Characterization of food allergies has produced abundant data on their clinical presentation, but the biological construct driving the pathology is a ghost in the machine. In this month’s issue, Vassallo and Camargo make an intrepid, but logical, gesture at a syncretic hypothesis of food allergy evolution.
The authors start with the epidemiologic observation that societal decreases in exposure to sunshine have led to a rise in vitamin D deficiency (VDD) and that these two changes are coeval with the increase in food allergies. They offer a hypothesis linking evidence of VDD to atopic progression, i.e., eczema, respiratory compromise, and food allergy. Specifically, they propose that VDD results in increased infection susceptibility and altered microbiota in the gut, which in turn, cause higher levels of mucosal barrier damage, permitting excessive exposure to food allergens through the “leaky gut.”
Vassallo and Camargo mention known associations between VDD, childhood obesity, and food allergy. Physiologic support for their hypothesis comes from recent evidence that vitamin D is critical to induction of tolerance, as well as antimicrobial peptide (AMP) production in the epithelium, and suppression of inflammatory responses.
It is the AMP factor that the authors use to tie VDD to the effector mechanism. In addition to increased susceptibility to infection, VDD causes dysregulation of AMPs in the intestine, supporting an abnormal intestinal flora. They also point to recent data that suggest VDD has a primary role in mucosal barrier compromise.
Wrapping up, Vassallo and Camargo note several incongruities, including that VDD prevalence is higher than food allergy prevalence and genetic atopic predispositions may act independently to increase food allergy risk, from which they suggest that multiple “hits” are required to result in food allergy. They urge future, cross-disciplinary research designed to examine their hypothesis that correction of VDD during pregnancy and early childhood will lead to improved tolerance, mucosal immunity, and balanced intestinal flora.
We asked the authors whether their hypothesis could be applied to adults as well as children:
JACI: You make the distinction between failure to develop tolerance as seen in childhood and loss of tolerance associated with adult onset of food allergy. Is there reason to believe that vitamin D supplementation might mitigate loss of tolerance as well?
Carlos Camargo: We have chosen to focus on children because that’s when most food allergy begins -- and where we have found supportive epidemiologic data (eg, our recent publication on season of birth and food allergy -- citation below). In brief, we found increased risk of food allergy among children born in fall/winter, as compared to spring/summer. We found no association between season of birth and food allergy in older patients. (Vassallo MF, Banerji A, Rudders SA, Clark S, Mullins RJ, Camargo CA Jr. Season of birth and food allergy in children. Ann Allergy Asthma Immunol 2010; 104: 307-313.)
While it’s theoretically possible that vitamin D supplementation might mitigate loss of tolerance in adults, we will continue to focus our research efforts on childhood food allergy.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Friday, July 30, 2010
Thursday, July 1, 2010
Guest post: A primer on human IgE antibody serology
Dear Readers:
In response to the concerns about an increase in the remote practice of allergy, which may possibly be influenced by direct allergy laboratory marketing campaigns, the AAAAI and ACAAI, in conjunction with Don Aaronson from the JCAAI formed a joint taskforce in 2006 on allergy diagnostic testing called the Specific IgE Test Task Force (SETTaF) . SETTaF’s purpose has been to develop educational materials that focus on the appropriate diagnostic evaluation of the allergic/suspected patient. In late 2008 SETTaF published a monograph directed at health care professionals, who care for allergic patients entitled the “Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology/American Academy of Allergy, Asthma and Immunology Specific IgE Test Task Force.”(1) The task force is currently engaged in the development of a PowerPoint presentation and several monographs on diagnostic allergy testing that are directed at primary care professionals.
The key message throughout these educational materials is that the allergy evaluation must be initiated by and culminated with the patient's clinical history. It must be directed by a health care professional with sufficient understanding of diagnostic allergy testing to use the information obtained from his/her evaluation of the patient to determine: 1. What diagnostic allergy tests to order. 2. How to interpret the diagnostic allergy test results. 3. How to use the information obtained from the allergy evaluation to develop an appropriate therapeutic treatment plan.
This issue of the Journal of Allergy and Clinical Immunology presents a monograph developed by SETTaF on serological measurement of allergen-specific IgE testing specifically for the North American allergist. Per the protocol of a joint AAAAI/ACAAI task force, the SETTaF’s monographs are reviewed by the Board of Directors/Regents of both organizations. During this review, a question and answer dialogue evolved and the organizations' Boards suggested including the ‘Q&A’ with the document.
The members of SETTaF hope you find the monograph educational. The following questions and answers represent the views of the individuals and not SETTaF or the Board of Directors/Regents of the AAAAI/ACAAI.
Sincerely,
Linda Cox, MD
SETTaF chair
Allergy Diagnostic Testing Primer: Questions and Answers
Below are some questions that were raised by ACAAI reviewers that will highlight some of the questions readers may have and an attempt by the authors to provide answers, where they are available.
Issue 1: Use of serum specific-IgE in clinical decision-making
Dana Wallace , MD (ACAAI president-elect): This report on the evolution of serum specific- IgE (s-IgE) testing is a timely and much needed document for the clinical allergist. While technically well written, it brings up perhaps more questions and confusion than it answers or clarifies. While the authors and many other academicians may find it clear and easy to understand, I am not sure that this will be the case for most clinicians. Particularly difficult will be the translation of this information into clinical decision-making support tools. It would be very helpful if an additional section could be added: “When and how to use specific IgE in vitro tests to improve patient care”. I would suggest that in this section, the authors try to answer the following questions (among others):
Linda Cox, MD ( SETTaF chair): I think one has to consider s-IgE similar to skin testing in terms of when and how it would be used in patient care and the decision on which type of test(s) would vary with the patient and other circumstances.
Brock Williams, PhD (Primer author and SETTaF member): The hard question to answer is when and how to use s-IgE testing to improve patient care. To me, this deals mostly with how to interpret the results and this is very patient dependent. Again the problem stems from the fact that allergic symptoms are variable both within and between individuals. This and the large number of variables (age, gender, exposure, infection, etc.) clearly need to be taken into account for the interpretation of s-IgE tests. We do know that s-IgE is closely linked to symptoms but levels and the allergens it is directed against differ among different individuals. Thus, in today’s world, s-IgE results will best be utilized by considering them as a risk factor rather than an absolute diagnostic fact.
Robert Hamilton, PhD: The ultimate decision of when to use a confirmatory IgE antibody test (skin test or serology) comes down to the physician deciding that there is sufficient clinical evidence to warrant a possible diagnosis of allergic disease. This concept is integral to the diagnostic algorithm built into the diagnostic practice parameters. As such, to try to list all the patient and physician decisions to determine when a diagnostic IgE antibody confirmatory test (skin test or serology) should be run is (in my opinion) out of the intended scope of this article. This article summarizes what we know and what we do not know about the assays used to detect allergen-specific IgE antibody. I agree with Brock that prudent use of a positive specific IgE antibody result is as a risk factor for allergic disease and not as a definitive indicator of the presence of allergic disease.
Issue 2: Which is the ‘best’ specific IgE assay?
Dana Wallace, MD: Which of the three methods of specific-IgE measurement described within the Primer is most beneficial for making clinical decisions or should they all be viewed as equal?
Linda Cox, MD: There is agreement that the results are not assay inter-changeable. One thought is the different assays may be measuring different antibodies.
Brock Williams, PhD: Comparability of different methods – most studies indicate that the Phadia ImmunoCAP is far above the other two tests in overall performance (accuracy, precision, and quantitative ability). The problem is that for certain allergens and levels of s-IgE the assays are somewhat in agreement. For others, they are very different. I find the explanation that these assays are sometimes measuring different populations of antibodies to be rather absurd. To begin with I have seen no proof of this concept and our studies with chimeric antibodies (where the total IgE = specific IgE) indicate that for those allergens investigated the Siemens assay (formerly DPC-Alastat/Immulite) has major problems with its calibration and the Hycor assay (Agilent) has problems with under-representation of allergen on some of their solid phases. The major user of the Hycor assay is Labcorp and we know in the past some have suggested that they have modified this test in house to make it more profitable. The ImmunoCAP results (done in triplicate with blinded samples) was ‘spot on’ in these cases.
