P. C. Doré

Immediate hypersensitivity to chlorhexidine is increasingly recognised in the United Kingdom

BACKGROUND Chlorhexidine is widely used as an antiseptic agent. It is a potentially allergenic substance that can cause severe hypersensitivity reactions. OBJECTIVE We describe six patients who had anaphylactic reactions attributed to chlorhexidine during surgery. These patients were exposed to chlorhexidine in gels, swabs and catheters. MATERIALS AND METHODS Six patients from three UK centres with clinical history suggestive of anaphylaxis during surgery are reported. Detailed history, review of case notes, determination of chlorhexidine specific IgE, mast cell tryptase and skin tests were performed. RESULTS On detailed assessment five of six patients demonstrated a previous history of reactions on re-exposure to chlorhexidine. All six patients had elevated specific IgE to chlorhexidine. Skin prick test with chlorhexidine was performed in four of the six patients and was found to be positive. CONCLUSION Immediate hypersensitivity to chlorhexidine appears to be common but underreported in the UK. We recommend that centres investigating patients with reactions during anaesthesia and surgery should routinely include testing for chlorhexidine allergy.

Do ribosomopathies explain some cases of common variable immunodeficiency

The considerable clinical heterogeneity of patients with common variable immunodeficiency disorders (CVID) shares some similarity with bone‐marrow failure disorders such as Diamond–Blackfan anaemia (DBA) and Shwachman–Diamond syndrome (SDS), now recognized as defects in ribosome biogenesis or ribosomopathies. The recognition of a patient with DBA who subsequently developed CVID lends support to our previous finding of a heterozygous mutation in the SBDS gene of SBDS in another CVID patient, suggesting that ribosome biogenesis defects are responsible for a subset of CVID. Genetic defects in the ribosomal translational machinery responsible for various bone marrow failure syndromes are recognized readily when they manifest in children, but diagnosing these in adults presenting with complex phenotypes and hypogammaglobulinaemia can be a challenge. In this perspective paper, we discuss our clinical experience in CVID patients with ribosomopathies, and review the immunological abnormalities in other conditions associated with ribosomal dysfunction. With genetic testing available for various bone marrow failure syndromes, our hypothesis that ribosomal abnormalities may be present in patients with CVID could be proved in future studies by testing for mutations in specific ribosomal genes. New knowledge might then be translated into novel therapeutic strategies for patients in this group of immunodeficiency disorders.

Serum Trough IgG level and Annual Intravenous Immunoglobulin Dose Are Not Related to Body Size in Patients on Regular Replacement Therapy

Therapeutic regimens of intravenous immunoglobulin are currently based on actual body weight. The relationship between immunoglobulin dose and serum IgG level in relation to body size was retrospectively explored in patients on replacement therapy. Data were collected as part of a national audit on immunoglobulin therapy in patients with common variable immunodeficiency. 107 patients received immunoglobulin titrated to optimum effect. Correlations were sought between body mass index, trough IgG levels, infusion frequency and total annual dose. The mean (±SD) trough IgG level was 8.4±1.6 g/L and annual immunoglobulin dose received was 456.8±129.4 g. There was no relationship between annual dose and trough IgG level, regardless of infusion frequency, or adjustment for weight or body mass index. These results support the clinical practice of immunoglobulin prescription by clinical outcome rather than fixed dose by body weight. Future studies exploring immunoglobulin efficacy should include treatment arms with dosages based on both ideal and actual body weight, as ideal body weight-based prescribing would save significant amounts of product.

Early indicators of immunodeficiency in adults and children: protocols for screening for primary immunological defects

Early recognition of primary immunodeficiency is essential to reduce morbidity and mortality, and yet failure to recognize these conditions is still a major problem for clinicians around the world. The problem is that general practitioners, physicians and paediatricians lack familiarity with these rare disorders, and lack guidance regarding the appropriate use of immunological investigations. A working party from the European Society for Immunodeficiencies (ESID) has published screening protocols for these rare disorders, which aim to help select which tests should be done in which patients. The success of these proposals will depend on all immunologists disseminating this information in a format that is suitable for the busy generalist, who may not be familiar with these immunological tests and concepts. Laboratories should expect increasing requests for these screening investigations, and should make themselves familiar with these protocols so that appropriate second‐line investigations can be arranged in a timely fashion. Speedy and effective communication between the laboratory and clinician is essential, and clinically interpreted reports are mandatory. Although these protocols are part of a screening process, their effectiveness in practice remains to be established, and further refinement will be required over time. The early involvement of the clinical immunologist in cases of suspected immunodeficiency is key.

