Indirect Morbidity of Venom Allergy measured by Venom-Allergy Quality of Life Questionnaire (VQLQ) in Jack Jumper Ant Allergic Patients

Background Insect Stings with the venoms of Hymenoptera species are well recognized as leading directly to allergic reactions in sensitised individuals. As with other hymenoptera venoms – Venom specific allergen Immunotherapy (VIT) to Jack Jumper Ants (JJA) Myrmecia pilosula has demonstrated efficacy in preventing the direct morbidity associated with severe venom-associated allergic reactions. Despite this, the indirect morbidity of severe allergy on associated background health related quality of life (HR-QoL) has not previously been assessed in patients with JJA venom allergy. Materials and methods M pilosula venom-allergic patients referred for treatment in a specialized quaternary venom treatment centre were surveyed with a venom specific HR-QoL questionnaire before and after receiving 12 months of allergen-specific venom-immunotherapy (VIT) according to JJA. A smaller subgroup also repeated this questionnaire after receiving JJA sting-challenge. Results 53 patients completed both pre-VIT and post-VIT QoL questionnaires. 83% of these patients achieved a minimal important difference (MID) of increased change in QoL of >0.5. Mean HR-QoL improved by 1.85, NNT = 1.2. There was no statistically significant difference when stratified by index-reaction grade, but appeared to be greater impairment, and subsequent improvement, Female vs Male. In the subgroup of 22 patients surveyed after VIT & re-surveyed after supervised sting challenge, Mean HR-QoL improvement 0.7, and 50% achieved a MID >0.5; therefore giving a ‘Number needed to sting’ = 2.0. Patients with the largest impairment in HR-QoL appeared to benefit the most from sting-challenge. Conclusion In JJA venom allergy the magnitude of indirect allergic morbidity, measured by HR-QoL, appears to be a separate phenomenon to that of the direct morbidity of clinical allergic sensitivity [as measured by index reaction grade.] Patient factors including gender may be important considerations for this indirect morbidity. As with direct allergic sensitivity, improvements in indirect morbidity can also be obtained by VIT treatment. In addition, formal supervised exposure with sting-challenge in patients may provide additional improvements in those with significant persistent allergy-related QoL impairment. Indirect Morbidity of Venom Allergy measured by Venom-Allergy Quality of Life Questionnaire (VQLQ) in Jack Jumper Ant Allergic Patients Kymble Spriggs 1,2, [email protected] (corresponding author) Elizabeth Leahy1, Nicole Weibel1, Sara Barnes1,3 Monash Health, Clayton, Australia The University of Melbourne, Parkville, Australia Monash University, Clayton, Australia The Authors attest there in no conflict of interest for the work contained within this manuscript.

Insect Stings with the venoms of Hymenoptera species are well recognized as leading directly to allergic reactions in sensitised individuals. As with other hymenoptera venoms – Venom specific allergen Immunotherapy (VIT) to Jack Jumper Ants (JJA) Myrmecia pilosula has demonstrated efficacy in preventing the direct morbidity associated with severe venom-associated allergic reactions. Despite this, the indirect morbidity of severe allergy on associated background health related quality of life (HR-QoL) has not previously been assessed in patients with JJA venom allergy.

M pilosula venom-allergic patients referred for treatment in a specialized quaternary venom treatment centre were surveyed with a venom specific HR-QoL questionnaire before and after receiving 12 months of allergen-specific venom-immunotherapy (VIT) according to JJA. A smaller subgroup also repeated this questionnaire after receiving JJA sting-challenge.

53 patients completed both pre-VIT and post-VIT QoL questionnaires. 83% of these patients achieved a minimal important difference (MID) of increased change in QoL of >0.5. Mean HR-QoL improved by 1.85, NNT = 1.2. There was no statistically significant difference when stratified by index-reaction grade, but appeared to be greater impairment, and subsequent improvement, Female vs Male. In the subgroup of 22 patients surveyed after VIT & re-surveyed after supervised sting challenge, Mean HR-QoL improvement 0.7, and 50% achieved a MID >0.5; therefore giving a ‘Number needed to sting’ = 2.0. Patients with the largest impairment in HR-QoL appeared to benefit the most from sting-challenge.