Robert Hamilton, PhD: I respectfully disagree with Brock on this issue. The most impartial examination of the inter-assay agreement issue indicates that all three methods display excellent precision, reproducibility and linearity. They do differ in the levels of IgE antibody that they detect and we currently do not know the reason for this. It is possibly a calibration issue, however, if there was a systematic bias caused by a calibration issue, we would see a consistent bias which we do not. My belief is that it has more to do with allergen heterogeneity between the methods. Thus to call the suggestion that the assays are measuring different populations of IgE antibody specificities "absurd" is too ‘heavy handed’. Brock, your data with the chimeric antibody are interesting and informative but not conclusive on a calibration issue.
We need to construct a better and more relevant experiment with human sera to try to dissect the answer to this question. Possibly this can be done with milk and peanut where we can identify the component specificities of IgE antibody using the ISAC and the components that are available on the ImmunoCAP. Then sera with defined distributions of IgE antibody can be analyzed by all 3 methods. So the binding of a serum containing 95% IgE anti-casein can be compared to a serum that contains 95% IgE anti-alpha-lactalbumin as a limited illustration of this concept. If we characterize many sera with a sufficient number of these component specificity distributions, we can examine this issue for a restricted number of allergen specificities.
In reality, we will probably not be able to definitively answer this question (at least to my satisfaction). So we are left with the conclusion that is stated in the primer article (which I believe is true) that these 3 assays measure different populations of IgE antibody. The causes are almost irrelevant as the 3 manufacturers are not in a position to change their assay formats. I discussed this issue personally with representative of each company during the last AAAAI meeting. At this point, we cannot say for sure which IgE antibody assay result is more "clinically relevant".
Issue 3: Is one assay too sensitive?
Dana Wallace, MD: Should one consider the Immulite too sensitive as it gives a higher reading of specific-IgE than the Hycor or ImmunoCap? Is there any general guide on comparing the results as the graph seems to show a trend?
Linda Cox, MD: One study did suggest Immulite overestimated s-IgE when the results of total IgE were compared with the hybridoma s-IgE results, which were all s-IgE. Brock and Bob are likely to have different answers
Brock Williams, PhD: The idea that if an assay gives a higher result it is better is fallacious. Again, the chimeric antibody results clearly demonstrate this. Accuracy is more important. Again, the calibration curve (total IgE tied to WHO standard) is very different for the Immulite system. This causes the amount of s-IgE measured to be overestimated particular at the high end with a number of different allergens. A requirement for quantification is that different dilutions (corrected for dilution) give you the same answer. In other words, they are linear and we have only seen this with the ImmunoCAP system.
The idea of sensitivity is also an area of great misunderstanding. This is because analytical sensitivity is a very different concept than clinical sensitivity and the two have often been confused. Analytical sensitivity deals with the low end of the assay, before you run into the background and is determined experimentally with statistical analysis in the laboratory. Clinical sensitivity deals with determining what level of s-IgE is capable of causing clinical symptoms upon exposure and in the near future, what particular allergenic substance it is directed against. Since the determination of clinical sensitivity depends upon the comparison to standards (patient history, puncture skin test, allergen organ challenges, etc.), which themselves have not been standardized and many of the cutoffs are arbitrary. In addition, the studies are dependent on the patient population studied so we really have very poor information in this area. Nevertheless, we mistakenly continue to use this concept to describe how well in a clinical sense these assays work. The same arguments can be used with regard to clinical specificity and, in my opinion, this has been very misleading in this field for quite some time.
Robert Hamilton, PhD: I agree with Brock that higher results produced by any one of the 3 assays are not more clinically relevant. The predictive power of the quantitative level of IgE antibody is discussed in the Primer article, with a caution that these published values need to be used judiciously. . On this issue I agree with what Brock has said about analytical versus clinical sensitivity. Analytically, all three assays can technically detect IgE antibody levels down to 0.1 kUa/L. Historically, the 0.35 kUa/L positive cutpoint was set based on the fact that levels above 0.35 had some clinical significance. We do not know and may never know the clinical significance of levels between 0.1 and 0.35 kUa/L. Interpretation also differs by allergen specificity as some clinicians judge low level Hymenoptera or peanut specific IgE levels differently than a ragweed specific IgE of the same level, because of their clinical relevance in relation to systemic reactions. Thus, a specific IgE level between 0.1 and 0.35 kUa/L needs to be cautiously and judiciously interpreted within the context of the patient’s clinical history.
Issue 4: Can the clinician compare a patient’s s-IgE if they were performed utilizing different assays?
Dana Wallace, MD: If one needs to compare levels of s-IgE and different methods have been used, should the clinician insist that they be repeated so that at least the methods match?
Recognizing that the ImmunoCap has the most published literature in food allergy and predictive levels for a negative food challenge, the clinician has often looked to this as preferred method. Is this still correct?
Linda Cox, MD: Yes. When the laboratory findings are inconsistent with the clinical history, it is recommended to repeat the analysis at the same or a different laboratory. If the results are different, how does the clinician interpret this data? Also recommend repeating with a different method-skin test if sIgE or vice versa. Clinical history is generally the deciding factor. This was a key message in the first SETTaF paper.
I believe the predictive value established in the earlier studies were somewhat specific to a particular population and cannot be universally applied across other age groups/disease.
Robert Hamilton, PhD: We know from the College of American Pathologists Proficiency Survey data that all 3 assay methods from 90% of the laboratories agree well in producing dichotomous measures of IgE antibody (presence/positive vs absence/negative). Therefore, if you are using IgE antibody measurements as a “risk factor” to consider with all the other variables in making the diagnosis, then the Immulite can detect the presence of IgE anti-peanut in a serum as well as an ImmunoCAP. So, if you are asking about the presence of IgE antibody as a risk factor, then “No”, re-analysis by a second assay method is not necessary.
However, there are the occasional spurious results generated by the occasional laboratory or spurious skin test results generated by the occasional clinic. These do occur. So, if the IgE antibody result (skin test or serology) is inconsistent with the clinical history, then it should be repeated, possibly with a different method. We learned this from Dr. Shapiro’s legal case involving Hymenoptera venom sensitivity.
If you are attempting to use the quantitative level to make a prediction about the presence of a clinically evident food allergy or wheeze in an asthmatic child, then published data will dictate what assay needs to be used. In this case the published quantitative predictive data to date are all from the ImmunoCAP. One cannot use the Immulite or Hycor data to make a decision based on published criteria generated with the ImmunoCAP. This will change if new published data are generated with the other two IgE antibody methods.
Issue 5: How important are patient characteristics (age, disease state, etc.) in interpreting s-IgE results?
Dana Wallace, MD: However, the article seems to imply that without knowing the age of the patient, the disease state, the allergen exposure mode and extent, and ratio of Specific IgE/Total IgE that was used in the published research studies and in the individual patient, these published guidelines may be inaccurate and perhaps useless. If this is the correct interpretation, it should be more clearly stated.
Just how important are the lack of affinity and clonality measurements in the overall clinical usefulness of interpreting the results of specific-IgE measurements?
Should we be dividing patient into groups below and above the 4% specific- IgE/Total IgE ratios? Would this help to predict severity of allergic reaction and/or response to treatment?
Linda Cox, MD: I not sure how important sIgE/total IgE. Again Bob and Brock can comment further. I think the importance of affinity and clonality is still be elucidated. This is an area that needs further research but an area of particular interest for Bob.
Brock Williams, PhD: I agree with Linda, that affinity and clonality are parameters that still need to be evaluated. I believe that the realization that certain allergens are much more relevant to symptom production (component resolved diagnosis) is likely to rectify this.
