±6 mg/dL, respectively.¹⁴ Notably, hypoglycaemia as a complication of AKI was not documented.

The other possible explanation of recurrent hypoglycaemia can be the decreased clearance of BV circulating in his body. The mechanisms by which melittin reduces blood glucose levels include depolarisation of β-cell membranes, increasing the extracellular calcium and calcium channels,¹⁵ activating cytosolic PLA2, increasing glucose transporter lipid uptake into adipose tissues¹⁶ and suppression of β-cell inflammation.¹⁷

Few studies conducted on animal models have reported that the use of BV is associated with lowering of blood sugar. Mousavi et al conducted a study on rats with diabetes where they reported that Iranian BV (Apis mellifera) can lower the blood glucose and lipid levels.¹⁵ Khulan et al conducted a study on the effects of Mongolian BV on hyperglycaemia and hyperlipidaemia in alloxan-induced rabbits with diabetes. In their study, they divided chinchilla rabbits into three groups: control, diabetic and BV-treated groups. The BV-treated group’s blood glucose levels decreased by 14.9%–26.5%.¹⁶

Prakash and Bhargava reported that BV from Apis cerana has antidiabetic activity.¹⁸ In this study, the control group comprised of unexposed humans while the test group consisted of beekeepers frequently exposed to BV. The baseline blood sugar levels of the test population (104 mg/dL) were lower than the control group (151 mg/dL). Moreover, the blood sugar level was found to be 81 mg/dL after bee sting in the test population.

Many studies which examined the biological and pharmacological profile of BV and melittin confirmed that they possess radioprotective, anti‐inflammatory, antibacterial, antiviral and anti‐cancer activities. For melittin to be used as an antidiabetic agent, its toxicity must be reduced.¹⁷

Our patient had over 50 bee sting marks on his face, trunk and bilateral upper limbs. Adults who receive 50–200 stings are prone to develop renal failure. Adults who have 200–500 stings often develop multiorgan failure and those with more than 500 stings have high risk of death.¹⁹ Patients with massive stinging should be evaluated with serial laboratory tests for days to detect the toxic effects of envenomation.²⁰

Treatment of bee sting patient comprises of sting removal, local ice compression, analgesics, antihistamines and steroids. Epinephrine is required for life-threatening anaphylaxis. There is no specific antidote available for bee envenomation. In case of multiple bee stings in a patient like ours with many risk factors, a detailed evaluation of serious manifestations, like AKI, may help us to identify the effects earlier and result in better outcome by treating the cause. Aggressive fluid therapy and alkaline diuresis are used to treat rhabdomyolysis and prevention of nephropathy.^{3 5 7} Plasmapheresis and dialysis have been tried in treating patients with nephropathy and ATN.²¹ Hypoglycaemia is treated with dextrose infusion until toxin effect wanes off.

Learning points.

• Although rare, bee envenomation can result in life-threatening complications like acute kidney injury, acute coronary syndrome, stroke, pancreatitis, multiorgan dysfunction syndrome and even death.

• Allergic manifestations of bee envenomation are successfully treated in primarily care level. However, toxin-mediated delayed conditions are infrequently reported.

• Patients presenting with a history of multiple bee sting of geriatric age group with comorbidities should be observed and evaluated appropriately as they are relatively more prone to complications.

• Notably, the patients afflicted with mass envenomation can develop hypoglycaemia which may be due to the antihyperglycaemic property of melittin.

• Early recognition and management of acute kidney injury can avert mortality in such cases.

Ethics statements

Patient consent for publication

Next of kin consent obtained.