Dear Editor,

Our best practice guidelines for the diagnosis of allergy advise that routine requesting of total IgE measurements is not necessary; instead we advise requesting allergen-specific IgE based on clinical findings. Khan et al. argue that measurement of total IgE levels permits ascertainment of possible false-negative or false-positive specific IgE results. However, the examples given provide only a circumstantial indication of the possibility of false positive or negatives in rare cases. In the context of primary care testing, the issue in question is whether total IgE should be requested systematically alongside all specific IgE requests, or only a posteriori in specific cases. Current evidence suggests that in the vast majority of cases, assessment of total IgE increases costs unnecessarily as it does not add to the diagnosis and management of allergy patients. In the example given of anaphylaxis, we would recommend such cases to be investigated in conjunction with a consultant immunologist.

The authors confirm that increased levels of total IgE may be found in situations without an allergic background, are therefore not predictive of allergic sensitisation and consequently have little positive predictive value for the diagnosis of allergy. We agree with this statement. Further, the authors acknowledge that low IgE does not rule out sensitisation, which can only be assessed by testing for allergen-specific IgE; one of the references quoted (Sinclaire d et al) – although advising that total IgE should be performed as a screening test which would exclude specific IgE if low – goes on to conclude that specific IgE testing should be performed regardless of total IgE levels when there are convincing clinical reasons to do so. We agree with this statement. The authors quote findings in support of a correlation between total IgE and specific IgE levels (Kerkhof m et al) in food allergy, although specific IgE alone was found to be just as reliable. We again agree.

The authors however, correctly point out that very high levels of total IgE can give false positive specific IgE results, which we did not specifically address in our guidelines. We agree this can be relevant, but feel that these situations are relatively rare and do not justify regular requesting of total IgE; our advice would be to request total IgE a posteriori if the results of specific IgE testing suggest that non- specific binding is the reason for the false positive (i.e. multiple or all allergens tested are positive).

Even though not mentioned in the letter, it is important to stress that measuring total IgE may have previously been of significance in calculating the amount (i.e. quantitation) of specific IgE present; this is now bypassed by the inclusion of international reference standards for total IgE in kits measuring specific IgE, enabling the expression of specific IgE quantitatively in international units rather than semi- quantitatively in scores.

Finally it is of note that the American Academy of Allergy, Asthma and Immunology (AAAAI) and American College of Allergy, Asthma and Immunology (ACAAI) recently published guidelines on food allergy (Annals Asthma Allergy Immunol, 2006, 96(3) supp:1-68) in which they neither mention nor recommend measurement of total IgE in patients with food allergy.

We are grateful for the comments by Khan et al. These guidelines are intended for regular review and wide professional input wherever possible.

Dear Editor,

The article by WS Smellie and colleagues[1] recommends not requesting total IgE levels when requesting 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. Although this may not be as important in the interpretation of aeroallergen-specific IgE results, this consideration is vital in determining possible causes of anaphylaxis.

High total IgE may cause false positive specific IgE tests. High IgE level are more common in males, smokers and severe eczema [2]. Mehl A and colleagues[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) but specific IgE estimations were just as reliable. M Kerkhof and colleagues demonstrated that the elevated total IgE ‘outpaces’ specific IgE in younger individuals (aged 20-44 years), suggesting that in this cohort, negative specific IgE should guide the clinician towards looking for IgE against other allergens [4].

Low IgE (<10 IU/ml) are rarely associated with findings of positive specific IgE results, although positive IgE at these low total IgE levels may be extremely significant [5]. Knowing that the total IgE is low becomes essential when interpreting negative specific IgE tests in the context of anaphylaxis for example.

Yours faithfully,

S Khan*
S Holding**
PC Doré**
WAC Sewell*

*Path Links Immunology, Scunthorpe General Hospital, Scunthorpe, DN15 7BH, UK.
**Department of Immunology, Hull Royal Infirmary, Hull, HU3 2JZ, UK.

Competing interests: None.

References

1.Smellie WS, Forth JO, McNulty CA, Hirschowitz L, Lilic D, Gosling R, Bareford D, Logan E, Kerr KG, Spickett GP, Hoffman J, Galloway A, Bloxham CA. Best practice in primary care pathology: review 2. J Clin Pathol. 2006 Feb; 59(2): 113-20.

2.Wuthrich B, Schindler C, Medici TC, Zellweger JP, Leuenberger P. IgE levels, atopy markers and hay fever in relation to age, sex and smoking status in a normal adult Swiss population. SAPALDIA (Swiss Study on Air Pollution and Lung Diseases in Adults) Team. Int Arch Allergy Immunol. 1996 Dec; 111(4):396-402.

3.Mehl A, Verstege A, Staden U, Kulig M, Nocon M, Beyer K, Niggemann B. Utility of the ratio of food-specific IgE/total IgE in predicting symptomatic food allergy in children. Allergy. 2005 Aug; 60(8): 1034-9.

4.Kerkhof, M., Dubois, A. E. J., Postma, D. S., Schouten, J. P. & Monchy, J. G. R. Role and interpretation of total serum IgE measurements in the diagnosis of allergic airway disease in adults. Allergy 2003; 58 (9): 905-911.

5.Sinclair D, Peters SA The predictive value of total serum IgE for a positive allergen specific IgE result.J Clin Pathol. 2004 ; 57(9): 956-9.