Robert Hamilton, PhD: Four variables contribute to the effectiveness of the IgE antibody response in inducing effector cell function: IgE antibody concentration, affinity, epitope clonality and specific to total IgE ratio or IgE specific activity. This has been clearly shown by the Christensen et al article in the JACI.2 All of these variables are important and constantly changing as the humoral immune response matures with continuing allergen exposure. And one of these alone cannot be shown at present to be an exclusive risk factor for interpreting IgE antibody results in the diagnostic decision process. I agree with Brock that future modifications to our serological assays (e.g., use of components, microarrays) may help us understand this better at the time of interpreting the diagnostic data. The patient demographics will always be critical to the interpretation of the IgE antibody serology as the clinical history is the final arbiter of the definitive diagnosis.
Issue 6: Is the significance of the s-IgE level different when the total IgE is low vs. high?
Dana Wallace, MD: Is it fair to say that when the total IgE level is very high, a high specific-IgE has limited meaning while a high specific-IgE with a low total IgE level is very significant?
Linda Cox, MD: Probably.
Brock Williams, PhD: Specific activity (s-IgE/T-IgE). While this concept makes some intuitive sense, it hasn’t yielded any concrete benefits. This is likely to be important when low levels of t-IgE are seen but really falls apart when multiple allergens and higher levels of s-IgE are seen. While this could be important in immunotherapy, presently it is an area for investigation and not ready for prime time in my opinion. This is particularly true when you investigate monosensitized patients, which is a rare situation for U.S. allergists. Again, I believe we have to further evaluate this concept in lieu of s-IgE to the allergens that actually are relevant (component resolved diagnosis).
Robert Hamilton, PhD: I agree with you all. The IgE specific activity has its most relevance when the total IgE is low and the % specific to total IgE is high. Use of the 4% IgE specific activity as a general criterion can be useful for evaluating patients on Xolair as Johannson et al have shown. However, we need more data to confirm its utility in applying it across the board in the general interpretation of IgE antibody data.
Issue 7: Can the clinician use the s-IgE/t-IgE ratio to predict response to allergen immunotherapy?
Dana Wallace, MD: Is there enough data for the clinician to calculate the specific IgE to total IgE ratio and predict the response to specific immunotherapy? If so what is the magic ratio? If not is there ongoing research that will answer this question? One paper looked at this and 16% was ≥16% was the magic number.3
Robert Hamilton, PhD: No. we need more data to show the utility of this measure in assessing immunotherapy efficacy. It should however be computed to evaluate its utility in future immunotherapy studies.
Brock Williams, Ph.D: I agree with Bob that it is premature to use s-IgE results to guide immunotherapy. This area certainly needs more study and again will probably be better understood when patients and their responses are understood in terms of the specific allergen components that are responsible for symptoms.
Issue 8: Can s-IgE be measured in a patient on Xolair® (omalizumab)?
Dana Wallace, MD: Should the clinician be using ImmunoCAP s-IgE when assessing the patient onXolair? What would be the utility of doing so?Is one looking for a defined endpoint?
Linda Cox, MD: I believe one can get reliable results with ImmunoCAP on s-IgE testing in patients on Xolair, which might be useful in determining if you are adequately dosing (i.e., under) but again Bob is the better person to answer this question
Brock Williams, PhD: Bob has shown quite clearly that the ImmunoCAP can be used with confidence in patients on Xolair.
Robert Hamilton, PhD: The article Brock is referring to clearly shows that IgE (total and allergen specific) can be accurately measured in patients on Xolair with the ImmunoCAP and not with the other two assay methods.4 The important questions are (1) what utility does the measurement of total IgE and specific IgE provide for a patient on Xolair? and (2) where do “free IgE” measurements (IgE not bound with Xolair) fit into the evaluation of the Xolair patient? Examine the Primer article as it addresses these questions.
Issue 9: Will ImmuoCAP rapid®, a non-quantitative allergy test designed for the office setting useful tool for primary care professionals?
Dana Wallace, MD: Will the ImmunoCAP rapid be a good tool for primary care physicians? Should we embrace it?
Linda Cox, MD: The rapid screen office allergy test, which is similar to a pregnancy test is intended for the primary care office. It will likely bring more attention to allergy and to the allergist. Thus, indirectly, I think it is good for the specialty, but there needs to be some education about appropriate use and referral.
Robert Hamilton, PhD: The ImmunoCAP rapid is FDA cleared and we will see how it fits into the overall diagnostic process in the USA. It is too early to tell if it will be useful or abused. The Primer article simply introduces the ImmunoCAP rapid . Allergists need to know that the ImmuoCAP rapid®, data may be introduced by the patient at an allergist’s office visit.
Brock Williams, Ph.D. The ImmunoCap rapid is much like a laboratory test for cholesterol in that it can be interpreted as a measure of risk. The caveats mentioned above in interpreting the results in lieu of the patient’s history most certainly will have to be evaluated on a case by case basis.
References:
1. Cox L, Williams B, Sicherer S, et al. Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology/American Academy of Allergy, Asthma and Immunology Specific IgE Test Task Force. Ann Allergy Asthma Immunol 2008;101:580-92.
2. Christensen LH, Holm J, Lund G, Riise E, Lund K. Several distinct properties of the IgE repertoire determine effector cell degranulation in response to allergen challenge. J Allergy Clin Immunol 2008;122:298-304.
3. Di Lorenzo G, Mansueto P, Pacor ML, et al. Evaluation of serum s-IgE/total IgE ratio in predicting clinical response to allergen-specific immunotherapy. J Allergy Clin Immunol 2009;123:1103-10, 10 e1-4.
4. Hamilton RG. Accuracy of US Food and Drug Administration-cleared IgE antibody assays in the presence of anti-IgE (omalizumab). J Allergy Clin Immunol 2006;117:759-66.
In response to the concerns about an increase in the remote practice of allergy, which may possibly be influenced by direct allergy laboratory marketing campaigns, the AAAAI and ACAAI, in conjunction with Don Aaronson from the JCAAI formed a joint taskforce in 2006 on allergy diagnostic testing called the Specific IgE Test Task Force (SETTaF) . SETTaF’s purpose has been to develop educational materials that focus on the appropriate diagnostic evaluation of the allergic/suspected patient. In late 2008 SETTaF published a monograph directed at health care professionals, who care for allergic patients entitled the “Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology/American Academy of Allergy, Asthma and Immunology Specific IgE Test Task Force.”(1) The task force is currently engaged in the development of a PowerPoint presentation and several monographs on diagnostic allergy testing that are directed at primary care professionals.
The key message throughout these educational materials is that the allergy evaluation must be initiated by and culminated with the patient's clinical history. It must be directed by a health care professional with sufficient understanding of diagnostic allergy testing to use the information obtained from his/her evaluation of the patient to determine: 1. What diagnostic allergy tests to order. 2. How to interpret the diagnostic allergy test results. 3. How to use the information obtained from the allergy evaluation to develop an appropriate therapeutic treatment plan.
This issue of the Journal of Allergy and Clinical Immunology presents a monograph developed by SETTaF on serological measurement of allergen-specific IgE testing specifically for the North American allergist. Per the protocol of a joint AAAAI/ACAAI task force, the SETTaF’s monographs are reviewed by the Board of Directors/Regents of both organizations. During this review, a question and answer dialogue evolved and the organizations' Boards suggested including the ‘Q&A’ with the document.
The members of SETTaF hope you find the monograph educational. The following questions and answers represent the views of the individuals and not SETTaF or the Board of Directors/Regents of the AAAAI/ACAAI.
Sincerely,
Linda Cox, MD
SETTaF chair
Allergy Diagnostic Testing Primer: Questions and Answers
Below are some questions that were raised by ACAAI reviewers that will highlight some of the questions readers may have and an attempt by the authors to provide answers, where they are available.
Issue 1: Use of serum specific-IgE in clinical decision-making
Dana Wallace , MD (ACAAI president-elect): This report on the evolution of serum specific- IgE (s-IgE) testing is a timely and much needed document for the clinical allergist. While technically well written, it brings up perhaps more questions and confusion than it answers or clarifies. While the authors and many other academicians may find it clear and easy to understand, I am not sure that this will be the case for most clinicians. Particularly difficult will be the translation of this information into clinical decision-making support tools. It would be very helpful if an additional section could be added: “When and how to use specific IgE in vitro tests to improve patient care”. I would suggest that in this section, the authors try to answer the following questions (among others):
Linda Cox, MD ( SETTaF chair): I think one has to consider s-IgE similar to skin testing in terms of when and how it would be used in patient care and the decision on which type of test(s) would vary with the patient and other circumstances.