In JJA venom allergy the magnitude of indirect allergic morbidity, measured by HR-QoL, appears to be a separate phenomenon to that of the direct morbidity of clinical allergic sensitivity [as measured by index reaction grade.] Patient factors including gender may be important considerations for this indirect morbidity. As with direct allergic sensitivity, improvements in indirect morbidity can also be obtained by VIT treatment. In addition, formal supervised exposure with sting-challenge in patients may provide additional improvements in those with significant persistent allergy-related QoL impairment.

Stinging insect allergy to the venom of Hymenoptera species is a well recognised environmental allergen leading directly to significant allergic reactions in sensitised individuals.(1) This direct allergic effect leads to morbidity via classic allergic symptoms such as urticaria, pruritus, angioedema; gastrointestinal disturbance with abdominal pain, nausea and vomiting; and severe symptoms including hypotension, dyspnoea and cardiovascular shock. The pattern of these direct downstream effects in an allergically-sensitised individual are well understood at a mechanistic level as a prototypic model of allergic reaction.(2) Similarly, allergen-specific Venom Immunotherapy (VIT) for a range of Hymenoptera species is well described, and validated as a treatment for this.(3, 4) Distinct from the classical direct morbidity of allergic reactions, patients with risk of significant allergic reaction also may have substantial indirect morbidity. This indirect morbidity enacts via stress and anxiety related to the possibility of the classical direct allergic reactions – and manifests through restriction and curtailment of participation in activities of daily living, and decreased quality of life(QoL).(5) Although without the theoretical mortality risk associated with the direct effects of allergy, these indirect effecs - may be pervasive and ever-present for patients. This may have a profound ongoing - and sometimes daily - impact, even in patients who have not experienced a sting and/or reaction for many years. Myrmecia Pilosula, or Jack Jumper Ant (JJA), is a Hymenoptera spp. native to South-Eastern Australia(6), with a known allergically potent venom, with a corresponding high regional population sensitisation estimated to be ~3%.(7) Venom immunotherapy(VIT) is clearly effective in clinically allergy patients with respect to direct morbidity.(8, 9) The effect on patients’ indirect morbidity such as QoL has not previously been studied.

Prospective approval for collection of Heath Related Quality of Life (HRQoL) data and was approved by the Human Research & Ethics Committee of Monash Health to use an adapted venom-specific instrument based on the VQLQ previously described by Oude Elberink et al.(10, 11) Informed consent to participate was obtained electronically from all participants at outset. Patients with clinically significant venom allergy with documented specific venom sensitivity for JJAs were invited to participate when undertaking VIT at our single quaternary referral state-centre providing JJA VIT. Surveys were administered electronically at timepoints: before commencement & and after receiving >12 months of therapy - and in a smaller subgroup - after receiving a sting challenge whilst established on VIT. Patients received standard-of-care JJA VIT using purified JJA venom immunotherapy (RHH, Hobart, Tas) to 50 mcg ongoing monthly maintenance dose in our treatment centre as previously described. (9) + (19) Minimally important clinical difference (MID) in HRQoL was defined as an improvement in an individual’s VQLQ score of more than 0.5.(12) To investigate baseline factors affecting results, patients were stratified by age and gender, and by severity of index reaction grade prior to VIT commencement as measure of severity of direct morbidity. Comparing those with the most severe index reactions - including objective hypotension, collapse or hypoxia [Brown grade 3] - to those of less severe reactions [Brown grade 1 and 2].(13) Statistical comparisons were made with paired Wilcoxon match pairs test to a two-tailed significant set to 0.05. Analysis was performed in Numbers (Apple Inc, California) and GraphPad Prism (Boston, Ma).

