Development and validation of a novel risk score for asthma exacerbations: The risk score for exacerbations

Asthma management involves achieving and maintaining current asthma control and preventing exacerbations. Reports have shown, however, that there can be a disassociation between these two goals, meaning control may be achieved but risk of exacerbations may remain, or the opposite. The identification of patients at risk of future severe exacerbations, whose asthma might be less treatment-responsive, or both could focus treatment selection. To this end, Bateman et al have developed a simple risk score for exacerbations (RSE) for clinical use (J Allergy Clin Immunol 2015; 135(6): 1457-64).

The authors analyzed a large data set of patients enrolled in studies comparing the efficacy of budesonide-formoterol (BUD/FORM) maintenance and reliever therapy with fixed-dose inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) therapy. They included patients whose symptoms were not controlled on Global Initiative for Asthma (GINA) treatment steps 3 and 4 and who had experienced 1 or more exacerbations in the previous year. Using multivariate analysis, they found 4 dominant (all P <.001) predictors for both the risk of uncontrolled asthma and severe exacerbations: GINA step, reliever use, postbronchodilator FEV₁, and 5-item Asthma Control Questionnaire score. Smoking status and asthma symptom scores were additional predictors for uncontrolled asthma, and body mass index was a fifth predictor for severe exacerbation.

Bateman et al show risk of uncontrolled asthma at 3 months of treatment and a severe exacerbation within 12 months can be estimated from simple clinical assessments. The prediction of treatment outcome could be particularly useful for patients similar to those in the current analysis, all of whom were receiving moderate-to-high ICS doses and 52% of whom were receiving LABAs and who had experienced at least 1 recent exacerbation, as it could identify patients who might benefit from intensified or alternative therapeutic measures.

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis

Platelet-activating factor (PAF) is a potent phospholipid-derived mediator thought to play a pivotal role in the etiology of numerous immune and inflammatory conditions. Our knowledge of its effects has broadened to include those as a vasodilator and broncho-constrictor, a contributor to host defenses, and a mediatory of the inflammatory response, and PAF has been well-demonstrated in experimental models to function as a central mediator of anaphylaxis. Gill et al review what we know (J Allergy Clin Immunol 2015; 135(6): 1424-32).

PAF is produced and secreted by several types of cells including mast cells, monocytes, tissue macrophages, eosinophils, endothelial cells, neutrophils, and platelets. It is implicated in platelet aggregation and activation through release of vasoactive amines in the inflammatory response, resulting in effects including increased vascular permeability, circulatory collapse, and decreased cardiac output. Studies have shown patients with acute allergic reactions had elevated PAF serum levels, and patients with severe anaphylaxis had higher levels still. The latter group had respiratory or cardiovascular compromise, where both organ systems were targets of PAF bioactivity.

PAF is rapidly hydrolyzed and degraded to an inactive metabolite, lysoPAF, by the enzyme PAF-acetylhydrolase (PAF-AH), whose activity correlates inversely with PAF levels and predisposition to severe anaphylaxis. Several studies have confirmed more rapid rates of inactivation of PAF result in milder allergic manifestations. There is much interest around the development of therapies that selectively block the actions of PAF as both long-term prophylaxis and emergency treatment. In animal models, treatment with platelet-activating factor receptor (PAF-R) antagonists significantly reduced the severity of peanut-induced anaphylaxis and accelerated recovery from anaphylactic reactions. We are, however, still in the early stages of understanding PAF signaling, and further investigation of its role in pathology and therapeutic modulation is anticipated.

The role of platelets in allergic airway inflammation

Platelets are anucleated blood elements involved in hemostasis and thrombosis. It is now understood that they can also act as inflammatory cells and contribute to host defense against infection, performing many functions normally associated with leukocytes. Studies have shown that platelet depletion compromises ability to resist microorganism infection. Given that many inflammatory diseases are the result of inappropriate activation of defense pathways, it is likely inappropriate platelet activation contributes to the pathogenesis of these diseases. Idzko et al present the currently available data investigating the role of platelets in allergic airway inflammation and asthma (J Allergy Clin Immunol 2015; 135(6): 1416-23).