Brock Williams, PhD (Primer author and SETTaF member): The hard question to answer is when and how to use s-IgE testing to improve patient care. To me, this deals mostly with how to interpret the results and this is very patient dependent. Again the problem stems from the fact that allergic symptoms are variable both within and between individuals. This and the large number of variables (age, gender, exposure, infection, etc.) clearly need to be taken into account for the interpretation of s-IgE tests. We do know that s-IgE is closely linked to symptoms but levels and the allergens it is directed against differ among different individuals. Thus, in today’s world, s-IgE results will best be utilized by considering them as a risk factor rather than an absolute diagnostic fact.
Robert Hamilton, PhD: The ultimate decision of when to use a confirmatory IgE antibody test (skin test or serology) comes down to the physician deciding that there is sufficient clinical evidence to warrant a possible diagnosis of allergic disease. This concept is integral to the diagnostic algorithm built into the diagnostic practice parameters. As such, to try to list all the patient and physician decisions to determine when a diagnostic IgE antibody confirmatory test (skin test or serology) should be run is (in my opinion) out of the intended scope of this article. This article summarizes what we know and what we do not know about the assays used to detect allergen-specific IgE antibody. I agree with Brock that prudent use of a positive specific IgE antibody result is as a risk factor for allergic disease and not as a definitive indicator of the presence of allergic disease.
Issue 2: Which is the ‘best’ specific IgE assay?
Dana Wallace, MD: Which of the three methods of specific-IgE measurement described within the Primer is most beneficial for making clinical decisions or should they all be viewed as equal?
Linda Cox, MD: There is agreement that the results are not assay inter-changeable. One thought is the different assays may be measuring different antibodies.
Brock Williams, PhD: Comparability of different methods – most studies indicate that the Phadia ImmunoCAP is far above the other two tests in overall performance (accuracy, precision, and quantitative ability). The problem is that for certain allergens and levels of s-IgE the assays are somewhat in agreement. For others, they are very different. I find the explanation that these assays are sometimes measuring different populations of antibodies to be rather absurd. To begin with I have seen no proof of this concept and our studies with chimeric antibodies (where the total IgE = specific IgE) indicate that for those allergens investigated the Siemens assay (formerly DPC-Alastat/Immulite) has major problems with its calibration and the Hycor assay (Agilent) has problems with under-representation of allergen on some of their solid phases. The major user of the Hycor assay is Labcorp and we know in the past some have suggested that they have modified this test in house to make it more profitable. The ImmunoCAP results (done in triplicate with blinded samples) was ‘spot on’ in these cases.
Robert Hamilton, PhD: I respectfully disagree with Brock on this issue. The most impartial examination of the inter-assay agreement issue indicates that all three methods display excellent precision, reproducibility and linearity. They do differ in the levels of IgE antibody that they detect and we currently do not know the reason for this. It is possibly a calibration issue, however, if there was a systematic bias caused by a calibration issue, we would see a consistent bias which we do not. My belief is that it has more to do with allergen heterogeneity between the methods. Thus to call the suggestion that the assays are measuring different populations of IgE antibody specificities "absurd" is too ‘heavy handed’. Brock, your data with the chimeric antibody are interesting and informative but not conclusive on a calibration issue.
We need to construct a better and more relevant experiment with human sera to try to dissect the answer to this question. Possibly this can be done with milk and peanut where we can identify the component specificities of IgE antibody using the ISAC and the components that are available on the ImmunoCAP. Then sera with defined distributions of IgE antibody can be analyzed by all 3 methods. So the binding of a serum containing 95% IgE anti-casein can be compared to a serum that contains 95% IgE anti-alpha-lactalbumin as a limited illustration of this concept. If we characterize many sera with a sufficient number of these component specificity distributions, we can examine this issue for a restricted number of allergen specificities.
In reality, we will probably not be able to definitively answer this question (at least to my satisfaction). So we are left with the conclusion that is stated in the primer article (which I believe is true) that these 3 assays measure different populations of IgE antibody. The causes are almost irrelevant as the 3 manufacturers are not in a position to change their assay formats. I discussed this issue personally with representative of each company during the last AAAAI meeting. At this point, we cannot say for sure which IgE antibody assay result is more "clinically relevant".
Issue 3: Is one assay too sensitive?
Dana Wallace, MD: Should one consider the Immulite too sensitive as it gives a higher reading of specific-IgE than the Hycor or ImmunoCap? Is there any general guide on comparing the results as the graph seems to show a trend?
Linda Cox, MD: One study did suggest Immulite overestimated s-IgE when the results of total IgE were compared with the hybridoma s-IgE results, which were all s-IgE. Brock and Bob are likely to have different answers
Brock Williams, PhD: The idea that if an assay gives a higher result it is better is fallacious. Again, the chimeric antibody results clearly demonstrate this. Accuracy is more important. Again, the calibration curve (total IgE tied to WHO standard) is very different for the Immulite system. This causes the amount of s-IgE measured to be overestimated particular at the high end with a number of different allergens. A requirement for quantification is that different dilutions (corrected for dilution) give you the same answer. In other words, they are linear and we have only seen this with the ImmunoCAP system.
The idea of sensitivity is also an area of great misunderstanding. This is because analytical sensitivity is a very different concept than clinical sensitivity and the two have often been confused. Analytical sensitivity deals with the low end of the assay, before you run into the background and is determined experimentally with statistical analysis in the laboratory. Clinical sensitivity deals with determining what level of s-IgE is capable of causing clinical symptoms upon exposure and in the near future, what particular allergenic substance it is directed against. Since the determination of clinical sensitivity depends upon the comparison to standards (patient history, puncture skin test, allergen organ challenges, etc.), which themselves have not been standardized and many of the cutoffs are arbitrary. In addition, the studies are dependent on the patient population studied so we really have very poor information in this area. Nevertheless, we mistakenly continue to use this concept to describe how well in a clinical sense these assays work. The same arguments can be used with regard to clinical specificity and, in my opinion, this has been very misleading in this field for quite some time.
Robert Hamilton, PhD: I agree with Brock that higher results produced by any one of the 3 assays are not more clinically relevant. The predictive power of the quantitative level of IgE antibody is discussed in the Primer article, with a caution that these published values need to be used judiciously. . On this issue I agree with what Brock has said about analytical versus clinical sensitivity. Analytically, all three assays can technically detect IgE antibody levels down to 0.1 kUa/L. Historically, the 0.35 kUa/L positive cutpoint was set based on the fact that levels above 0.35 had some clinical significance. We do not know and may never know the clinical significance of levels between 0.1 and 0.35 kUa/L. Interpretation also differs by allergen specificity as some clinicians judge low level Hymenoptera or peanut specific IgE levels differently than a ragweed specific IgE of the same level, because of their clinical relevance in relation to systemic reactions. Thus, a specific IgE level between 0.1 and 0.35 kUa/L needs to be cautiously and judiciously interpreted within the context of the patient’s clinical history.
Issue 4: Can the clinician compare a patient’s s-IgE if they were performed utilizing different assays?
Dana Wallace, MD: If one needs to compare levels of s-IgE and different methods have been used, should the clinician insist that they be repeated so that at least the methods match?
Recognizing that the ImmunoCap has the most published literature in food allergy and predictive levels for a negative food challenge, the clinician has often looked to this as preferred method. Is this still correct?
Linda Cox, MD: Yes. When the laboratory findings are inconsistent with the clinical history, it is recommended to repeat the analysis at the same or a different laboratory. If the results are different, how does the clinician interpret this data? Also recommend repeating with a different method-skin test if sIgE or vice versa. Clinical history is generally the deciding factor. This was a key message in the first SETTaF paper.
I believe the predictive value established in the earlier studies were somewhat specific to a particular population and cannot be universally applied across other age groups/disease.
