Matthew C. Bell

Severe Asthma: An Expanding and Mounting Clinical Challenge

Although all patients with asthma have variable airflow obstruction, airway inflammation, and bronchial hyperresponsiveness, some have disease that is severe in many aspects: persistent airflow obstruction, ongoing symptoms, increased frequency of exacerbations, and, most importantly, a diminished response to medications. A number of definitions have emerged to characterize the clinical features of severe asthma, but a central feature of this phenotype is the need for high doses of medications, especially corticosteroids, in attempts to achieve disease control. The prevalence of severe asthma is also undergoing reevaluation from the usual estimate of 10% to larger numbers on the basis of medication needs and the lack of disease control achieved. At present, the underlying mechanisms of severe asthma are not established but likely reflect a heterogeneous pattern, rather than a single unifying process. Guideline-directed treatment for severe asthma has limits with usual approaches centered on high doses of inhaled corticosteroids, long-acting β-agonists, and trials with omalizumab, the monoclonal antibody to IgE. With the development of approaches to recognize asthma phenotypes with distinct pathogenesis and hence unique therapeutic targets, it is hoped that a personalized strategy in treatment directed toward disease-specific features will improve outcomes for this high-risk, severely affected population of patients.

Prevention of anaphylaxis related to mast cell activation syndrome with omalizumab

The concept of mast cell activation syndrome (MCAS) has evolved over the last several decades to describe cases involving evidence of profound mast cell degranulation without an obvious trigger or evidence of aberrant mast cell proliferation.1 In 2010, Akin, et al. proposed a set of diagnostic criteria including: 1) absence of evidence of primary or secondary causes of mast cell activation (including mastocytosis); 2) episodic symptoms consistent with mast cell mediator release affecting ≥2 organ systems; 3) evidence of an increase in a validated urinary or serum marker of mast cell activation; and 4) a decrease in severity of symptoms with anti-mediator therapy including histamine 1 and 2 receptor antagonists, leukotriene antagonists, or mast cell stabilizers.1 Treatment of MCAS involves the use of one or more of the aforementioned classes of medications,2 while prednisone, cyclosporine A, methotrexate, and azathioprine are alternatives when treatment with more conservative therapy fails.2 Treatment of refractory cases presents a difficult dilemma for the clinician. We present a case of the successful use of omalizumab (monoclonal antibody to IgE) in the treatment of a pediatric patient who met the proposed diagnostic criteria for MCAS. Our patient is an 11 year old male with a history of eczema and viral-induced wheezing who presented in September 2010 for evaluation of presumed anaphylactic reactions to both cherries and blackberries. Symptoms included hives and breathing difficulty. He had an additional episode with similar symptoms for which a trigger was not identified. In the weeks preceding these events, he reported headache, flushing, abdominal pain, diarrhea, and fatigue. Percutaneous skin prick testing using common aeroallergen extracts and cherry was negative. Complete blood count showed a white blood cell count of 12,500/μL with a lymphocyte predominance and normal numbers of eosinophils, basophils, and monocytes. Serum tryptase was 15.8 μg/dL (normal 0.4–10.9 μg/dL). A monospot was positive, which was potentially significant as the presence of heterophile antibodies can increase tryptase levels.3 Total IgE was 26 IU/mL. The child was counseled on avoidance of cherries and blackberries, prescribed an epinephrine auto-injector, and started on oral cetirizine at 10 mg twice daily. Over the next four months, he continued to experience frequent abdominal pain, diarrhea, urticaria and flushing, as well as episodic anaphylactoid reactions requiring the use of epinephrine several times per month. Tryptase levels remained elevated (17.8 μg/dL; 19.8 μg/dL). Histamine-1 receptor blockade was increased to twice daily cetirizine plus twice daily loratadine (“4× therapy”) with continuation of twice daily ranitidine. Symptoms improved but persisted, and bone marrow biopsy was obtained to exclude systemic mastocytosis or monoclonal mast cell activation syndrome (MMAS). Normal marrow morphology was noted with the absence of a large population of mast cells or spindle-shaped mast cells. CD25 staining was negative. Additionally, a chronic urticaria index, which tests for presence of autoantibodies to the high-affinity IgE (FceRI) receptor, was within normal limits. Polymerase chain reaction for the KIT (D816V) mutation commonly found in systemic mastocytosis and MMAS was unable to be performed due to lack of amplifiable nucleic acid in the specimen. Upper and lower endoscopy did not show the presence of mast cell aggregates in the bowel wall. The patient improved on a prolonged course of oral corticosteroids, but symptoms increased after their discontinuation and he was started on omalizumab as a steroid-sparing agent in April 2011. He continues to receive omalizumab 150 mg subcutaneously every 4 weeks. He had rapid improvement in symptoms and has had one episode of urticaria with shortness of breath in the 10 months on omalizumab therapy. The patient continues on H1 receptor blockade with twice daily cetirizine and loratidine and H2 receptor blockade with twice daily ranitidine. This case supports the potential efficacy of omalizumab for MCAS in children not responding to maximal anti-histamine therapy. Molderings, et al. recently reported benefit with omalizumab therapy in 1 of 2 patients with monoclonal mast cell activation syndrome.4 There have been other reports of successful treatment of systemic mastocytosis with omalizumab.5,6 The mechanisms underlying the symptomatic improvement of patients with MCAS treated with omalizumab are not fully understood. The binding and inactivation of IgE by omalizumab leads to a decreased level of IgE available for binding to mast cells, leading to downregulation of FceRI.7 Others have proposed that omalizumab may interfere with mast cell mediator release.8 In sum, omalizumab may be an efficacious therapy for treatment resistant MCAS, and further studies are needed to ascertain what factors lead to improvement in MCAS patients receiving omalizumab.