Of particular relevance to allergic inflammation, it has been shown that platelets express IgE receptors on their surfaces. They play an essential role in killing certain parasites, and platelet activation has been shown to accompany allergen exposure of sensitized patients. Platelet activation has also been observed in patients with asthma, measured as an increase in the levels of a number of platelet-derived mediators in peripheral blood or in bronchoalveolar lavage fluid (BAL). It is evident that platelets can release a number of spasmogens that can constrict human airway smooth muscle, including 5-HT, which has been demonstrated to induce bronchoconstriction in asthmatic patients. And platelet depletion has been reported to reduce allergen-induced bronchial hyperresponsiveness in sensitized rabbits, associated with a reduction in eosinophil infiltration in the lungs.

The increasing number of observations suggesting a dichotomy of platelet activation between the signaling involved in thrombosis and hemostasis and the activation during inflammatory responses has considerable implication. For example, using adenosine diphosphate (ADP), the authors have recently demonstrated that P2Y₁ receptors are required for platelet activation by inflammatory stimuli, whereas PY₁₂ receptors required for platelet aggregation have no such effect. The dichotomy of function opens the real possibility of developing anti-inflammatory and anti-allergic therapies that target the novel pathways of platelet activation. It also raises the possibility of finding novel biomarkers for assessing disease, given the clear role of platelets in leukocyte recruitment.

Platelets in aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is an acquired syndrome that is irreversible and debilitating. A chronic inflammatory disease characterized by the triad of asthma, nasal polyposis, and pathognomonic respiratory reactions after the ingestion of aspirin, it presents with an onset in young adulthood. Estimations indicate there are approximately 1.2 million adults in the United States living with AERD. Its pathogenesis likely involves disturbances in the mechanisms that regulate tissue recruitment of immune effector cells and activity of the 5-LO/LTC₄S pathway. There is substantial evidence that platelets contribute to these mechanisms. Laidlaw et al review the evidence regarding asthma in general and AERD in particular (J Allergy Clin Immunol 2015; 135(6): 1407-14).

Platelets lack a nucleus and have no DNA. They are derived from cytoplasmic fragments of megakaryocytes and have a life span in the circulation of approximately 8-10 days before being removed by the spleen. In addition to their role in hemostasis, activated platelets can activate other immune cells, and upon adhesion to granulocytes, they can facilitate granulocyte recruitment into body tissues. They also secrete mediators including chemokines and lipids, which are released upon platelet activation. All of these contribute to symptomatic asthma exacerbations. Specific to AERD, patients with the condition have high numbers of platelet-adherent granulocytes in their nasal polyp tissue, which contributes to the overproduction of cysteinyl leukotrienes.

Whether or not the circulating platelets implicated in AERD possess an intrinsic defect is still unknown. In vitro stimulation studies have shown platelets from AERD patients released nearly twice as much ATP when activated with platelet-activating factor than those from healthy controls did. The platelets also released significantly increased levels of TXB₂, which was not seen in the controls. Differences in biochemistry seem possible, suggesting trials examining targeted anti-platelet therapeutics may be appropriate. Studies have also suggested therapies aimed at reducing numbers of platelet-leukocyte aggregates, T-prostanoid receptor blockade, and P2Y₁₂ receptor antagonism all may be of use, and relevant clinical trials are in their early stages.

Celiac Disease

Given an increasing awareness of gluten-related disorders, medical professionals are encountering patients diagnosed with celiac disease or thought to have food intolerance to gluten. Green et al provide a review of the pathogenesis, clinical manifestations, diagnosis, and management of celiac disease (J Allergy Clin Immunol 2015; 135(5):1099-1106).

