Friday, December 6, 2013
Peanut allergy is a well known food allergy estimated to include 3-4% of the US population and accounts for a disproportionate number of severe allergic reactions. The vast majority of food allergy death is related to peanut allergy and is often ingested accidentally despite strict food avoidance. Peanut allergy sensitivity often fails to diminish over time compared to other food allergens causing a lifetime of anxiety and food avoidance for patients and families. The only effective treatment option for this epidemic other than food avoidance is ready access to injectable epinephrine.
Recent clinical trials using double blind, placebo controlled food challenges (DBPCFC) have reported success with allergen immunotherapy and desensitization with common food allergens including peanut. Although long term tolerance can be achieved with daily intake, most patients experienced mild to severe symptoms including anaphylaxis which occurred in up to 25% of patients with a high peanut specific IgE. Nevertheless, these trials demonstrate that oral food challenge is a useful method for treating food allergies by increasing the threshold for tolerance with possible resolution.
Schneider et al hypothesized that treatment with an anti-IgE monoclonal antibody (mAb) such as omalizumab may contribute to a more rapid desensitization with greater success (Journal of Allergy and Clinical Immunology 2013; 132(6): 1368-1374). Omalizumab binds free IgE which inhibits allergic reactions and is currently approved for older children and adults with moderate to severe asthma.
The authors administered the drug prior to and during oral peanut desensitization to 13 children who failed initial DBPCFC at low doses (< 100 mg of peanut flour). After pretreatment, all subjects tolerated initial desensitization doses given on the first day, including the maximum dose of 500 mg of peanut flour and 12 subjects reached the maximum daily dose of 4000mg/day within a median time of 8 weeks, at which point omalizumab was discontinued. The 12 subjects continued the 4000mg/day of peanut flour and subsequently tolerated a challenge of 8000 mg which is up to 400 times the dose that was tolerated before desensitization. Of the 13 subjects, 6 experienced mild or no allergic symptoms, 6 had a grade 2 reaction, and 2 had a grade 3 reaction which all responded rapidly to treatment.
These results suggest that omalizumab can facilitate a more rapid oral desensitization in high risk patients with high peanut specific IgE. Schneider’s results provide strong evidence that omalizumab can effectively reduce allergic reactions and expedite rapid oral desensitization. Larger studies are currently under way to confirm the beneficial role of omalizumab in facilitating oral peanut desensitization.
Questions for the authors:
Could this treatment be used for other severe allergic diseases not yet indicated? Could longer treatment with omalizumab prevent or reduce other side effects such as eosinophil esophagitis?
Further studies would be needed to determine whether this approach can be applied to other severe allergic diseases. We don't know if longer treatment with omalizumab would reduce reactions during desensitization since this was not part of the study.
Unlike bacteria or fungi, herpes viruses establish life-long infection in the human host through latent genomic persistence within the host cells nuclei and are thus considered part of the human microbiome. The ability of the virus to interact with the human genome influences allergic and atopic disease due to the bias these patients have towards a Th2 profile. Dr. David Dreyfus examined the role of common human herpes viruses on the microbiome of atopic patients, who have more severe and atypical disease when infected (J Allergy Clin Immunol 2013; 132(6): 1278-1286).
The herpes virus Epstein Barr (EBV or mononucleosis) expresses latency in lymphocytes and has co-evolved with humans long enough to encode for a protein that resembles the cytokine IL-10, as well as other cytokines by activating host transcription factors. The author explains that EBV and other herpes viruses encode for microRNAs that cause immunomodulation of distant cells. This lead to studies suggesting that EBV infection early in life is protective against atopic disease compared to infection later in life, where there is a predisposition to atopic disease. Atopic patients that have a primary infection of EBV can have a more severe non-specific rash that can be mistaken for allergic diseases or other infectious diseases and can be misdiagnosed.
Another ubiquitous herpes virus, VZV or shingles, becomes latent in neuronal cells and reactivation risk increases with age as the natural antibodies decline over time. The current VZV vaccine has been successful for a decade, reducing the VZV associated morbidity and mortality especially in the elderly. However, studies suggest that children who receive the vaccine have an increased incidence for atopic disease compared to children that are infected naturally with the virus, suggesting there could be a protective benefit to natural infection. Like VZV, Human Simplex Virus 1 and 2 (HSV1 and HSV 2) become latent in the neuron after primary infection of subcutaneous and pulmonary epithelial cells. The author explains that infants and others that are immunodeficient are at high risk of pulmonary syndromes such as bronchitis and pneumonia, and neurologic syndromes such as encephalitis. The most common atypical presentation of the virus is a severe skin rash called eczema herpeticum among atopic patients. This is similar to the severe drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) seen with the reactivation of HSV6, also referred to as roseola, which is present in both atopic and non-atopic patients. Furthermore, another related herpes virus, cytomegalovirus (CMV) can cause cutaneous symptoms similar to EBV, as well as chronic inflammation and cardiovascular disease due to its latency in macrophages that are associated with vascular inflammation by directly inducing Th2 cytokines.
Molecular evidence suggests that herpes viruses have been co-evolving with the human immune system since before the origin of the adaptive immune system. The herpes microbiome along with environmental factors such as improved global hygiene that prevents the exposure to a variety of components interact with each other to create the atopic phenotype. Dr. Dreyfus emphasizes that this information can positively impact the care for the allergic and atopic patient populations. Clinicians must have a heightened awareness of the various presentations of herpes viruses to avoid unnecessary testing and treatments for drug allergy or autoimmune disease.
Questions for the author:
What are the effects of the herpes microbiome on other allergic diseases? Is there an increase in Th2 dependent disease in patients who express viral lesions and reactivation of herpes viruses?
Regarding the question of effects of herpes on atopic disease, in addition to the references cited in my article particularly regarding an increase in atopic disease in pediatric patients who receive the varicella vaccine vs wild type virus there is a more recent article just published with some more experimental observations on this question:
Sohlberg, E. et al (2013) Cytomegalovirus-Seropositive Children Show Inhibition of an In Vitro EBV infection That Is Associated with CD8+ CD57+ T-cell Enrichment and IFN-gamma. Journal of Immunology 191:5669