Robert S. Call

Risk factors for asthma in inner city children

Inner city children have the highest prevalence and the highest mortality rates for asthma in the United States. The purpose of this study was to evaluate sensitization and exposure to common indoor allergens among children aged 3 years to 15 years seen for treatment of asthma at Grady Memorial Hospital, Atlanta, Ga. Eighty children in this study were enrolled in the emergency department and 64 in hospital clinics. Dust from 57 homes, assayed for three indoor allergens (dust mite, cat, and cockroach), revealed similar exposure for asthma and control groups. Sixty-nine percent of the children with asthma had IgE antibodies to dust mite, cockroach, or cat; only 27% of the control subjects were similarly sensitized (p < 0.001). Of 35 children with asthma 21 had both sensitization and significant exposure to the relevant allergen; this was true for only 3 of 22 control subjects (odds ratio, 9.5; p < 0.001). Neither sensitization nor exposure to cat allergen was common in this population. The results show that black children in inner city Atlanta are exposed to high levels of mite and cockroach allergens and that a high proportion of the children with asthma are sensitized to these allergens; the combination of sensitization and exposure is a major risk factor for asthma in this population.

Association of sensitization to Alternaria allergens with asthma among school-age children

BACKGROUND Molds in the Alternaria genus, normally found on outdoor vegetation, produce some of the most common fungal allergens to elicit a skin test response. OBJECTIVES The objectives of this study were to evaluate a serum assay for IgE antibodies to Alternaria allergens and to establish the prevalence of sensitization to Alternaria allergens among children and adults enrolled in epidemiologic studies of asthma. In addition, the significance of sensitization to Alternaria allergens as a risk factor for asthma was compared with that of sensitization to indoor allergens or pollens. METHODS Using the Pharmacia Capsulated Hydrophobic Carrier Polymer (CAP) system, we have evaluated the significance of Alternaria allergens by using sera from several epidemiologic studies of asthma. RESULTS Comparisons between serum assays and skin test results suggest that this in vitro assay yields results similar to those for traditional RASTs and is as sensitive as skin prick testing. In each of the groups studied, sensitization to Alternaria allergens was more common among asthmatic than control subjects, and in two studies the relationship was highly significant. Alternaria allergens were significantly associated with asthma in middle schools in Charlottesville, Virginia and Los Alamos, New Mexico but not in Albemarle County, Virginia. Logistic regression analysis of the results for the three schools identified an association between sensitization to Alternaria allergens and asthma independent of, but not as strong as, that found between sensitization to indoor allergens and asthma (p < 0.001). CONCLUSIONS The Pharmacia CAP system is a useful tool for measuring specific IgE to Alternaria allergens. Although not as important as sensitization to dominant local indoor allergens, sensitization to Alternaria allergens appears to be a significant independent risk factor for asthma in children in some locations of the United States.

Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis

BACKGROUND Perennial allergic rhinitis (PAR) is a persistent allergic inflammation of the upper respiratory tract due to year-round allergen exposure. OBJECTIVE To evaluate the leukotriene receptor antagonist montelukast for the treatment of PAR. METHODS Protocol 265 was a 2-arm study performed during the winter. After a placebo run-in period, adults with perennial allergen sensitivity and active symptoms of PAR were randomized to receive 10 mg of montelukast (n=1002) or placebo (n=990) once daily during a 6-week, double-blind, active-treatment period. The primary end point was the daytime nasal symptoms score, defined as the average of scores for nasal congestion, rhinorrhea, and sneezing rated daily by patients. RESULTS Statistically significant improvements in PAR symptoms were seen in patients treated with montelukast. Their daytime nasal symptoms scores were reduced during treatment compared with those of the placebo group: the difference between treatments in least squares mean change from baseline was -0.08 (95% confidence interval [CI], -0.12 to -0.04; P < .001). Montelukast treatment also improved global evaluations of allergic rhinitis by patients and Rhinoconjunctivitis Quality of Life Questionnaire scores: differences vs the placebo group were -0.15 (95% CI, -0.27 to -0.04; P < .01) and -0.15 (95% CI, -0.24 to -0.06; P < .001), respectively. Other end points that showed statistically significant improvement with montelukast treatment were nighttime symptoms and each of the 4 nasal symptoms (congestion, rhinorrhea, sneezing, and itching). The treatment effects of montelukast were stable and persistent during the entire 6 weeks of treatment. CONCLUSION Montelukast provided statistically significant relief of PAR symptoms during 6 weeks of treatment.

Investigating severe and fatal asthma.

BACKGROUND Severe asthma continues to present a major therapeutic problem despite advances in our understanding of the disease. Innovative ideas for investigating the underlying causes and treatment of severe asthma are few, and many patients still become dependent on oral steroids. We describe two separate studies: first, a prospective investigation measuring the responses of persons with severe asthma to an allergen-free environment; second, a retrospective analysis of factors associated with eight fatalities and one near fatality caused by asthma exacerbations. METHODS In the prospective study 17 persons with severe asthma were admitted to a hospital clinical research unit containing an allergen-free room for steroid dose reduction. Peak flow measurements, treatment requirements, and evidence of infection were followed up. In the retrospective study, the cases of nine patients who had been evaluated for asthma and who subsequently died during an asthma attack were reviewed; where possible allergen levels in their house dust and specific IgE antibodies to common indoor allergens were measured. RESULTS Analysis of the patients in the prospective study revealed two categories of responses to steroid dose reduction: (1) asthmatic persons who either maintained or improved peak flow values on steroid reduction; these patients were predominantly allergic to indoor allergens; (2) asthmatic persons whose condition deteriorated; these patients were unable to tolerate reduction in steroid dose. The second group included persons with sensitization to fungal antigens who had asthmatic exacerbations in association with culture-documented fungal colonization. The retrospective study revealed that in five of the eight fatalities caused by asthma, exposure to a relevant allergen had occurred at home before death. CONCLUSION Some steroid-dependent persons with severe asthma are allergic to inhalant allergens and may benefit from avoiding allergens. In some cases there is no evidence that antigen exposure from diet, inhalants, fungal infections, or sinusitis is relevant to their disease. However, persons with severe asthma include individuals infected with and sensitized to fungal antigens. The results suggest that cases of severe asthma should be investigated to identify treatable causes.

