We report on a 35 year old patient, who experienced a severe anaphylactic reaction after a honey bee sting in 2007 with hypotension and loss of consciousness (Grad IV reaction). Sensitization on bee venom (BV) was confirmed with specific IgE in serum (i1, 24 kU/l) and intradermal test (positive prick test at 0.01 ug/l), while no specific IgE against wasp (i3) were detectable. Thus, venom specific immunotherapy (VIT) with bee venom extract was initiated in June 2008 and performed according to international guidelines with 100’000 SQE every 4 weeks and was well tolerated by the patient.4,5
In January 2013 a follow-up control after almost 5 years of immunotherapy was performed. Specific IgE antibodies for bee venom (i1) decreased from 24 to 6 kU/l, while specific IgG were raised as expected after 5 years of VIT (see table 1). Unexpectedly serum tryptase level, in normal range in 2008 (3.3 ug/l) was now elevated to 21 ug/l.6,7 Thus further investigations revealed some teleangiectesia on the tronc and swelling on mechanical pressure (positive Darier sign), a skin biopsy showed increased numbers of mast cells compatible with cutaneous mastocytosis.7 Except of sporadic dizziness no symptoms compatible with systemic mastocytosis were reported by the patient; c-Kit mutation was not detectable. However, a bone marrow aspirate showed two minor criteria of systemic mastocytosis (increased number of abnormal mast cells > 25%, expression of aberrant CD25 cells).8
Table 1: Patient serum analysis on molecular sensitization patterns
Patient serum analysis (time of sting provocation)
|
rApi m1
|
rApi m2
|
rApi m3
|
|
rApi m4
|
rApi m10
|
IgE kU/l
|
89.2
|
>100
|
1.85
|
|
9.94
|
10.5
|
IgG4 ug/l
|
>50000
|
7285
|
272
|
|
>50000
|
241
|
Comparison data: serum of a protected patient
|
rApi m1
|
rApi m2
|
rApi m3
|
rApi m4
|
rApi m10
|
IgE kU/l
|
1.6
|
15.9
|
0.22
|
2.3
|
2.42
|
IgG4 ug/l
|
>50000
|
15190
|
19320
|
>50000
|
1800
|
Patient serum analysis (time of sting provocation; 1 month later; after 6 months of VIT)
|
rApi m1
|
rApi m2
|
rApi m3
|
rApi m4
|
rApi m5
|
rApi m10
|
Date**
|
IgE kU/l
|
89.2
|
>100
|
1.85
|
9.94
|
9.9
|
10.5
|
T + 3 days
|
IgG4 ug/l
|
>50000
|
7285
|
272
|
>50000
|
1890
|
241
|
T + 3 days
|
IgG4 ug/l
|
>50000
|
7692
|
339
|
>50000
|
2470
|
533
|
T + 28 days
|
IgG4 ug/l
|
>50000
|
10640
|
1716
|
>50000
|
3834
|
<200
|
T + 7 months *
|
IgG4 ug/l
|
|
|
|
|
|
<200
|
T + 4 years°
|
(*) 6 months after reaching triple VIP maintenance dose (100’000 SQE plus 300 mg HBV concomitant with Omalizumab)
(**) T stands for day of sting challenge
° in between well tolerated 3years after sting challenge, under VIT mot Omalizumab and 200ug HBV
The patient was working as a gardener and therefore had a need to know his level of protection due to a high risk of re-stings – also knowing that patients with a tolerated sting challenge have a better quality of life.9 It is known that patients with mastocytosis are at higher risk for severe or even fatal anaphylaxis, after stopping or even during venom specific immunotherapy (VIT).10
Regarding the promising levels of decreased specific IgE and increased IgG4 against BV, we agreed finally on the patient will on a sting challenge with a honey bee, performed according to international guidelines for safety measurements to check whether protection by VIT was achieved and under ongoing VIT. Sting challenge was performed 10 days after last injection of maintenance dose. The patient was monitored with ECG, non-invasive blood pressure and pulse oximetry and intravenous access was established. The sting was performed on the patient’s forearm; the stinger was left for 1 min in situ before being removed.
Four minutes later the patient reacted with a generalized flush and nausea, followed by cramps and vomiting. Despite immediately administered of two doses of 0.3 mg of adrenaline given intramuscularly and 250 mg of methylprednisolone as well as 2 mg of clemastine intravenously, the condition of the patient worsened. He developed within minutes severe emesis and dyspnea, followed by tachycardia and hypotension. Chest compressions were immediately started, and the CPR (cardio-pulmonary resuscitation) in-house alarm was triggered. Two minutes later the in-house CPR team arrived initiated advanced CRP treatment. At this moment the SpO2 level was above 60%, the patient showed signs of central hypoxia, non-invasive blood pressure could not be measured and central carotid pulse was extremely weak. Assisted ventilation was started. Simultaneously the ECG showed 2nd degree AV block for about 30 seconds, followed by ventricular fibrillation. Defibrillator was attached and patient was endotracheal intubated. CPR was performed, strictly following international CPR guidelines.11,12 The patient had to be external defibrillated (biphasic with 200 J) twice, followed by pulseless electric activity (PEA) for further 4 minutes. PEA limited and led to asystolia for a cumulative 24 minutes. Thereafter, ventricular fibrillation recurred, and patient was external defibrillated twice again. After a total of 32 minutes of CPR, intravenous administration of 10 mg adrenaline and 2000 ml isotonic fluid return of spontaneous circulation (ROSC) occurred. Amiodarone, fentanyl, rocuronium, propofol and midazolame was intravenously administrated and the patient was hemodynamically stabilized. The patient was transferred to the emergency department, where a central venous and an arterial catheter were inserted and a cumulative 1500 ml isotonic fluid administrated (results of initial and before discharge arterial analyzes are summarized in Table 2.). The patient was finally transferred to intensive care unit, where therapeutic hypothermia for 24 hours was initiated.
Table 2
Pathophysiologic changes during and after CPR
|
Initial analyze (time: 12:26)
|
Admission to ICU (time: 13:13)
|
pH
|
7.058
|
7.197
|
pCO2 (kPa)
|
5.93
|
5.51
|
pO2 (kPa)
|
26.1
|
28.4
|
Hkt (%)
|
0.543 (*)
|
0.548 (*)
|
Hb (mmol/l)
|
17.7
|
17.9
|
Lactat(mg/dl)
|
11.2
|
6.2
|
Glucose (mmol/l)
|
18
|
15.1
|
HCO3 (mmol/l)
|
11.9
|
15.5
|
Base excess
|
-19.5
|
-12.4
|
Total fluid administration
|
2000 ml
|
3500 ml
|
(*) Demonstration of vasoplegia, as a direct consequence of anaphylactic shock. |
The patient recovered slowly, initially showing transitory signs of “posttraumatic” such as reduced fine motor skills and concentration. However, during a several months rehabilitation program these steadily improved so that finally no permanent sequalae remained and the patient has returned to his former work.
The treatment of the patient was continued with Omalizumab and 300 ug honey venom extract every 4 weeks. With this treatment he seems to be protected as 3 years after the reported anaphylactic event the patient got stung again several times. Once he was stung simultaneously by two honey bees during his work; all stings were well tolerated. Interestingly, levels of IgG4 against Api m10 remained low.