There are currently three major wheat-related food illnesses: celiac disease (CD), non-celiac gluten sensitivity (NCGS), and wheat allergy. CD is an autoimmune disorder involving both an innate and adaptive response in genetically predisposed individuals. Unlike food allergies, the pathogenesis of CD is not mediated by an immediate hypersensitivity reaction via an immunoglobulin (IgE) dependent mechanism. Instead, gluten protein is a pathogenic agent activated by the enzyme tissue transglutaminase (TTG) allowing its presentation to CD4+ T cells in the small intestine. NCGS is a term that refers to a spectrum of clinical phenotypes, without the identification of characteristic histologic or serologic abnormalities. Wheat allergy is distinct from both, in that it is an IgE mediated hypersensitivity response that occurs within minutes to hours of wheat ingestion.

Celiac disease has prevalence of nearly 1% among Western nations. Its distribution extends into such disparate populations as the Middle East, South America, Asia, and North Africa. A proposed reason for this trend is a globalizing world market bringing wheat-based foods into cultures that traditionally relied on gluten-free grains. There is evidence CD is a missed diagnosis in many children where infection and malnutrition are the presumed etiology for diarrheal illness. Its pathogenesis depends on the interaction of three factors. The first is predisposing genes, HLA DQ2 and DQ8, and the second is exposure to gluten. The third, environmental factors, includes many under investigation, including breastfeeding and the intestinal microbiome.

There is increasing evidence that CD includes extra-intestinal manifestations, and the terminology for describing it is changing to allow for these. Common presentations include anemia and osteoporosis. Despite increased awareness of the condition and gluten, the rate of diagnosis in the US remains low, with less than 20% of those with the actual condition having been diagnosed. The IgA TTG assay is the initial test of choice to detect antibodies associated with CD. Treatments in addition to the gluten-free diet, such as intraluminal agents, immunomodulators, and vaccination, are currently under investigation.

Question for the authors: 
Is there data available for the prevalence of wheat allergy in Western nations?

Although some overlap exists in the symptoms attributed to wheat allergy, specific pathophysiological reactions to wheat are currently classified into three categories: 1) IgE hypersensitivity associated wheat allergy 2) autoimmune IgA related celiac disease and 3) non celiac gluten sensitivity (NCGS). The prevalence of IgE related wheat allergy, which is most common in childhood, is estimated around 0.4-1.3%. Our review describes the prevalence of celiac disease near 1% in Western nations; however, the incidence of celiac disease has increased over time, and there is evidence of its underdiagnosis among the general population. NCGS is currently not as well understood as the other two wheat related allergies, and estimates of its prevalence are wide-ranging from 0.5-6%.

Immunopathophysiology of food protein-induced enterocolitis syndrome

Food protein-induced enterocolitis syndrome (FPIES) and food protein-induced proctocolitis are non-IgE-mediated gastrointestinal allergies. Our current understanding of the mechanisms of these allergies linking exposure to the typical symptoms of vomiting, hypotension, and diarrhea falls behind that of other food-induced allergic disorders. Accompanying a comprehensive review of clinical features by Nowak-Wegrzyn that also appears in this issue, Berin assesses the state of our knowledge of the immune mechanisms of FPIES (J Allergy Clin Immunol 2015; 135(5):1108-1113).

FPIES is most commonly triggered by the protein component in cow’s milk, but a host of other foods can be triggers as well. Many of the foods that trigger FPIES reactions are also IgE-mediated food allergens, such as soy, fish, wheat, and egg, but many are not common in that regard. For example, rice is the third most common cause of FPIES in US cohorts, followed by oats. The fact that a range of common foods have the potential to trigger it is in contrast to celiac disease, in which pathology is triggered by a well-defined antigen in a restricted subset of foods.

Studies have demonstrated FPIES leads to changes in the intestinal architecture in response to chronic exposure to a trigger such as milk. Avoiding milk results in normalization, and its reintroduction results in a recurrence of partial villous atrophy. While this is similar to celiac disease, the two conditions differ in pathophysiology. For example, the latter is thought to be a food antigen-triggered autoimmunity. There is a lack of evidence for an autoimmune component in FPIES, but there is an association between it and atopy. There is mast cell degranulation in common between the two, which is an important factor that requires investigation.