Robert Hamilton, PhD: We know from the College of American Pathologists Proficiency Survey data that all 3 assay methods from 90% of the laboratories agree well in producing dichotomous measures of IgE antibody (presence/positive vs absence/negative). Therefore, if you are using IgE antibody measurements as a “risk factor” to consider with all the other variables in making the diagnosis, then the Immulite can detect the presence of IgE anti-peanut in a serum as well as an ImmunoCAP. So, if you are asking about the presence of IgE antibody as a risk factor, then “No”, re-analysis by a second assay method is not necessary.
However, there are the occasional spurious results generated by the occasional laboratory or spurious skin test results generated by the occasional clinic. These do occur. So, if the IgE antibody result (skin test or serology) is inconsistent with the clinical history, then it should be repeated, possibly with a different method. We learned this from Dr. Shapiro’s legal case involving Hymenoptera venom sensitivity.
If you are attempting to use the quantitative level to make a prediction about the presence of a clinically evident food allergy or wheeze in an asthmatic child, then published data will dictate what assay needs to be used. In this case the published quantitative predictive data to date are all from the ImmunoCAP. One cannot use the Immulite or Hycor data to make a decision based on published criteria generated with the ImmunoCAP. This will change if new published data are generated with the other two IgE antibody methods.
Issue 5: How important are patient characteristics (age, disease state, etc.) in interpreting s-IgE results?
Dana Wallace, MD: However, the article seems to imply that without knowing the age of the patient, the disease state, the allergen exposure mode and extent, and ratio of Specific IgE/Total IgE that was used in the published research studies and in the individual patient, these published guidelines may be inaccurate and perhaps useless. If this is the correct interpretation, it should be more clearly stated.
Just how important are the lack of affinity and clonality measurements in the overall clinical usefulness of interpreting the results of specific-IgE measurements?
Should we be dividing patient into groups below and above the 4% specific- IgE/Total IgE ratios? Would this help to predict severity of allergic reaction and/or response to treatment?
Linda Cox, MD: I not sure how important sIgE/total IgE. Again Bob and Brock can comment further. I think the importance of affinity and clonality is still be elucidated. This is an area that needs further research but an area of particular interest for Bob.
Brock Williams, PhD: I agree with Linda, that affinity and clonality are parameters that still need to be evaluated. I believe that the realization that certain allergens are much more relevant to symptom production (component resolved diagnosis) is likely to rectify this.
Robert Hamilton, PhD: Four variables contribute to the effectiveness of the IgE antibody response in inducing effector cell function: IgE antibody concentration, affinity, epitope clonality and specific to total IgE ratio or IgE specific activity. This has been clearly shown by the Christensen et al article in the JACI.2 All of these variables are important and constantly changing as the humoral immune response matures with continuing allergen exposure. And one of these alone cannot be shown at present to be an exclusive risk factor for interpreting IgE antibody results in the diagnostic decision process. I agree with Brock that future modifications to our serological assays (e.g., use of components, microarrays) may help us understand this better at the time of interpreting the diagnostic data. The patient demographics will always be critical to the interpretation of the IgE antibody serology as the clinical history is the final arbiter of the definitive diagnosis.
Issue 6: Is the significance of the s-IgE level different when the total IgE is low vs. high?
Dana Wallace, MD: Is it fair to say that when the total IgE level is very high, a high specific-IgE has limited meaning while a high specific-IgE with a low total IgE level is very significant?
Linda Cox, MD: Probably.
Brock Williams, PhD: Specific activity (s-IgE/T-IgE). While this concept makes some intuitive sense, it hasn’t yielded any concrete benefits. This is likely to be important when low levels of t-IgE are seen but really falls apart when multiple allergens and higher levels of s-IgE are seen. While this could be important in immunotherapy, presently it is an area for investigation and not ready for prime time in my opinion. This is particularly true when you investigate monosensitized patients, which is a rare situation for U.S. allergists. Again, I believe we have to further evaluate this concept in lieu of s-IgE to the allergens that actually are relevant (component resolved diagnosis).
Robert Hamilton, PhD: I agree with you all. The IgE specific activity has its most relevance when the total IgE is low and the % specific to total IgE is high. Use of the 4% IgE specific activity as a general criterion can be useful for evaluating patients on Xolair as Johannson et al have shown. However, we need more data to confirm its utility in applying it across the board in the general interpretation of IgE antibody data.
Issue 7: Can the clinician use the s-IgE/t-IgE ratio to predict response to allergen immunotherapy?
Dana Wallace, MD: Is there enough data for the clinician to calculate the specific IgE to total IgE ratio and predict the response to specific immunotherapy? If so what is the magic ratio? If not is there ongoing research that will answer this question? One paper looked at this and 16% was ≥16% was the magic number.3
Robert Hamilton, PhD: No. we need more data to show the utility of this measure in assessing immunotherapy efficacy. It should however be computed to evaluate its utility in future immunotherapy studies.
Brock Williams, Ph.D: I agree with Bob that it is premature to use s-IgE results to guide immunotherapy. This area certainly needs more study and again will probably be better understood when patients and their responses are understood in terms of the specific allergen components that are responsible for symptoms.
Issue 8: Can s-IgE be measured in a patient on Xolair® (omalizumab)?
Dana Wallace, MD: Should the clinician be using ImmunoCAP s-IgE when assessing the patient onXolair? What would be the utility of doing so?Is one looking for a defined endpoint?
Linda Cox, MD: I believe one can get reliable results with ImmunoCAP on s-IgE testing in patients on Xolair, which might be useful in determining if you are adequately dosing (i.e., under) but again Bob is the better person to answer this question
Brock Williams, PhD: Bob has shown quite clearly that the ImmunoCAP can be used with confidence in patients on Xolair.
Robert Hamilton, PhD: The article Brock is referring to clearly shows that IgE (total and allergen specific) can be accurately measured in patients on Xolair with the ImmunoCAP and not with the other two assay methods.4 The important questions are (1) what utility does the measurement of total IgE and specific IgE provide for a patient on Xolair? and (2) where do “free IgE” measurements (IgE not bound with Xolair) fit into the evaluation of the Xolair patient? Examine the Primer article as it addresses these questions.
Issue 9: Will ImmuoCAP rapid®, a non-quantitative allergy test designed for the office setting useful tool for primary care professionals?
Dana Wallace, MD: Will the ImmunoCAP rapid be a good tool for primary care physicians? Should we embrace it?
Linda Cox, MD: The rapid screen office allergy test, which is similar to a pregnancy test is intended for the primary care office. It will likely bring more attention to allergy and to the allergist. Thus, indirectly, I think it is good for the specialty, but there needs to be some education about appropriate use and referral.
Robert Hamilton, PhD: The ImmunoCAP rapid is FDA cleared and we will see how it fits into the overall diagnostic process in the USA. It is too early to tell if it will be useful or abused. The Primer article simply introduces the ImmunoCAP rapid . Allergists need to know that the ImmuoCAP rapid®, data may be introduced by the patient at an allergist’s office visit.
Brock Williams, Ph.D. The ImmunoCap rapid is much like a laboratory test for cholesterol in that it can be interpreted as a measure of risk. The caveats mentioned above in interpreting the results in lieu of the patient’s history most certainly will have to be evaluated on a case by case basis.
References:
1. Cox L, Williams B, Sicherer S, et al. Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology/American Academy of Allergy, Asthma and Immunology Specific IgE Test Task Force. Ann Allergy Asthma Immunol 2008;101:580-92.
2. Christensen LH, Holm J, Lund G, Riise E, Lund K. Several distinct properties of the IgE repertoire determine effector cell degranulation in response to allergen challenge. J Allergy Clin Immunol 2008;122:298-304.
3. Di Lorenzo G, Mansueto P, Pacor ML, et al. Evaluation of serum s-IgE/total IgE ratio in predicting clinical response to allergen-specific immunotherapy. J Allergy Clin Immunol 2009;123:1103-10, 10 e1-4.
