Answer:
This degree of elevation of IgE is indeed very unusual but very high values are associated with atopic dermatitis. The mechanism may be that the damage of the epithelial barrier increases immune exposure to environmental allergens stimulating the formation of IgE. However, usually the specificity of such large amounts of IgE cannot be determined, suggesting that the increase in IgE is nonspecific. Superantigen function of bacterial toxins from organisms colonizing the skin, especially staphylococcus, is another potential mechanism of stimulating IgE without specificity. However, it is also possible the IgE reflects a primary immune dysregulation such as STAT3 (signal transducer and activator of transcription 3), tyrosine kinase 2 (TYK2) and dedicator of cytokinesis 8 gene (DOCK8). These genetic defects are associated with abnormal signaling of Th17 cells as well as Type I Interferon, IL-6, IL-10, IL-12 and IL-23. These defects are associated with infections with bacteria such as staphylococcus and candida. Th17 dysfunction is also associated with neutrophil dysfunction which increases risk of infection.
My suggestion would be to assess the risk and history of infection and, if in your opinion there is a greater occurrence of infection, I would check quantitative immunoglobulins (IgG, IgA, IgM), lymphocyte subsets and in vitro proliferation of lymphocytes to antigens and mitogens. You can request genetic testing for the genes noted above from various commercial genetic testing laboratories. If your patient does not have infections, then I would not expect the above tests to show any abnormalities and I would not do the testing. I would treat his eczema aggressively and consider alternative, corticosteroid sparing therapies such as narrow band UVB light therapy, oral methotrexate, oral azathioprine or oral calcineurin inhibitors such as cyclosporine or tacrolimus. All of these therapies have associated risk and this risk would need to be balanced by evidence that the eczema and quality of life improves with less systemic corticosteroid therapy. The use of monoclonal anti-IL5 (mepolizumab) would be of interest but is approved only for asthma and not for eczema and the results have been disappointing (Oldhoff). Omalizumab is not likely to be of help since there is no way to dose sufficiently for the level of IgE and clinical results are inconsistent (Krathen; Lane; Sheinkopf; Belloni). There are exciting data from newer biologics and cytokines which may be very useful in the future (Beck,Brar, Shroff).
1. Oldhoff, J. M., et al. "Anti‐IL‐5 recombinant humanized monoclonal antibody (Mepolizumab) for the treatment of atopic dermatitis." Allergy 60.5 (2005): 693-696.
2. Krathen RA, Hsu S. Failure of omalizumab for treatment of severe adult atopic dermatitis. J Am Acad Dermatol 2005;53:338–340.
3. Lane JE, Cheyney JM, Lane TN, et al. Treatment of recalcitrant atopic dermatitis with omalizumab. J Am Acad Dermatol 2006;54:68–72.
4. Sheinkopf LE, Rafi AW, Do LT, et al. Efficacy of omalizumab in the treatment of atopic dermatitis: a pilot study. Allergy Asthma Proc 2008;29:530–537.
5. Belloni B, Ziai M, Lim A, et al. Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels. J Allergy Clin Immunol 2007;120:1223–1225.
6. Beck, Lisa A., et al. "Dupilumab treatment in adults with moderate-to-severe atopic dermatitis." New England Journal of Medicine 371.2 (2014): 130-139.
7. Brar, Kanwaljit, and Donald YM Leung. "Recent Considerations in the Use of Recombinant Interferon Gamma for Biological Therapy of Atopic Dermatitis." Expert opinion on biological therapy just-accepted (2016).
8. Shroff, Anjali, and Emma Guttman-Yassky. "Successful use of ustekinumab therapy in refractory severe atopic dermatitis." JAAD Case Reports 1.1 (2015): 25-26.
9. Rockefeller University. Pilot study of ustekinumab for subjects with chronic atopic dermatitis.
10. Japanese study of ustkinumab for severe atopic dermatitis. Defects in Jak-STAT-mediated cytokine signals cause hyper-IgE syndrome: lessons from a primary immunodeficiency. Minegishi Y, Karasuyama H. Int Immunol. 2009;21(2):105.
Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic manifestations and susceptibility to infections with extracellular bacteria and fungi, which frequently occur in the skin and lung. Atopic manifestations in HIES include extremely high serum IgE levels, eczema and eosinophilia. Most of the extracellular bacterial infections are associated with disproportionally milder inflammation than normal, which was originally described as having a 'cold abscess'. Non-immunological abnormalities are also observed in most patients with HIES, including a distinctive facial appearance, scoliosis, hyper-extensive joints and retained primary teeth. Recent studies have demonstrated that hypomorphic mutations in signal transducer and activator of transcription 3 result in the classical multisystem form of HIES, whereas a null mutation in tyrosine kinase 2 causes the autosomal recessive form of HIES that is associated with viral and mycobacterial infections. Analyses of cytokine responses in both types of HIES have revealed defects in signal transduction for multiple cytokines including IL-6 and IL-23, leading to impaired T(h)17 function. These results suggest that the defect in multiple cytokine signals is the molecular basis of the immunological and non-immunological abnormalities in HIES and that the susceptibility to infections with extracellular bacteria and fungi in HIES might be associated with the defect in T(h)17 cell differentiation.
Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.
Al Khatib S, Keles S, Garcia-Lloret M, Karakoc-Aydiner E, Reisli I, Artac H, Camcioglu Y, Cokugras H, Somer A, Kutukculer N, Yilmaz M, Ikinciogullari A, Yegin O, Yüksek M, Genel F, Kucukosmanoglu E, Baki A, Bahceciler NN, Rambhatla A, Nickerson DW, McGhee S, Barlan IB, Chatila T
J Allergy Clin Immunol. 2009;124(2):342.
Background: The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation.
Objective: To elucidate mechanisms underlying different forms of HIES.
Methods: A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining withanti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively.
Results: Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps.
Conclusion: In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.
Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.
Woellner C, Gertz EM, Schäffer AA, Lagos M, Perro M, Glocker EO, Pietrogrande MC, Cossu F, Franco JL, Matamoros N, Pietrucha B, Heropolitańska-Pliszka E, Yeganeh M, Moin M, Español T, Ehl S, Gennery AR, Abinun M, Breborowicz A, Niehues T, Kilic SS, Junker A, Turvey SE, Plebani A, Sánchez B, Garty BZ, Pignata C, Cancrini C, Litzman J, Sanal O, Baumann U, Bacchetta R, Hsu AP, Davis JN, Hammarström L, Davies EG, Eren E, Arkwright PD, Moilanen JS, Viemann D, Khan S, Maródi L, Cant AJ, Freeman AF, Puck JM, Holland SM, Grimbacher B. J Allergy Clin Immunol. 2010;125(2):424.
Background: The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells.
Objective: To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients.
Methods: We collected clinical data, determined T(H)17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE>1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation.
Results: In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T(H)17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) T(H)17 cells but were distinct by markedly reduced IFN-gamma-producing CD4(+)T cells.
Conclusion: We propose the following diagnostic guidelines for STAT3-deficient HIES. Possible: IgE>1000IU/mL plus a weighted score of clinical features>30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.
Combined immunodeficiency associated with DOCK8 mutations.
Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, Matthews HF, Davis J, Turner ML, Uzel G, Holland SM, Su HC. N Engl J Med. 2009;361(21):2046.
Background: Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown.
Methods: We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry.
Results: Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma-leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes.
Conclusions: Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency.
Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome.
Engelhardt KR, McGhee S, Winkler S, Sassi A, Woellner C, Lopez-Herrera G, Chen A, Kim HS, Lloret MG, Schulze I, Ehl S, Thiel J, Pfeifer D, Veelken H, Niehues T, Siepermann K, Weinspach S, Reisli I, Keles S, Genel F, Kutukculer N, Kutuculer N, Camcioğlu Y, Somer A, Karakoc-Aydiner E, Barlan I, Gennery A, Metin A, Degerliyurt A, Pietrogrande MC, Yeganeh M, Baz Z, Al-Tamemi S, Klein C, Puck JM, Holland SM, McCabe ER, Grimbacher B, Chatila TA. J Allergy Clin Immunol. 2009;124(6):1289.
Background: The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60% to 70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining patients with hyper-IgE syndrome, the genetic etiology has not yet been identified.
Objectives: We aimed to identify a gene that is mutated or deleted in autosomal recessive hyper-IgE syndrome.
Methods: We performed genome-wide single nucleotide polymorphism analysis for 9 patients with autosomal-recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with 12 patients from 7 additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal-recessive hyper-IgE syndrome.
Results: Subtelomeric biallelic microdeletions were identified in 5 patients at the terminus of chromosome 9p. In all 5 patients, the deleted interval involved dedicator of cytokinesis 8 (DOCK8), encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of patients without large deletions revealed 16 patients from 9 unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, and single exon deletions and microdeletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+T cells.
Conclusions: Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T-cell activation and T(h)17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE.
I hope this information is of help to you and your patient.
All my best.
Dennis K. Ledford, MD, FAAAAI