Both patient characteristics and IVIG product-specific mechanisms may affect eosinophils in immunoglobulin-treated Kawasaki disease.

Editor Kuo et al. suggest that higher eosinophil counts postintravenous immunoglobulin (IVIG) administration are an indicator of IVIG responsiveness in patients with Kawasaki disease (KD) (1). Both patient phenotype and choice of IVIG product may explain their findings. Polymorphisms in the PAF-AH gene have been shown to be associated with IVIG resistance in KD (2) and naturally occurring anti-Siglec-8 autoantibodies in IVIG preparations can lead to spontaneous apoptosis of eosinophils (3). These eosinophil-reducing factors should be considered before assuming that a low eosinophil count is enough to warrant a second course of IVIG therapy. Platelet-activating factor (PAF) primes eosinophils and promotes the release of cysteinyl leukotrienes and cyclo-oxygenase products (PGE2, PGD2, TXB2, PGF2a) (4). PAF priming lowers the normal life span of eosinophils (5). The phospholipase A2 enzyme, PAF acetylhydrolase (PAF-AH) hydrolyzes PAF and oxidizes phospholipids to biologically inactive molecules. Deficiency of PAF-AH has been shown to increase the risk of development of asthma (6) and atherosclerosis (7). The most prevalent lossof-function mutation identified in the PAF-AH gene G994T abolishes the enzyme activity (8), and in 76 Japanese KD children significantly more patients with the GT (heterozygous)/TT (homozygous) genotype had longer duration of fever and higher C-reactive protein, and required additional IVIG (i.e., lower PAF-AH activity correlated with IVIG resistance) (2). There were no differences in total white cell or neutrophil counts or incidence of coronary arterial lesions between the two groups. It can be inferred that the increased PAF activity in PAF-AH-deficient individuals lowers the viability of eosinophils and partly explains the low eosinophil count seen in the IVIG-resistant patients in Kuo s study (1). Anti-sialic acid binding immunoglobulin-like lectin-8 (Siglec-8) autoantibodies are present in IVIG. In the presence of IL-5, GM-CSF, IFN-c or TNF-a, anti-Siglec-8 leads to spontaneous apoptosis of eosinophils (3). These autoantibodies cause additional eosinophil death via a caspase-independent pathway dependent on reactive oxygen species that are elevated in KD. Changes in cell counts (i.e., lymphocytes, neutrophils, eosinophils, or platelets) observed after IVIG administration may be related to antiSiglec-8 differences within the preparations. The significance of these autoantibodies in normal individuals is unclear at present, so correlation of the anti-Siglec-8 levels in KD patients and IVIG responses may reveal their role in the disease. Another important difference between IVIG products is varying amounts of IgG glycosylation, as post-translational modification with Nlinked glycans at Asn297 of Fc portion of IgG alters the immunomodulatory potential by binding onto specific Fcc receptors (9). It is therefore important to consider these and other factors as contributing to the pathophysiological changes observed after IVIG administration. Hence, it would be useful to know the IVIG products that were used in Kuo s study. Even though various validated scoring systems may predict responsiveness to IVIG (10), it is important to realize that the efficacy of an IVIG product depends on the donor population, stabilizers, viral elimination techniques, and other aspects, and as such each IVIG product is unique in its own right. Pediatr Allergy Immunol 2008: 19: 186–187

Intravenous immunoglobulin‐induced neutropenia

Editor, The article by Sonia Lemos and colleagues mentions autoimmune and drug-induced causes of neutropenia in primary immunodeficient patients (1), but it is important to consider that autoantibodies in intravenous immunoglobulin (IVIG) preparations can also cause neutropenia. IVIG products from various manufacturers when used in high doses (2 g/kg) have been reported to induce neutropenia and reports to date are tabulated (Table 1). In a retrospective comparative cohort study on children with immune thrombocytopenic purpura, IVIG therapy resulted in significantly more neutropenic episodes (18 of 64 IVIG courses, 28%) than anti-D therapy (0 of 64, 0%) (8). However, anti-D IVIG therapy can also cause neutropenia (15, 16). The reassuring fact is that IVIG-induced neutropenia is transient (counts return to normal within 2 wk) and apart from oral ulcers, no severe infectious complications have been reported to occur during the episode. The autoantibodies in IVIG preparations that potentially lead to neutropenia are: (i) antineutrophil antibodies (6, 7); (ii) atypical antineutrophil cytoplasmic antibodies (ANCA) (17, 18); and anti-Siglec-9 (sialic acid binding Ig-like lectin, Siglec) antibodies (19). Others have