4. Hamilton RG. Accuracy of US Food and Drug Administration-cleared IgE antibody assays in the presence of anti-IgE (omalizumab). J Allergy Clin Immunol 2006;117:759-66.
A new genotype associated with abnormal NFκB function in immunodeficiency without ectodermal dyplasia
A scaffolding protein, NEMO, associated with a complex required in the NFκB translocation pathway has been previously associated with ectodermal dysplasia-associated immune deficiency (EDID) syndrome. The syndrome is X-linked, and presents clinically as a history of recurrent infections, hypogammaglobulinemia, and poor memory B cell function. Affected individuals have abnormalities of ectoderm-derived tissues, such as hair, skin, nails, and teeth. NEMO, in complex with inhibitor of NFκB kinase (IKK) proteins, is necessary for NFκB translocation and gene activation.
This month, Mooster et al. describe a male patient and brother with immunodeficiency, but without ectodermal dysplasia, that was traced to a novel gene mutation in the 5’ untranslated region in the NFκB essential modifier gene (NEMO) gene. They report that TLR-activated production of TNFα and IFNα in peripheral blood is significantly decreased in the index patient, consistent with impaired innate immune response.
The authors find that a G→T mutation in the +1 position of the intron 1B causes destruction of the exon 1B to exon 2 splice in the NEMO gene. Two abnormally sized NEMO mRNAs with intact coding regions are produced, causing inefficient translation that results in inadequate levels of functional NEMO proteins. NEMO mRNA is 4-fold lower and NEMO protein expression is 8-fold lower in the index patient as compared to normal controls. The brother of the index patient is also affected by the same mutation. Their report is the first description of an immunodeficiency that results from decreased levels of functional NEMO protein, rather than functionally impaired protein.
The authors comment that the absence of ectodermal involvement suggests that either normal ectodermal development has a less stringent requirement for NEMO than does immune function, or other NEMO isoforms are able to compensate for the reduction in the 1B isoform.
We asked the authors about the implications of their report:
JACI: In your conclusion, you suggest that clinical work-up of patients presenting with immunodeficiency consistent with EDID, but without ectodermal involvement, should be evaluated for NEMO mRNA and proteins levels, followed by coding analysis. What implications does the characterization of these patients have for their treatment?
Jana Mooster and Douglas McDonald: In patients with immunodeficiency consistent with EDID, but without ectodermal dysplasia or even with a normal NEMO coding sequence, one should consider evaluating NEMO protein levels and NFκB function. Patients with NEMO deficiency but without ectodermal dysplasia can appear clinically similar to patients with common variable immune deficiency. NEMO deficiency, however, is known to cause susceptibility to atypical mycobacterial infections. Thus, identification of a NEMO mutation identifies patients that require monitoring for potential atypical mycobacterial infections.
We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
This month, Mooster et al. describe a male patient and brother with immunodeficiency, but without ectodermal dysplasia, that was traced to a novel gene mutation in the 5’ untranslated region in the NFκB essential modifier gene (NEMO) gene. They report that TLR-activated production of TNFα and IFNα in peripheral blood is significantly decreased in the index patient, consistent with impaired innate immune response.
The authors find that a G→T mutation in the +1 position of the intron 1B causes destruction of the exon 1B to exon 2 splice in the NEMO gene. Two abnormally sized NEMO mRNAs with intact coding regions are produced, causing inefficient translation that results in inadequate levels of functional NEMO proteins. NEMO mRNA is 4-fold lower and NEMO protein expression is 8-fold lower in the index patient as compared to normal controls. The brother of the index patient is also affected by the same mutation. Their report is the first description of an immunodeficiency that results from decreased levels of functional NEMO protein, rather than functionally impaired protein.
The authors comment that the absence of ectodermal involvement suggests that either normal ectodermal development has a less stringent requirement for NEMO than does immune function, or other NEMO isoforms are able to compensate for the reduction in the 1B isoform.
We asked the authors about the implications of their report:
JACI: In your conclusion, you suggest that clinical work-up of patients presenting with immunodeficiency consistent with EDID, but without ectodermal involvement, should be evaluated for NEMO mRNA and proteins levels, followed by coding analysis. What implications does the characterization of these patients have for their treatment?
Jana Mooster and Douglas McDonald: In patients with immunodeficiency consistent with EDID, but without ectodermal dysplasia or even with a normal NEMO coding sequence, one should consider evaluating NEMO protein levels and NFκB function. Patients with NEMO deficiency but without ectodermal dysplasia can appear clinically similar to patients with common variable immune deficiency. NEMO deficiency, however, is known to cause susceptibility to atypical mycobacterial infections. Thus, identification of a NEMO mutation identifies patients that require monitoring for potential atypical mycobacterial infections.
We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Tuesday, June 1, 2010
Tracking peanut and tree nut allergy in the US
Peanut and tree nut allergies garner attention because reactions to these common foods are characteristically severe, are responsible for the majority of fatalities caused by food allergy, are persistent, and appear to be increasing in prevalence. Although there is great interest in tracking the prevalence of these allergies, determining the exact number of those affected over time has remained elusive.
To estimate the general population prevalence of food allergies, researchers have sometimes had to content themselves with assessments based on self-report of “convincing” reactions, because the diagnostic standard of oral challenge is impractical, risky, and expensive. Using this approach, Sicherer et al (J Allergy Clin Immunol 2010;125:1322-6) report findings of the most recent cross-sectional telephone survey to collect self-reported information on peanut, tree nut, and, additionally, sesame allergy. They employed the same survey used in 1997 and 2002 to assess prevalence in 2008, then compared the results from all three surveys.
Significant increases in peanut/tree nut and tree nut allergy in children were reported from 2002 to 2008, though increase in peanut allergy was not significant in that period. Self-reported peanut allergy in children increased significantly from 0.4% in 1997 to 1.4% in 2008. Tree nut allergy also showed significant increased from 0.2% to 1.1% across the same period. Sesame allergy was reported from only 13 survey participants at a rate of 0.1%; however, 2008 was the first year that information on sesame allergy was collected. The authors report that no significant increase in peanut and/or tree nut allergy was reported in adults.
They suggest that possible explanations for the increased rate of self-reported peanut allergy might be increased availability of peanuts in many food products, especially in highly allergenic roasted form, as well as oral exposure that is either immunologically too early or late, and/or environmental exposure. Also, Sicherer et al. point out that the prevalence in US children is similar to the prevalence reported by recent studies in Canada, the UK, and Australia.
We asked lead author Scott Sicherer, MD, from Mount Sinai School of Medicine, to comment on the study. “To my knowledge, this is the first attempt to track these allergies on a population basis in the US using the same methods thrice over a decade,” says Sicherer. “A recent review of the food allergy literature in JAMA [Journal of the American Medical Association] pointed out that due to various methodological issues, we do not have solid data on prevalence, with estimates that food allergy affects more than 1-2% but less than 10% of the population and there are limited data on time trends. Although our study has limitations inherent to self reported allergy and participation rates of telephone surveys, it provides an interesting perspective supporting a likely increase of childhood peanut/tree nut allergies and underscores that millions are affected by these allergies.”
Readers interested in this topic might also want to see the article by Ben-Shoshan et al., also in the June issue (J Allergy Clin Immunol 2010;125: 1327-1335), which looks at prevalence of peanut, tree nut, fish, shellfish, and sesame allergies in Canada.
We want to hear from you. Please feel free to post your questions or comments below. All questions and comments will be forwarded to the authors for a response.
To estimate the general population prevalence of food allergies, researchers have sometimes had to content themselves with assessments based on self-report of “convincing” reactions, because the diagnostic standard of oral challenge is impractical, risky, and expensive. Using this approach, Sicherer et al (J Allergy Clin Immunol 2010;125:1322-6) report findings of the most recent cross-sectional telephone survey to collect self-reported information on peanut, tree nut, and, additionally, sesame allergy. They employed the same survey used in 1997 and 2002 to assess prevalence in 2008, then compared the results from all three surveys.
