Treatment of peanut allergy with omalizumab

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.

Atopic disease and the herpes microbiome

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

Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor кB and c-Jun N-terminal kinase activation

Inhaled glucocorticoids are often highly effective in treating symptoms of asthma exacerbations, however they are ineffective at treating and preventing exacerbations brought on by rhinovirus infection, especially in children.  Glucocorticoids act by binding to glucocorticoid receptors (GR) α which become activated and translocate to the nucleus, leading to the activation of down-stream anti-inflammatory pathways.  Papi et al sought to determine the mechanistic actions of glucocorticoids during rhinovirus infection by studying factors in these anti-inflammatory pathways (J Allergy Clin Immunol 2013; 132(5): 1075-1085).

Using a variety of assays and human bronchial epithelial cells, the authors determined that the rhinovirus RV-16 reduces the ability of dexamethasone to inhibit the pro-inflammatory cytokine IL-1β induction of the chemokine CXCL8.  They went on to show that there is an RV-16 dependent impairment of dexamethasone-induced GRα nuclear translocation that is mediated by the transcription factor NFкB p65 as well as the c-JUN N-terminal Kinase, JNK-1, both pro-inflammatory pathways.  To solidify this finding, Papi attempted to reverse the RV-16 induced attenuation of GR nuclear translocation by dexamethasone with inhibitors of NFкB and JNK. Their results indicate that independently, both inhibitors partially rescued the impairment and the combination of both inhibitors totally restored dexamethasone sensitivity. The authors show that rhinovirus infection inhibits glucocorticoid mechanisms of action and impair both the transactivation and transrepression activities of dexamethasone, implying that rhinovirus infection targets an upstream aspect of GR activation. 

These finding suggest a novel molecular mechanism for rhinoviruses, the biggest trigger of asthma exacerbations, to impair the ability of glucocorticoids to control airway inflammation.  These data indicate a strategy through which rhinovirus infection can overcome the anti-inflammatory defense but also indicate approaches that might reverse this process.  The discovery of completely inhibiting both NFкB and JNK pathways reverses glucocorticoid resistance identifies new therapeutic approaches for asthma and rhinoviruses in general for which there is no effective treatment available.

Questions for the authors:

Are there other markers or pathways that are involved that could be considered therapeutic approaches for treatment?

Yes, it is possible that the mechanisms by which rhinovirus inhibit corticosteroid activity involves the activation of other pro-inflammatory pathways, as 1) rhinovirus induces the production of multiple inflammatory mediators; 2) rhinovirus inhibits an upstream step of the mechanism of action of corticosteroids. We analyzed the keys/main mediators, but many other could be affected.

Could there be other pro-inflammatory cytokines that are up-regulated that amplify the effect of rhinoviruses?

Several pro-inflammatory mediators are induced by rhinovirus infection (Hansell TT. Lancet. 2013). They are likely affected by the mechanisms we described in the study as they are upstream steps of the mechanism of action of corticosteroids.

Predictors of response to tiotropium versus salmeterol in asthmatic adults

The severity of asthma symptoms is well known to be attenuated by inhaled corticosteroid (ICS) due to their anti-inflammatory effect.  Long-acting β-agonists (LABA) and long acting muscarinic antagonists (LAMA) are current treatment options for patients that do not respond well to low dose ICSs.  Using data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network’s Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid, Peters et al sought to determine individual and differential responses of asthmatic patients to salmeterol (LABA) and tiotropium (LAMA) when added to an inhaled corticosteroid, as well as predictors of a positive clinical response to the end points FEV₁, morning peak expiratory flow (PEF), and asthma control days (ACDs) (J Allergy Clin Immunol 2013; 132(5):1068-1074).

In the attempt to personalize the best treatment options for patients, investigators have used a variety of strategies, including the use of biomarkers, patient-specific and physiologic “predictors” and genetic/genomic approaches.  Predictors of response that have been investigated by researchers include short-acting bronchodilators and leukotriene modifiers, but more recently, predicting the response to glucocorticoids, namely ICSs have contributed valuable insight into this framework.  The author’s interest in long-acting bronchodilators, such as LABAs and LAMAs stems from the lack of information that has been published concerning these predictors of response, including intra-subject response of asthmatic patients treated with both a LABA and a LAMA.

