Chlorhexidine Allergy in 4 Specialist Allergy Centres in the UK, 2009-2013

32 Pages·2017·0.37 MB·English

This is a repository copy of Chlorhexidine Allergy in 4 Specialist Allergy Centres in the UK,
2009-2013: Clinical Features and Diagnostic Tests..
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Version: Accepted Version
Article:
Egner, W. orcid.org/0000-0002-2654-9881, Helbert, M., Sargur, R. et al. (6 more authors)
(2017) Chlorhexidine Allergy in 4 Specialist Allergy Centres in the UK, 2009-2013: Clinical
Features and Diagnostic Tests. Clinical And Experimental Immunology. ISSN 0009-9104
https://doi.org/10.1111/cei.12944
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Clinical Experimental Immunology
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Page 1 of 30 Clinical Experimental Immunology
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4 Chlorhexidine Allergy in 4 Specialist Allergy Centres in the UK,
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7 2009-2013: Clinical Features and Diagnostic Tests
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Clinical Experimental Immunology Page 2 of 30
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4 Authors
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6 1. Dr. William Egner
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Corresponding Author: [email protected]
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Clinical Immunology and Allergy Unit
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Northern General Hospital
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19 2. Dr. Matthew Helbert
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Department of Allergy and Immunology
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Central Manchester University Hospitals NHS Foundation Trust
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Manchester, UK
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28 3. Dr. Ravishankar Sargur
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30 Clinical Immunology and Allergy Unit r