Significant increases in peanut/tree nut and tree nut allergy in children were reported from 2002 to 2008, though increase in peanut allergy was not significant in that period. Self-reported peanut allergy in children increased significantly from 0.4% in 1997 to 1.4% in 2008. Tree nut allergy also showed significant increased from 0.2% to 1.1% across the same period. Sesame allergy was reported from only 13 survey participants at a rate of 0.1%; however, 2008 was the first year that information on sesame allergy was collected. The authors report that no significant increase in peanut and/or tree nut allergy was reported in adults.
They suggest that possible explanations for the increased rate of self-reported peanut allergy might be increased availability of peanuts in many food products, especially in highly allergenic roasted form, as well as oral exposure that is either immunologically too early or late, and/or environmental exposure. Also, Sicherer et al. point out that the prevalence in US children is similar to the prevalence reported by recent studies in Canada, the UK, and Australia.
We asked lead author Scott Sicherer, MD, from Mount Sinai School of Medicine, to comment on the study. “To my knowledge, this is the first attempt to track these allergies on a population basis in the US using the same methods thrice over a decade,” says Sicherer. “A recent review of the food allergy literature in JAMA [Journal of the American Medical Association] pointed out that due to various methodological issues, we do not have solid data on prevalence, with estimates that food allergy affects more than 1-2% but less than 10% of the population and there are limited data on time trends. Although our study has limitations inherent to self reported allergy and participation rates of telephone surveys, it provides an interesting perspective supporting a likely increase of childhood peanut/tree nut allergies and underscores that millions are affected by these allergies.”
Readers interested in this topic might also want to see the article by Ben-Shoshan et al., also in the June issue (J Allergy Clin Immunol 2010;125: 1327-1335), which looks at prevalence of peanut, tree nut, fish, shellfish, and sesame allergies in Canada.
We want to hear from you. Please feel free to post your questions or comments below. All questions and comments will be forwarded to the authors for a response.
Exactly how can specific IgE levels help in the diagnosis of food allergy?
An important question for researchers and clinicians who work with food allergies is whether food-specific IgE and skin prick test results can be used reliably as ersatz measures of allergen sensitization (see also our News Beyond Our Pages blog from May 14). The reason is that the clinical standard for food allergy diagnoses is double-blind, placebo-controlled food challenge, which is expensive, costly, and requires dedicated personnel and facilities because of the risk of anaphylaxis.
In a Letter to the Editor in JACI (J Allergy Clin Immunol 2010;125:1391-2), van Nieuwaal et al. report results from a study conducted in 103 children with suspected peanut allergy. Peanut-specific IgE levels were correlated to results of diagnostic food challenge to evaluate the predictive power of specific IgE and food challenges were performed regardless of a possible history of anaphylaxis. The population was very atopic as well, with greater than 80% having atopic dermatitis. The authors report that peanut-specific IgE was correlated to positive food challenge results in approximately 55% of the children. Specificity of IgE values of 10.4 [92%], 24.8 [98%] and 25.5 kU/L [100%] were significant for predicting outcome of food challenge. The authors note that the specific IgE levels were not sensitive, though, and that values lower than these do not indicate that there would be no reaction to oral food challenge.
The authors conclude that using these IgE levels as cutoffs would obviate diagnostic oral food challenges in at least some of the children. Oral food challenge would still be needed to determine the sensitivity and severity of the peanut allergy.
We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
In a Letter to the Editor in JACI (J Allergy Clin Immunol 2010;125:1391-2), van Nieuwaal et al. report results from a study conducted in 103 children with suspected peanut allergy. Peanut-specific IgE levels were correlated to results of diagnostic food challenge to evaluate the predictive power of specific IgE and food challenges were performed regardless of a possible history of anaphylaxis. The population was very atopic as well, with greater than 80% having atopic dermatitis. The authors report that peanut-specific IgE was correlated to positive food challenge results in approximately 55% of the children. Specificity of IgE values of 10.4 [92%], 24.8 [98%] and 25.5 kU/L [100%] were significant for predicting outcome of food challenge. The authors note that the specific IgE levels were not sensitive, though, and that values lower than these do not indicate that there would be no reaction to oral food challenge.
The authors conclude that using these IgE levels as cutoffs would obviate diagnostic oral food challenges in at least some of the children. Oral food challenge would still be needed to determine the sensitivity and severity of the peanut allergy.
We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Monday, May 3, 2010
Food allergy: An immunological picture of atopy development
What, exactly, does the phenotypic evolution of food allergy look like? Which factors, such as environment or genotype, exert the most influence? Is food allergen avoidance the key or is it irrelevant? The NIH/NIAID-supported Consortium of Food Allergy Research (CoFAR) has established an infant cohort with likely milk and/or egg allergy with the intent to describe and characterize the natural history of food allergies in children in hopes of being able to answer these questions.
In this month's issue of the JACI, Sicherer et al. present early results from the 1st of several studies being conducted by CoFAR. [Access this article for free at: http://www.jacionline.org/article/S0091-6749(10)00430-6/fulltext.] Their question: Among infants presenting with a clinical reaction to milk and/or egg, and a positive prick skin test (PST) to either, or children with moderate to severe atopic dermatitis and a positive skin test to milk or egg, what factors will be associated with developing a peanut allergy and resolution or persistence of milk/egg allergy? The authors note that known clinical allergy to peanuts was an exclusion; nevertheless, almost 70% of the infants had evidence of sensitization to peanut, with 27% having greatly elevated peanut-IgE (> 5 kUA/L). They compare sensitivity of PST and serum IgE and report significant association of wheal size and IgE concentrations across milk, egg, and peanut. They do note that there was unexpected discordance between peanut PST and peanut-specific serum IgE, where some infants have one positive and the other negative. In these cases, the serum IgE is more sensitive than the PST in detecting sensitization, which is in contradiction to the conventional wisdom that PST in infants is more sensitive.
In vitro analyses demonstrate that CD25 and IL4 expression are up-regulated in milk and peanut sensitized infants; this is not the case for egg sensitivity, where there was only a slight increase in CD25 expression and no related increase in IL4. The authors further address Th2 bias by looking at GATA3/Tbet ratios. Surprisingly, they found no increased GATA3/Tbet ratios, though GATA3 was detectable. Since Sicherer et al. speculate that Th2 activation is the background to food allergy, what is providing the increased IL4? The authors suggest that basophils may have been the source of IL4 in the sensitized infants.
Wrapping up, Sicherer et al. address the astonishingly high prevalence of peanut sensitization in their cohort and suggest that this indicates a need for caution in introducing peanut to infants with the enrollment characteristics and that clinical testing for food allergy may be warranted.
We asked first author Scott Sicherer, MD, for his take on the study's findings:
JACI: In your opinion, what is the most likely point of exposure leading to peanut sensitization in the infants?
Dr. Sicherer: We will be evaluating potential determinants that could include maternal ingestion, household exposure and other factors, but these are under analysis.
JACI: The findings associated with CD25 and IL4 gene expression under egg stimulation were not remarkable and you attributed this to possible effects of using whole egg extracts. What mechanism might account for the diminished IL4 expression associated with whole extracts?
Dr. Sicherer: We were surprised that egg behaved differently in the in vitro studies and are currently considering the possibility that if we had used a stimulant that was enriched with a major egg allergen, for example ovomucoid, we may have seen a response that was more similar to the milk (caseins) or peanut response.
JACI: Is it conceivable that basophils might be the source of IL4?
Dr. Sicherer: Our preparations were enriched for CD25. Basophils constitutively express CD25, are enriched with mononuclear cells during density gradient isolation and produce high levels of IL-4 in sensitized subjects. Recently, basophils have been implicated in allergy model systems for playing an important role in priming and enhancing memory Th2 responses. Murine basophils have been shown to express IL-4 in the absence of detectable GATA-3 or c-maf, expression, suggesting that IL-4 may be regulated distinctly in these cells. Thus, new paradigms are emerging that basophils play a key role in directing Th2 responses and our data may provide additional support for this observation. Preliminary studies utilizing flow cytometry revealed that basophils (CD3- CD123+ CD203+ HLA-DR dim and IL4+) are present in the CD25 preparation.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.