53 patients (including adults and children) completed both pre-VIT and post-VIT QoL questionnaires were included in the primary analysis cohort. A smaller group of 22 patients completed the survey whilst established on VIT and then after receiving a sting-challenge to demonstrate tolerance as previously reported. (9) Baseline characteristics of both these patient groups are shown in Table 1. In the primary cohort there was high median impairment evident at baseline of 3.7. Impairment severity by tertile in the method of Fischer et al(14) demonstrates high or moderate levels of impairment at baseline for 92% of patients. Effect of Index Reaction Severity off HRQoL When stratified by severity of index reaction there was no statistically significant difference in HRQoL scores either before, or after treatment - with an identical mean QoL improvement of 1.8 between severe vs Low/Moderate severity groups. [See Figure 1 – Primary Cohort Baseline HRQoL by Reaction Grade]. Although not adequately powered to further investigate this, baseline gradient of impairment appeared to trend in reverse with those experiencing lower grades of index reaction have greater impairment at baseline. HRQoL improvement after Venom Immunotherapy There was a strong and statistically significant improvement HRQoL, with a mean improvement of 1.9 between patients measured before and after 12-months of VIT (P < 0.0001). [See Figure 2 – Primary Cohort before and after VIT]. 83% of patients achieved an increase of the specified minimal clinically important difference (MID) in HRQoL of 0.5 on VQLQ. Number needed to treat (NNT) with VIT to achieve this benefit was therefore 1.2. (See Table 2: HRQoL as effected by VIT) Age effects on HRQoL When stratified by age (Adults vs Children) children there was not a statistically significant different in baseline impairment, nor in improvement - with a similar proportion benefitting by achieving a MID and corresponding NNT to obtain this result. [see table 2 - HRQoL improvement post VIT] Gender effects on HRQoL With respect to QoL impairment by gender, there was an apparent reduced baseline average QoL in females vs male (3.4 vs 4.0) although this did not reach statistical significance in the whole cohort of adults and children. However, when stratifying into adults vs children(<18 years old) the effect became clearer in adult female vs male (3.1 vs 4.1, p <0.05). This had a corresponding greater improvement in females QoL with VIT treatment - F vs M (2.1 vs 1.6 points improvement) although these average gender differences in impairment remained numerically evident, they did not reach statistical significance at the 95% confidence level (5.2 vs 5.7; p = 0.099). [See figure 3: Adult HRQoL Baseline and post-VIT by Gender] [And also Table 3 - HRQOL effects by tertile stratified by age and gender] QoL Improvement after Sting Challenge A subgroup of 22 patients were surveyed after receiving 12 months of VIT and re-surveyed after a supervised sting challenge. This sting appeared to significantly decrease patients’ residual impairment even further – reducing those with severe impairment to less than 10%. (See figure 4: VIT Sting Cohort: Pre & post sting). Mean HR-QoL improvement - over and above that already experienced from 12mo of VIT - was 0.7 and 50% achieved a MID >0.5; therefore giving a ‘Number needed to sting’ for meaningful improvement in QoL = 2.0. Patients with the largest residual impairment in HR-QoL appeared to benefit the most from sting-challenge procedure. And correspondingly those with low or no impairment did not appear to benefit as meaningfully from sting challenge (See Figure 5 – Additional effect of sting challenge on HRQoL, change in VQLQ post sting vs VQLQ on VIT) Again there appeared to be a trend toward greater impairment female vs male QoL at baseline [4.7 vs 5.7, p = 0.12] and post sting [5.5 vs 6.2, p = 0.07].