The facts that FPIES commonly develops in response to the first food introduced into the diet and adverse reactions can develop in response to many foods that are not typically allergenic suggests there may be a regulatory defect in patients with FPIES. The presence and phenotype of food-specific T cells in the intestinal mucosa of patients with FPIES needs to be demonstrated, as has been done with celiac patients. There is even less data to explain the immune basis of acute FPIES reactions. In one case study, milk administered via enema resulted in diarrhea and weight loss, whereas drinking the milk induced vomiting, pallor, and diarrhea in the same infant. Thus, the chronic and acute manifestations of FPIES can be triggered at different sites. Is processing of the allergen during digestion required to trigger symptoms? Much remains to be investigated about its underlying immune mechanisms.

Anaphylaxis: Unique aspects of clinical diagnosis and management in infants (birth to age 2 years)

Anaphylaxis is reported to occur with increasing frequency in infants. An illustrated Rostrum on the diagnosis, treatment, and long-term management of anaphylaxis in this age group has been published by Simons and Sampson (J Allergy Clin Immunol 2015;135: 1125-31).

Foods such as milk, egg, and peanut are by far the most common triggers of anaphylaxis in infancy, although medications and other triggers can also be implicated. Infants with anaphylaxis typically present with sudden onset of skin signs such as generalized urticaria, respiratory symptoms such as cough, wheeze, stridor, and dyspnea, and/or gastrointestinal symptoms such as persistent vomiting.

Clinical criteria for diagnosis of anaphylaxis are validated for use in children and adults, but have not yet been validated for use in infants. A high index of suspicion is required to diagnose anaphylaxis in babies, as they cannot describe symptoms such as itching, and signs of infant anaphylaxis such as flushing, dysphonia, incontinence, and behavior changes (irritability, somnolence) also occur in healthy infants.

The differential diagnosis of anaphylaxis in infancy includes unique entities such as congenital abnormalities of the respiratory tract or gastrointestinal tract, and food protein-induced enterocolitis syndrome. Epinephrine injection is the treatment of choice in both clinical and community settings.

Co-morbidities that increase the risk of severe anaphylaxis are not well-defined, but probably include croup, bronchiolitis, or asthma; likewise, amplifying co-factors are not well-defined in this age group.

Long-term management focuses on follow-up with a physician, preferably an allergy/immunology specialist who can train caregivers of infants to recognize and treat anaphylaxis in the community and help them to prevent anaphylaxis episodes.

Epinephrine auto-injectors (EAIs) are under-prescribed and under-used for anaphylaxis in infants. In a study in which a minority of infants with severe anaphylaxis were treated with epinephrine, reasons for not using it included failure to recognize anaphylaxis symptoms and being afraid to inject epinephrine.

Strict avoidance of exposure to culprit allergens (as confirmed by skin prick tests and specific IgE measurements) prevents recurrences but requires sustained vigilance from all the infant’s caregivers. Natural desensitization to foods such as milk or egg eventually occurs in many infants and children, especially those with mild initial reactions and low levels of sensitization.

Simons and Sampson have outlined specific goals for research on anaphylaxis in infancy. These include validation of the clinical criteria for diagnosis, studies of infant co-morbidities and amplifying co-factors that increase the risk of severe anaphylaxis, development of EAIs containing a 0.1 mg epinephrine dose suitable for this age group, and inclusion of infants in prospective studies of immune modulation to prevent anaphylaxis.

 Question for the authors: In addition to being alert to the possibility of some infants eventually undergoing natural desensitization to milk or egg and helping to facilitate this desensitization, what other possibilities for prevention of anaphylaxis in infants do you see?

Answer: In an important prospective randomized trial in carefully-selected, high-risk infants age 4-11 months (Du Toit G et al, N Engl J Med 2015;372:803-13), early introduction of peanut significantly decreased the frequency of the development of peanut allergy and modulated immune responses to peanut. Although it remains to be proven whether these findings can be translated to other foods such as milk and egg and additional questions need to be addressed, this research suggests that the increase in prevalence of food-induced anaphylaxis in infants might eventually be halted.