Diminished But Not Forgotten: Effects of Aging on Magnitude of Spacing Effect Benefits

OBJECTIVES Age-related changes in memory performance are common in paired associate episodic memory tasks, although the deficit can be ameliorated with distributed practice. Benefits of learning episode spacing in older adults have been shown in single-session studies with spaced presentations of items followed by a test. This study examined the magnitude of the spacing effect benefit in older adults relative to younger adults when given a multiday spacing effect paradigm. METHOD We examined the impact of spacing gap (~15min vs. 24hr) in younger (N = 51, Mage = 19 years, SD = 0.6) and older (N = 54, Mage = 65 years, SD = 8.8) adults with a 10-day retention interval. RESULTS Spacing of learning episodes benefited both younger and older adults. There was an age-related difference in the magnitude of this benefit that has not been observed in earlier studies. DISCUSSION These results suggest that spacing benefited the long-term memory of older adults, however the effect was diminished and qualitatively different from that of younger adults.

Long-term memory, sleep, and the spacing effect.

Many studies have shown that memory is enhanced when study sessions are spaced apart rather than massed. This spacing effect has been shown to have a lasting benefit to long-term memory when the study phase session follows the encoding session by 24 hours. Using a spacing paradigm we examined the impact of sleep and spacing gaps on long-term declarative memory for Swahili–English word pairs by including four spacing delay gaps (massed, 12 hours same-day, 12 hours overnight, and 24 hours). Results showed that a 12-hour spacing gap that includes sleep promotes long-term memory retention similar to the 24-hour gap. The findings support the importance of sleep to the long-term benefit of the spacing effect.

A Preliminary Investigation of the Reinforcement Function of Signal Detections in Simulated Baggage Screening: Further Support for the Vigilance Reinforcement Hypothesis.

The vigilance reinforcement hypothesis (VRH) asserts that errors in signal detection tasks are partially explained by operant reinforcement and extinction processes. VRH predictions were tested with a computerized baggage screening task. Our experiment evaluated the effects of signal schedule (extinction vs. variable interval 6 min) and visual field complexity (dial vs. baggage x-ray) on search behavior rates. There was a main effect for signal schedule [F (1, 20) = 14.0, p = .001, prep = 0.99], but no effects for field complexity or interaction. The VRH suggests that performance errors in visual screening work may be reduced through operant conditioning of search behaviors by intensive management of artificially planted signals.

Effect of signaling reinforcement on resistance to change in a multiple schedule

This study evaluated the effect of a signal on resistance to change using a multiple schedule of reinforcement. Experiment 1 presented pigeons with three schedules: a signaled delay to reinforcement schedule (a two-link chain schedule with a variable-interval 120-s initial link followed by a 5-s fixed-time schedule), an unsignaled delay schedule (a comparable two-link tandem schedule), and an immediate, zero-delay variable-interval 125-s schedule. Two separate disruption procedures assessed resistance to change: extinction and adding a variable-time 20-s schedule of reinforcement to the inter-component interval. Resistance to change tests were conducted twice, once with the signal stimulus (the terminal link of the chain schedule) present and once with it absent. Results from both disruption procedures showed that signal absence reduced resistance to change for the pre-signal stimulus. In probe choice tests subjects strongly preferred the signal stimulus over the unsignaled stimulus and exhibited no reliable preference when given a choice between the signal stimulus and immediate stimulus. Experiment 2 presented two equal signaled schedules where, during resistance to change tests, the signal remained for one schedule and was removed for the second. Resistance to change was consistently lower when the signal was absent.