Here we have presented the first reported HRQoL-data in Ant-venom associated allergic disease. This data also suggests downstream efficacy of both VIT, and sting-challenge as treatments for indirect morbidity/HRQoL in ant-allergic patients. Allergic reactions associated with venom allergy are understood mechanistically as a prototypic form of allergic reaction.(2, 15) The associated direct effects and morbidity (ie that from immediate IgE-mediated allergic reactions) are classically described and treated. Similarly, these direct effects are very amenable to treatment/prevention with the application of VIT - with evidence of high levels of effectiveness for a range of Hymenoptera species, including Bees, wasp, and ants - and subsequent representation as standard of care in guidelines.(3, 4) However, despite this - and in part perhaps because of VIT’s evidential clarity of direct effectiveness - indirect morbidity may often not be explicitly considered in patient consultations and counselling. Although patients may not suffer directly from a venom-associated allergic reaction for many years, the impact of the real possibility of having one may have profound effects and cause suffering indirectly on an ongoing basis. This is particularly an issue for our cohort of JJA allergic patients in regional and rural Australia who live within the habitat of these native ants and are exposed, and reminded of them, on a daily basis. Prior work, initially by Oude Elberink, et al(5) demonstrated these indirect effects via HRQoL in those allergic to wasp venom - and recognised this indirect morbidity as a significant disease burden in Europe - and reason to consider VIT - even in the setting of low severity direct effects or a likely low frequency sting event. Perhaps surprisingly, the severity of Index reaction in other Hymenoptera species has not been found to be associated with measures of Indirect morbidity via HRQoL.(5, 16, 17) And in fact occasionally lower grades of index reaction appear associated with higher levels of anxiety in selected groups.(18) Our presented data supports this - and that severity of Index reaction does not appear to be the major driver for subsequent HRQoL – perhaps emphasising that these indirect morbidities are untethered from those mechanistically direct allergic ones. This suggests that other patient factors beyond classic allergic mechanisms are at play - and are further evident in the apparent effects of gender demonstrated in our results. Female adults appearing to experience greater HRQoL impairment at baseline in similarly characterised severity of index reaction - an effect previously measured in allergy to other Hymenoptera species.(5, 14) Interestingly, other authors have reported lower grades of index reaction appear associated with higher levels of anxiety in when stratified by gender(18) suggesting gender is a specific risk factor to be considered for more significant HRQoL impairment. Gender difference in health seeking behaviors may also have effects in the underlying treatment populations. Our ant-specific data adds to that of other Hymenoptera species VIT treatment studies - that VIT significantly improves this HRQoL that exists independent of reaction severity. Similarly our data supports the contention that sting challenge may be useful as an additional tool available to improve HRQoL in those patients with residual/resistant impairment despite VIT. As such, HRQoL may be an important measure to ascertain in patients independent of their apparent tolerance to VIT. Practitioners may be advised to consider and discuss/measure residual indirect QoL morbidity in patients otherwise seemingly progressing well on ongoing VIT treatments. These data are limited in that they required voluntary active patient participation in QoL surveys adjacent to their treatment. Although out data appears to contain representative spreads in terms of demographics and both severity of index reaction and baseline QoL, self-selection may introduce unknown biases. Given the variability of participation, and absence of an untreated control, background effects on HRQoL, including that of time itself, are not detected. Greater numbers of participants in further monitoring studies may be able to strengthen and confirm trends within our data, as would aggressive consistency in data collection at other time points to support more robust conclusions.