Utilizing information from 210 asthmatic adults, the authors discovered that the use of tiotropium with a low dose of ICS resulted in a superior primary outcome compared to doubling the ICS alone, as assessed by improvement of morning PEF, evening PEF, a decrease in ACDs, and an increase in FEV₁.  Salmeterol had a similar but less robust response, and subjects showed a differential response to tiotropium for FEV₁, but not for salmeterol.  Furthermore, younger patients responded better to tiotropium in terms of ACDs.  Peters also reports that large numbers of patients responded to either salmeterol or tiotropium, but not to both agents.  This suggests that at the time of administration, different mechanisms were operating to produce airway constriction and symptoms in these 2 groups of patients.  Finally, although the use of a short-acting bronchodilator did predict a positive response to a long-acting bronchodilator controller of the same class, albuterol response better predicted a response to tiotropium than did ipratropium. 

While these findings need to be replicated in an independent study, the data suggest that asthmatics that have suboptimal asthma control using ICSs alone, with airway obstruction as demonstrated by a reduced FEV₁/FVC ratio, a positive response to albuterol, or both, should be good candidates for treatment with tiotropium as an add-on therapy.  This could be used for patients where combination ICS-LABA therapy fails or when ICS monotherapy in inadequate for symptom control.  

Exhaled NO levels and blood eosinophil counts independently associate with wheeze and asthma events

Eosinophils and exhaled Nitric Oxide (NO) levels are prominent features of asthma.  It is known that both exhaled NO and blood eosinophil counts (B-Eos) are markers of local and systemic eosinophil inflammation respectively, and are elevated in patients with the disease. However, little is known about the association of these markers with wheeze and asthma events.  Malinovschi et al [J Allergy Clin Immunol 2013; 132(4):821-827] examined subjects from National Health and Nutrition Examination Survey 2007-2008 and 2009-2010 to determine individual and independent B-Eos and Fraction of Exhaled Nitric Oxide (FENO) levels in relation to wheeze, asthma diagnosis, and asthma events.

From the cross sectional study, 12,408 subjects ranging from 6-80 years old were selected who had FENO measurements and blood differential counts.  The authors report that the prevalence of current asthma and wheeze increased progressively with FENO values and B-Eos values.  Furthermore, there was an increase in asthma attacks and asthma related ED visits which associated with an increase in both FENO and B-Eos respectively. While intermediate or high FENO and B-Eos levels were independently associated with having asthma, wheeze, and asthma attacks, only the B-Eos values were independently associated with asthma-related ED visits. 

Malinovschi explains that these 2 markers cannot be used interchangeably but rather in combination due to the finding that the correlation between the markers is weak. This indicates that they represent 2 different inflammatory pathways with separate trigger mechanisms, contrary to previous thought.  The B-Eos levels associated with asthma-related ED visits, which is in-line with recent findings that eosinophilic asthma patients receiving anti-IL-5 treatment have a reduction in severe asthma symptoms. Whereas FENO values appear to precede moderate but not severe asthma exacerbations and signal local IL-4/IL-13 mediated mechanisms in bronchial mucosa that are triggered by aeroallergen exposure. 

The authors conclude that both local and systemic Th2 cytokine-driven mechanisms, partly with different triggers, are involved in eosinophilic asthma, suggesting a double-hit mechanism for the development of respiratory symptoms and asthma.   The clinical significance of assessing both of these components for individualizing treatment warrants further study.

A major allergen of public health relevance in the inner city of Baltimore

The prevalence of asthma is ubiquitous across the United States, but the major allergens of public health relevance that contribute to the disease vary across geographical regions.  Within inner cities, the 2 most common allergens are mouse and cockroach. Ahluwalia et al [J Allergy Clin Immunol 2013; 132(4):830-835] sought to determine the relevant antigen(s) most highly associated with inner city asthma morbidity within Baltimore city. The motivation of their study was not only to aid in the management of asthma within the community but to assist in the reduction of levels of these antigens community wide. 

The authors selected 144 children between 7 and 10 years old that had been clinically identified with asthma at least one year before the start of the study.  At the start of the study, they underwent skin prick tests and had clinical data collected at baseline and again at 3, 6, 9, and 12 months.  At the same time points, settled house dust samples were collected to quantify indoor allergens.  The participants were grouped based on sensitization and exposure status of common allergens from the dust samples. 