In this month's issue of the JACI, Sicherer et al. present early results from the 1st of several studies being conducted by CoFAR. [Access this article for free at: http://www.jacionline.org/article/S0091-6749(10)00430-6/fulltext.] Their question: Among infants presenting with a clinical reaction to milk and/or egg, and a positive prick skin test (PST) to either, or children with moderate to severe atopic dermatitis and a positive skin test to milk or egg, what factors will be associated with developing a peanut allergy and resolution or persistence of milk/egg allergy? The authors note that known clinical allergy to peanuts was an exclusion; nevertheless, almost 70% of the infants had evidence of sensitization to peanut, with 27% having greatly elevated peanut-IgE (> 5 kUA/L). They compare sensitivity of PST and serum IgE and report significant association of wheal size and IgE concentrations across milk, egg, and peanut. They do note that there was unexpected discordance between peanut PST and peanut-specific serum IgE, where some infants have one positive and the other negative. In these cases, the serum IgE is more sensitive than the PST in detecting sensitization, which is in contradiction to the conventional wisdom that PST in infants is more sensitive.
In vitro analyses demonstrate that CD25 and IL4 expression are up-regulated in milk and peanut sensitized infants; this is not the case for egg sensitivity, where there was only a slight increase in CD25 expression and no related increase in IL4. The authors further address Th2 bias by looking at GATA3/Tbet ratios. Surprisingly, they found no increased GATA3/Tbet ratios, though GATA3 was detectable. Since Sicherer et al. speculate that Th2 activation is the background to food allergy, what is providing the increased IL4? The authors suggest that basophils may have been the source of IL4 in the sensitized infants.
Wrapping up, Sicherer et al. address the astonishingly high prevalence of peanut sensitization in their cohort and suggest that this indicates a need for caution in introducing peanut to infants with the enrollment characteristics and that clinical testing for food allergy may be warranted.
We asked first author Scott Sicherer, MD, for his take on the study's findings:
JACI: In your opinion, what is the most likely point of exposure leading to peanut sensitization in the infants?
Dr. Sicherer: We will be evaluating potential determinants that could include maternal ingestion, household exposure and other factors, but these are under analysis.
JACI: The findings associated with CD25 and IL4 gene expression under egg stimulation were not remarkable and you attributed this to possible effects of using whole egg extracts. What mechanism might account for the diminished IL4 expression associated with whole extracts?
Dr. Sicherer: We were surprised that egg behaved differently in the in vitro studies and are currently considering the possibility that if we had used a stimulant that was enriched with a major egg allergen, for example ovomucoid, we may have seen a response that was more similar to the milk (caseins) or peanut response.
JACI: Is it conceivable that basophils might be the source of IL4?
Dr. Sicherer: Our preparations were enriched for CD25. Basophils constitutively express CD25, are enriched with mononuclear cells during density gradient isolation and produce high levels of IL-4 in sensitized subjects. Recently, basophils have been implicated in allergy model systems for playing an important role in priming and enhancing memory Th2 responses. Murine basophils have been shown to express IL-4 in the absence of detectable GATA-3 or c-maf, expression, suggesting that IL-4 may be regulated distinctly in these cells. Thus, new paradigms are emerging that basophils play a key role in directing Th2 responses and our data may provide additional support for this observation. Preliminary studies utilizing flow cytometry revealed that basophils (CD3- CD123+ CD203+ HLA-DR dim and IL4+) are present in the CD25 preparation.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.
Vitamin D and corticosteroid use in children
Evidence is accumulating rapidly for the association between vitamin D insufficiency, lung function, and corticosteroid use and sensitivity. Pivotal studies have been published examining a number of parameters, including effect of latitude, skin pigmentation, and body mass index.
In this month's JACI, Searing et al. provide the first report on prevalence of vitamin D insufficiency or deficiency in children with asthma living in latitudes higher than 20° N. [This article can be accessed for free at http://www.jacionline.org/article/S0091-6749(10)00505-1/fulltext.] Several significant correlations are reported: age, BMI, and positive skin tests are inversely correlated to vitamin D levels, while FEV1% and FEV1/FVC ratio are significantly correlated to vitamin D level.
The authors demonstrate significant association between inhaled corticosteroids, oral steroid use, and total steroid dose with low levels of vitamin D. They suggest that insufficient vitamin D might increase asthma severity, requiring greater treatment intervention or possibly that down-regulation of glucocorticoid pathways due to insufficient vitamin D dictates the need for increased steroid doses.
In vitro analyses of vitamin D activity in PBMCs demonstrated that vitamin D augments induction of MKP-1 and IL10 by steroids. Additionally, effects were observed that support vitamin D supplementation to increase steroid sensitivity, thereby permitting lower doses to obtain an optimal response.
We asked Dr. Daniel Searing, first author on the paper, about the implications of this research:
JACI: Is there baseline evidence of decreased vitamin D levels secondary to corticosteroid exposure in pediatric asthma patients?
Dr. Searing: Our study demonstrated correlations between vitamin D levels and steroid exposure in pediatric asthmatic patients from northern latitudes. To our knowledge, this is the first study looking at vitamin D levels in this patient population. Our study was not designed to examine causation of the low vitamin D levels. We are conducting a study currently looking to examine vitamin D levels in patients with asthma while also controlling for other known confounders (age, BMI, etc) to examine how strong the correlation of corticosteroid use and vitamin D levels is.
JACI: Is it possible that vitamin D insufficiency/deficiency is iatrogenic in children with asthma?
Dr. Searing: It is possible that low vitamin D levels are iatrogenic. However, the vitamin D levels in our patients with asthma seem to mirror levels in the general pediatric population. Whether escalating amounts of corticosteroid therapy in worsening asthma directly lower vitamin D levels versus other potential causes, such as vitamin D having effects on glucocorticoid pathways that leads to higher doses to achieve treatment effect is unknown at the present time. Future studies will help clarify this issue.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
In this month's JACI, Searing et al. provide the first report on prevalence of vitamin D insufficiency or deficiency in children with asthma living in latitudes higher than 20° N. [This article can be accessed for free at http://www.jacionline.org/article/S0091-6749(10)00505-1/fulltext.] Several significant correlations are reported: age, BMI, and positive skin tests are inversely correlated to vitamin D levels, while FEV1% and FEV1/FVC ratio are significantly correlated to vitamin D level.
The authors demonstrate significant association between inhaled corticosteroids, oral steroid use, and total steroid dose with low levels of vitamin D. They suggest that insufficient vitamin D might increase asthma severity, requiring greater treatment intervention or possibly that down-regulation of glucocorticoid pathways due to insufficient vitamin D dictates the need for increased steroid doses.
In vitro analyses of vitamin D activity in PBMCs demonstrated that vitamin D augments induction of MKP-1 and IL10 by steroids. Additionally, effects were observed that support vitamin D supplementation to increase steroid sensitivity, thereby permitting lower doses to obtain an optimal response.
We asked Dr. Daniel Searing, first author on the paper, about the implications of this research:
JACI: Is there baseline evidence of decreased vitamin D levels secondary to corticosteroid exposure in pediatric asthma patients?
Dr. Searing: Our study demonstrated correlations between vitamin D levels and steroid exposure in pediatric asthmatic patients from northern latitudes. To our knowledge, this is the first study looking at vitamin D levels in this patient population. Our study was not designed to examine causation of the low vitamin D levels. We are conducting a study currently looking to examine vitamin D levels in patients with asthma while also controlling for other known confounders (age, BMI, etc) to examine how strong the correlation of corticosteroid use and vitamin D levels is.
JACI: Is it possible that vitamin D insufficiency/deficiency is iatrogenic in children with asthma?
Dr. Searing: It is possible that low vitamin D levels are iatrogenic. However, the vitamin D levels in our patients with asthma seem to mirror levels in the general pediatric population. Whether escalating amounts of corticosteroid therapy in worsening asthma directly lower vitamin D levels versus other potential causes, such as vitamin D having effects on glucocorticoid pathways that leads to higher doses to achieve treatment effect is unknown at the present time. Future studies will help clarify this issue.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
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