Pitfalls in the Diagnosis of Latex Allergy

BACKGROUND Screening patients for latex allergy prior to surgery is an important but intensive procedure. The appropriate testing strategy for diagnosing latex (Hevea brasiliensis) allergy involves in-vitro specific IgE or skin prick testing. The sensitivity and specificity of both tests are influenced by patient-specific factors or manufacturing processes that alter the clinically relevant allergens in skin testing solutions. METHODS Total IgE and latex-specific IgE testing was introduced as a screening test. Skin prick testing was done on patients with a high probability of latex allergy and negative specific IgE with total IgE <100 kU/L. SDS-PAGE was done on the non-ammoniated latex (NAL) and newly introduced ammoniated latex (AL) reagents for the clinically relevant allergens. RESULTS 51 patients had a total IgE <100 (range, 2.8-99.0 kU/L), and 10% had a positive skin test. 60% of positive skin tests would have been missed with lower total IgE cut-offs of 50 kU/L (6% of referrals). SDS-PAGE of the NAL solution showed 3 prominent bands with molecular weights of approximately 20, 24 and 42 kDa that correlated with Hev b 6, Hev b 3 and Hev b 7/13, respectively. In contrast, the AL solution showed 3 very faint higher molecular weights bands that did not correlate with clinically relevant antigens. CONCLUSIONS Increasing the cut-off value of total IgE for allergen-specific IgE testing increased the sensitivity of the specific IgE test. The NAL reagent had a greater number of clinically significant allergens at higher concentrations than AL, which may have implications for the clinical sensitivity of the newer AL reagent.

The value of total IgE levels in the context of specific allergy

Dear Editor The article by Niggermann B et al. (1) did not consider total IgE when interpreting allergen-specific IgE. We agree that total IgE on its own neither rules in nor rules out the diagnosis of allergy. However, total IgE levels are useful in the interpretation of specific IgE tests, because they permit the ascertainment of possible false-negative or false-positive results. The authors mention that in 22% of cases the clinician remained uncertain of the diagnosis even after the specific IgE results were available. This could mean that the lack of a total IgE was one of the reasons why appropriate comments were not appended to the results during laboratory validation. In addition, clinical details provided by the clinician help the laboratory estimate the prior test probability in patients who were subjected to allergy testing. High total IgE is associated with poor specificity for specific IgE antibodies. High IgE levels are more common in males, smokers and severe eczema (2), and this false-positivity should be mentioned by the laboratory to enable the clinician make an informed judgement of the results. Mehl et al. (3) found that the ratio of food-specific/total IgE had a significant correlation with outcome from food challenge (cow s milk, hen s egg, wheat and soy) although specific IgE estimations were considered to be just as reliable. Kerkhof et al. (4) demonstrated that the elevated total IgE outpaces specific IgE in younger individuals (aged 20–44 yr), suggesting that in this cohort, negative-specific IgE should guide the clinician towards looking for IgE against other allergens. This may perhaps be one of the reasons why the authors mention that primary care physicians did not appreciate negative results and gave advice regarding allergen avoidance in the absence of symptoms against the corresponding allergen (1). Low IgE (<10 IU/ml) is rarely associated with findings of positive-specific IgE resulting in false-negative results (i.e. poor sensitivity), although positive IgE at low total IgE levels may be extremely significant (5). The correlation between specific IgE result and allergic disease is not perfect. The cut-off value of 0.35 KUA/l that is used to identify affected individuals provides information about likelihood of allergy, which is affected by the probability of being affected before the test (prior probability). Allergy tests provide most information when the prior probability is 0.5, and positive results to one allergen and negative to another could lead to posterior probabilities of >0.95 and <0.05, respectively, for a suspected allergic reaction (6). Hence, random screening of allergens would not provide useful information and would certainly undermine the true significance of the specific IgE antibody test.