Preference and resistance to change in concurrent variable-interval schedules

Pigeons were trained on a multiple schedule in which separate concurrent schedules were presented in the two components of the schedule. During one component, concurrent variable-interval 40-sec variableinterval 80-sec schedules operated. In the second component, concurrent variable-interval 40-sec variableinterval 20-sec schedules operated. After stable baseline performance was obtained in both components, extinction probe choice tests were presented to assess preference between the variable-interval 40-sec schedules from the two components. The variable-interval 40-sec schedule paired with the variableinterval 80-sec schedule was preferred over the variable-interval 40-sec schedule paired with the variableinterval 20-sec schedule. The subjects were also exposed to several resistance-to-change manipulations: (1) prefeeding prior to the experimental session, (2) a free-food schedule added to timeout periods separating components, and (3) extinction. The results indicated that preference and resistance to change do not necessarily covary.

Resistance to extinction, generalization decrement, and conditioned reinforcement

This study investigated generalization decrement during an extinction resistance-to-change test for pigeon key pecking using a two-component multiple schedule with equal variable-interval 3-min schedules and different reinforcer amounts (one component presented 2-s access to reinforcement and the other 8s). After establishing baseline responding, subjects were assigned to one of the two extinction conditions: hopper stimuli (hopper and hopper light were activated but no food was available) or Control (inactive hopper and hopper light). Responding in the 8-s component was more resistant to extinction than responding in the 2-s component, the hopper stimuli group was more resistant to extinction compared to the Control group, and an interaction between amount of reinforcement, extinction condition, and session block was present. This finding supports generalization decrement as a factor that influences resistance to extinction. Hopper-time data (the amount of time subjects spent with their heads in the hopper) were compared to resistance-to-change data in an investigation of the role of conditioned reinforcement on resistance to change.

CONDITIONED REINFORCEMENT IN CHAIN SCHEDULES WHEN TIME TO REINFORCEMENT IS HELD CONSTANT

Two alternative approaches describe determinants of responding to a stimulus temporally distant from primary reinforcement. One emphasizes the temporal relation of each stimulus to the primary reinforcer, with relative proximity of the stimulus determining response rate. A contrasting view emphasizes immediate consequences of responding to the stimulus, the key factor being the conditioned reinforcement value of those immediate consequences. To contrast these approaches, 4 pigeons were exposed to a two-component multiple schedule with three-link chain schedules in each component. Only middle-link stimuli differed between chains. Baseline reinforcement probabilities were 0.50 for both chains; during discrimination phases it was 1.0 for one chain and 0.0 for the other. During discrimination phases pigeons responded more to the reinforcement-correlated middle link than to the extinction-correlated middle link, demonstrating that responding was affected by the probability change. Terminal link responding was also higher in the reinforced chain, even though the terminal link stimulus was identical in both chains. Of greatest interest is initial link responding, which was temporally most distant from reinforcement. Initial link responding, necessarily equal in the two chains, was significantly higher during the 1.0/0.0 discrimination phases, even though overall reinforcement probability remained constant. For 3 of 4 birds, in fact, initial-link response rates were higher than terminal-link response rates, an outcome that can be ascribed only to the potent conditioned reinforcement properties of the middle-link stimulus during the discrimination phases. Results are incompatible with any account of chain behavior based solely on relative time to reinforcement.

Addressing Antimicrobial Resistance to Treat Children With Atopic Dermatitis in a Tertiary Pediatric Allergy Clinic

Background. Secondary skin infection with Staphylococcus aureus is a significant problem in atopic dermatitis (AD) patients. Objective. This study evaluated antimicrobial resistance patterns of S aureus isolates from skin lesions in AD patients and empiric antimicrobial prescribing patterns. Methods. Resistance patterns from positive skin cultures obtained from AD patients in the Allergy/Immunology clinic from May 1, 2006, to December 31, 2008, were compared with all outpatient wound cultures over the same period. Results. Fifty-nine cultures were obtained from 38 AD patients. S aureus was the most common pathogen cultured from AD patients (53/59 cultures). S aureus resistance to clindamycin and methicillin differed significantly between the study group and the outpatient reference population (37.7% vs 9.4% and 45.3% vs 76.4%). Clindamycin was the most commonly prescribed antimicrobial (59%). Overall, 31.4% of organisms showed resistance to the antimicrobial prescribed. Conclusions. Susceptibility profiles of S aureus isolates from AD patients vary significantly from that of the general population.