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32 Sheffield Teaching Hospitals NHS Trust
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Sheffield
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4. Mrs. Kirsty Swallow
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41 Clinical Immunology and Allergy Unit
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5. Professor Nigel Harper
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Department of Anaesthesia
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Page 3 of 30 Clinical Experimental Immunology
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4 6. Dr. Tomaz Garcez
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6 Department of Immunology
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Central Manchester University Hospitals NHS Foundation Trust
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Manchester, UK
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7. Dr. Sinisa Savic
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15 Department of Immunology,
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17 Leeds Teaching Hospitals
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8. Dr. Louise Savic
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Department of Anaesthetics,
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Leeds Teaching Hospitals
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31 9. Dr. Eren Effren
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Department of Immunology
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Southampton General Hospital,
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40 Abbreviations
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42 CI Confidence Interval w
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NMBA Neuromuscular Blocking Agent
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BAT Basophil Activation Test
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SPT Skin Prick Test
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51 IDT Intradermal Skin Test
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53 sIgE Specific IgE
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55 kUA/L kilounits (arbitrary) of sIgE per litre
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Clinical Experimental Immunology Page 4 of 30
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4 SUMMARY
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9 We describe an observational survey of diagnostic pathways in 104 patients attending four
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chlorhexidine reactions. The majority were life threatening. Men undergoing urological or
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cardiothoracic surgery predominated. Skin prick testing and sIgE testing were the most
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common tests used for diagnosis. Fifty-three % of diagnoses were made on the basis of a
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20 single positive test. Where multiple tests were performed the sensitivity of intradermal,
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22 basophil activation and srkin prick testing was 68% (50-86%), 50% (10-90%) and 35% (17-55%)
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24 respectively. Seven percent were negative on screening tests initially, and 12 cases were only
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positive for a single test despite multiple testing. Intradermal tests appeared most sensitive in
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this context. e
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32 Additional sensitisation to other substances used perioperatively, particularly neuromuscular
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34 blocking agents (NMBA), was found in 28 patients, emphasising the need to test for possible
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36 allergy to all drugs to which the patient was exposed even where chlorhexidine is positive.
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Key Words
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Chlorhexidine Allergy
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Anaesthesia
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Skin Tests
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51 Specific IgE
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53 Anaphylaxis
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Page 5 of 30 Clinical Experimental Immunology
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Clinical Experimental Immunology Page 6 of 30
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4 INTRODUCTION
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9 Chlorhexidine is increasingly recognised as a significant allergen in the perioperative setting
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11 [1]. We aimed to describe and compare a larger series of cases from multi-centre British
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13 specialist allergy clinics [1] [2]. This increase is thought to be driven by increased use of
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chlorhexidine and increased awareness of allergy, even though there remains some evidence
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of under-diagnosis [2] [3] [4]. Unlike most perioperative reactions [5], the majority of reported
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patients have been men, frequently undergoing urological or cardiothoracic surgery in non-UK
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22 and single centre studiesr.
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24 The performance of tests for chlorhexidine allergy has been estimated in single centres and
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26 there is published guidance on how to do tests for chlorhexidine allergy [6] [7], but it is not
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clear if these observations can be geneeralized to other clinic cohorts or countries [7]. We also
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set out to determine whether we could estim ate sensitivity for the different tests available for
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diagnosing chlorhexidine allergy in a routine clinical setting and identify the most effective
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35 diagnostic strategy for determining sensitisation. Fienally, multiple reactivity has been reported
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Page 7 of 30 Clinical Experimental Immunology
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4 MATERIALS AND METHODS
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7 Data collection
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Data on all patients diagnosed with chlorhexidine allergy was retrospectively collected from
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records of four regional UK Allergy Centres (Sheffield Teaching Hospitals, Central Manchester
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14 University Hospitals NHS Foundation Trust, Southampton University Hospitals, and Leeds
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16 Teaching Hospitals) between 2009 and 2015. The patients were seen following routine
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18 referral into anaesthetic drug reaction clinics. The investigations carried out were not
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20 harmonised across clinics. Many of our series had only one test (most commonly SPT or sIgE)
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and the first positive test prevented further testing. The sequence of further testing differed
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between centres (only one offered BAT), between patients and across time (increasing use of
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27 IDT in patient who were negative ein screening tests in some centres). As the data were
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29 collected as part of routine clinical audit, ethics committee approval was not required.
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31 Gender, chlorhexidine preparation used, the clinical setting, details of the reaction,
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33 investigations performed (skin prick and / or inRtradermal test, specific IgE and basophil
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activation test) and final clinical diagnosis were obtained.
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Skin prick testing (SPT) was carried out using undiluted clear or pink Hydrex® (Chlorhexidine
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42 gluconate Solution 20% BP (Ph Eur) 2.5% v/v, denatured ethanol Bw 96%, purified water BP,
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44 Carmosine (E122)) with positive (histamine 10mg/ml) and negative (normal saline) controls:
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46 SPT was positive if a wheal ≥ 3mm than negative control was present at 15- 20 minutes, as
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reported previously and as per 2011 guidance [[7] [6]. All other drug skin prick tests were
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carried out in accordance with 2011 guidance. Both pink & clear Hydrex was used to exclude
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any possible reactions due reactors to the colourant in some centres.
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Clinical Experimental Immunology Page 8 of 30
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4 Intradermal testing (IDT) was performed using 20 microlitre injections of chlorhexidine
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6 gluconate (clear or pink or both, as appropriate to the clinic) 1:1000 dilution and normal saline,
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administered on the volar aspect of the forearm. The results were interpreted as previously
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described [3] [7]. A positive IDT was defined as the mean of orthogonal weal diameters of at
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least 3mm greater than the negative control, in the presence of a flare [3] [7].
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15 Chlorhexidine sIgE was measured by immunoassay (ImmunoCAP) on the Phadia ImmunoCap
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17 1000 Analyser (Thermo Scientific, Loughborough, UK). A sIgE level >0.35 kUA/L was deemed
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19 positive in Sheffield, Leeds and Southampton and ≥ 0.4 kUA/L in Manchester (functionally
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equivalent to >0.35 as this laboratory reported measurement to a single decimal place only).
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All laboratories performed daily internal quality control and participated in the UK National
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External Quality Assurance Scheme for allergen specific IgE with satisfactory performance.
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30 At Sheffield and Southampton, Basophil Arctivation Tests (BAT, Buhlmann FlowCast,

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32 Switzerland) were analysed on a Beckman Coulter EPICS XL flow cytometer. The chlorhexidine
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used to stimulate the basophils was from the same source as the skin prick tests.
35 e
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Chlorhexidine was used at concentrations of 0.05%, 0.0v05%, 0.0005% and 0.00005% for
37
i
38
Hydrex® “clear” and 0.02%, 0.002% and 0.0002% for Hydrex® “pink”. A wide range of
39
e
40
41 concentrations were used to assess the strength of sensitisation and exclude potential irritant
42 w
43 or toxic concentrations in patients and controls in view of the lack of experience,
44
45 harmonisation and validation of this test.
46
47
Positive controls (Fc(cid:540)RI and fMLP), negative control (background) and a normal volunteer
48
49
control were performed for each run. Fluorescently labelled antibody to CCR3 was used to
50
51
identify basophils. Activated basophils were differentiated from resting basophils using a
52
53
54 fluorescently labelled antibody to CD63, which only becomes expressed on the cell surface
55
56 when basophils are activated [8]. A positive response was present if two or more
57
58
59
60