Indirect Morbidity due to venom allergy, as measured by HRQoL questionnaires is a separate phenomena from that of the direct morbidity associated with reactions to Jack Jumper Ants. As shown with other Hymenoptera species, this appears to be independent to the severity of Index allergic reaction, and patient specific factors such as gender, appear to be a risk factor. JJA VIT is associated with significant improvement on HRQoL, and Sting challenge appears to be a potential additional treatment available for those with residual QoL impairments. Figure 1: Primary Cohort Baseline HRQoL by Index Reaction Grade Figure 2 Primary Cohort: HRQoL Before & After VIT | Patients with pre & post VIT HRQoL (n = 53) | VIT Patients with pre & post Sting-Challenge HRQoL (n = 22) | || | Adults (>18y) | n (% cohort) | 37 (70%) | 18 (82%) | | Mean age (range) | 55 (20 - 73) | 53 (20 - 77) | | | Children | n (% cohort) | 16 (30%) | 4 (18%) | | Mean age (range) | 10 (5 - 16) | 10 (7 - 11) | | | Gender | Female no. (%) | 27 (51%) | 12 (60%) | | Index Brown Reaction Grade [n (%)] | ||| | Grade 1 | 2 (4%) | 2 (9%) | | | Grade 2 | 28 (53%) | 6 (27%) | | | Grade 3 | 23 (43%) | 14 (65%) | | | Mean HRQoL Impairment | ||| | Prior to VIT start | 3.7 (High impairment) | - | | | On VIT prior to Sting | - | 5.1 (Moderate impairment) | | | Impairment prior to intervention (VIT or Sting) | ||| | High (VQLQ 6.1) | 4 (8%) | 5 (22.7%) | Table 1 – Baseline Characteristics of the two cohorts | HRQoL Pre-VIT | HRQoL Post-VIT | Mean QoL difference | No. with MID (+0.5) | % achieving MID | NNT for MID in HRQoL | ||| | Entire Cohort | n = 53 | 3.7 | 5.5 | 1.9 | 44 | 83% | 1.20 | | | Gender | |||||||| | Female | Female n = 27 (51%) | 3.4 | 5.4 | 2.0 | 22 | 81% | 1.23 | | | Male | Male n = 26 (49%) | 4.0 | 5.7 | 1.7 | 22 | 85% | 1.18 | | | Adults | 37 (70% of Cohort) | 3.6 | 5.5 | 1.9 | 30 | 81% | 1.23 | | | Female | 19 of 37 (51% of Adults) | 3.1 | 5.2 | 2.1 | 16 | 84% | 1.19 | | | Male | 18 of 37 (49% of Adults) | 4.1 | 5.7 | 1.6 | 14 | 78% | 1.29 | | | Children | 16 (30% of Cohort) | 3.9 | 5.7 | 1.9 | 14 | 88% | 1.14 | | | Female | 8 of 16 (50% of children) | 4.0 | 5.8 | 1.8 | 6 | 75% | 1.33 | | | Male | 8 of 16 (50% of children) | 3.8 | 5.7 | 1.9 | 8 | 100% | 1 | | | Index Reaction Grade | |||||||| | Grade 1 | 2 (4%) | 3.00 | 5.20 | 2.20 | 2 | 100% | 1.0 | | | Grade 2 | 28 (53%) | 3.69 | 5.57 | 1.88 | 23 | 82% | 1.22 | | | Grade 3 | 23 (43%) | 3.74 | 5.52 | 1.78 | 19 | 83% | 1.21 | Table 2 – HRQoL improvement post VIT Figure 3 : Adult HRQoL Baseline & Post-VIT by gender Figure 4: VIT Sting Cohort Pre & Post Sting Figure 5: Additional effect of sting challenge on HRQoL after VIT by pre-sting VQLQ | Pre-VIT | Post-VIT | ||||| | Impairment severity | n = 53 | 53 | 53 | ||| | High (VQLQ 6.1) | 4 | 7.5% | 17 | 32.1% | || | Impairment severity | |||||| | Adults compared to Children | |||||| | ADULTS | n = 37 | 37 | 37 | ||| | High (VQLQ 6.1) | 4 | 10.8% | 12 | 32.4% | || | CHILDREN | n = 16 | 16 | 16 | ||| | High (VQLQ 6.1) | 0 | 0.0% | 6 | 37.5% | || | Impairment severity by Gender | |||||| | (Adults AND Children) | Female | n = 27 | 27 | 27 | || | High (VQLQ 6.1) | 1 | 3.7% | 7 | 25.9% | || | Male | n = 26 | 26 | 26 | ||| | High (VQLQ 6.1) | 3 | 11.5% | 10 | 38.5% | || | Impairment by Adults vs Children then by gender. | |||||| | ADULTS | Female Adults | n = 19 | 19 | 19 | || | High (VQLQ 6.1) | 1 | 5.3% | 4 | 21.1% | || | Male Adults | n = 18 | 18 | 18 | ||| | High (VQLQ 6.1) | 3 | 16.7% | 8 | 44.4% | || | CHILDREN | Female Children | n = 8 | 8 | 8 | || | High (VQLQ 6.1) | 0 | 0.0% | 3 | 37.5% | || | Male Children | n = 8 | 8 | 8 | ||| | High (VQLQ 6.1) | 0 | 0.0% | 3 | 37.5% | Table 3 - HRQOL effects by tertile stratified by age and gender

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Authors Metrics & Citations Metrics Article Usage 326views 213downloads Citations Download citation Kymble Spriggs, Elizabeth Leahy, Nicole Weibel, et al. Indirect Morbidity of Venom Allergy measured by Venom-Allergy Quality of Life Questionnaire (VQLQ) in Jack Jumper Ant Allergic Patients. Authorea. 22 June 2024. DOI: https://doi.org/10.22541/au.171906729.91333668/v1 DOI: https://doi.org/10.22541/au.171906729.91333668/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.