Results indicated that mouse was the most relevant allergen with regard to asthma outcomes.  Both mouse and cockroach sensitization and exposure was significantly associated with an increased prevalence of heath care use for asthma, but only mouse sensitization and exposure was associated with higher levels of pulmonary inflammation.  Furthermore, the authors report that mouse IgE levels were also associated with poor asthma health whereas cockroach-specific IgE levels were not.   The authors went on to determine that the relationships between asthma outcomes and mouse antigen were independent of cockroach antigen. 

Ahluwalia points out that although cockroach antigen is prevalent and has some effect on outcomes, mouse antigen appears to be the strong driver of asthma morbidity among Baltimore City children.  Their data show that mouse allergen is strongly associated with a range of outcomes, including acute asthma visits, pulmonary inflammation, and lung function.  There is a profound clinical implication of these data by allowing for specific treatments for the patients and reduction of the mouse antigen at the community level.

Question for the authors: If individual urban communities used this type of study to determine the primary antigen(s) that cause community wide allergy and asthma exacerbation, what type of outcomes do you anticipate both clinically and financially both within the community and across the country? 

This question is terrific and gets to the heart of whether community-wide environmental interventions would be expected to have a broad public health benefit - by, for example, reducing asthma ED visits or hospitalizations - and what the associated costs would be.  The best means we have of estimating the potential public health impact is to calculate the proportion of asthma-related hospitalizations, for example, that can be attributed to sensitization and exposure to a particular allergen in a community.  We have done this using another Baltimore City population and estimated that between 20 and 25% of hospitalizations for asthma among Baltimore City children may be attributed to mouse allergen sensitization and exposure. In terms of costs, one multifaceted environmental intervention cost about $1500 per child [Morgan W et al NEJM 2004], which is currently the best estimate we have for the cost of an effective environmental intervention.  Whether the reduction in hospitalizations expected with, for example a mouse-targeted public health intervention in Baltimore, would be worth the cost remains to be seen.  However, a year's supply of controller medication typically costs more than $1500, so that if a mouse-targeted environmental intervention was at least as effective as controller medication, a strong case could be made to allocate more public health resources to target mouse infestation and for insurance to cover such an intervention.  Thus, the data accumulated to date suggest that a public health approach to environmental control has the potential to make a meaningful dent in asthma morbidity and asthma-related costs, not just in Baltimore City, but also in other communities with high asthma prevalence and morbidity.

Primary NK immunodeficiencies

Keeping on the topic of natural killer cells, Jordan Orange, MD, PhD contributes a review on immunodeficiencies associated with NK cell dysfunction [J Allergy Clin Immunol 2013; 132(3):515-525].  The author provides a concise review of NK cell biology, covering their intrinsic activities of cytotoxicity, tumor surveillance, and co-stimulation and signaling.  Orange points out that NK cell deficiency [NKD] is a subset of primary immunodeficiency diseases [PID] that is difficult to diagnose and treat because of the limited clinical information and testing available. 

Like other PID, the author notes that NKD patients are characterized by a susceptibility to chronic and/or severe viral infections, especially herpes viruses.  Accurate diagnosis hinges on determining that the seminal deficiency is associated with NK cells, and that NKD is not secondary to other causes. The author provides an algorithm for identifying primary NKD. 

Orange discusses the current classification of NKD into two types:  classical NKD and functional NKD.  Classical NKD [CNKD] is characterized by severe depletion or absence of NK cells in peripheral blood, while functional NKD [FNKD] is typified by the presence of peripheral NK cells with impaired or abrogated activity.  He points out that there is some overlap in these phenotypes in the reported cases.  Orange further discusses the subtypes of CKND and their associated genetic abnormalities.  In his discussion of FNKD, the author reports on the first identified subtype, FNKD1, which involves a defect in the IgG receptor. 

Orange continues describing the clinical cases that have been reported and the availability and applicability of diagnostics for NKD.  The author also reviews briefly other PID that effect NK cell immunity, but that affect other components of the immune system in the majority.  Addressing the clinical treatment of NKD, he notes that intervention is focused on the herpetic infection susceptibility and employs approved antivirals such as gancyclovir.  Additionally, the author reports that severe presentations of NKD have been treated successfully with stem cell transplantation.