Dust Mite Allergen Avoidance in the Treatment of Hospitalized Children with Asthma

BACKGROUND Asthma is a leading cause of hospital admission in children. The majority of children with asthma are sensitized and exposed to inhalant allergens that may contribute to chronic airway inflammation. OBJECTIVE To evaluate the practicality and effects of dust mite (D. farinae and D. pteronyssinus) allergen avoidance in homes of children hospitalized with acute asthma. METHODS Children 5 to 18 years of age who were admitted with asthma to a suburban Atlanta hospital were randomly assigned, without knowledge of allergen sensitization or exposure in their houses, to active (n = 13) or placebo (n = 10) treatment group. Active treatment included encasing mattress, box springs, and pillows in allergen impermeable covers; weekly hot water wash of bed linens; replacement of bedroom carpet with polished flooring; and 3% tannic acid spray to living room carpet. Placebo treatment included permeable encasing for bedding, cold water wash, and water spray for carpet. Dust samples were analyzed for dust mite, cockroach, and cat allergens, while serum samples were analyzed for IgE antibodies to the same allergens. Outcome measures included daily peak expiratory flow rates, spirometry, methacholine inhalation challenge, and hospital readmission. RESULTS Children in both groups were similar by demographics, sensitization, and exposure to dust mite allergen. Allergen levels fell > 3-fold in many active and placebo homes. Children in the active group had improved PEFR at 3 and 6 months after intervention (P < .04, P < .05, respectively). Six of seven children in the study who were sensitized and exposed to dust mite allergen demonstrated improved PEFR at 3 months when allergen levels fell in both bedding and bedroom floor. There was no difference in FEV1 or methacholine challenge, although a few children in either group could tolerate methacholine because of bronchial hyperreactivity. Six children (four active and two placebo) were readmitted to hospital during the study. CONCLUSION Increases in PEFR were recorded among children in the active treatment group and also among sensitized patients whose dust mite allergens fell. These results support the hypothesis that avoidance can be effective even among children admitted to hospital. The study was complicated by insufficient numbers of mite-allergic children and poor compliance with diaries and the protocol. Recruitment from the hospital resulted in participants with more severe asthma than anticipated. The results also suggest that many of the patients in this group will continue to have exacerbations triggered by upper or lower respiratory tract infections.

The association of hypersensitivity diseases with Dermatophyte infections

Natural exposure to foreign antigens induces immune responses, which may be protective or may give rise to hypersensitivity disease. In general, the distinctions are clear, and it is relatively easy to classify immune responses in this way. Thus, Diphtheria toxoid/toxin produces protective IgG antibodies; pollen antigens induce immediate hypersensitivity; a delayed hypersensitivity response induced by BCG was considered to be protective and poison ivy induces contact sensitivity. However, there are antigens where the line between protective and allergic responses becomes blurred. A good example of these is the Dermatophyte fungi of the genus Trichophyton. It is well known that delayed hypersensitivity skin tests and in vitro T cell responses to Trichophyton are common among adults [1]. Indeed, Trichophyton extract is included as part of the battery of skin tests used to evaluate delayed hypersensitivity. However, it has been repeatedly reported that some patients with chronic intertrigo or fungal nail infections have weal and flare skin responses to Trichophyton extracts [2-5]. More recently, it has been confirmed that these weal responses correlate with serum IgE antibodies to Trichophyton [4,5]. Thus, athletes foot infections can give rise to either immediate or delayed hypersensitivity. We have also reported the purification of an allergen Tri t I from T. tonsurans, which binds IgE antibodies but does not give delayed responses [6]. This suggests that the two forms of immune responses are directed against different proteins. The difference in immune response may be relevant to both protective immunity and associated allergic responses. Both Hay, and Honbo and Jones, separately suggested that patients who develop immediate hypersensitivity tend to have more severe fungal infection of the skin [3,4]. However, this is more difficult to evaluate today because of the availability of potent topical antifungals. On the other hand there have been persistent reports associating urticaria, rhinitis and asthma with the combination of fungal infection and specific IgE antibodies [2,5,7,8,9]. The first reports were from Sultzberger and his colleagues in the 1930s, who recommended that Trichophyton skin tests should be part of the routine evaluation of allergic patients [2]. In the current issue comes a report from Israel confirming that there are patients presenting with perennial rhinitis who have both immediate hypersensitivity skin tests and chronic Trichophyton infections [10]. They also report that some of the patients responded to treatment with systemic antifungals. There are several interesting features of this report, in particular the diagnosis was made with prick tests (i.e. the diagnosis did not require intradermal skin tests); in addition, they report that their patients did not have chronic sinusitis. Our experience is that many of the Trichophyton sensitive patients who present with asthma have chronic sinusitis with or without nasal polyps. Some of these cases had presented to ENT surgeons with sinusitis several years before they developed asthma [9,11]. In agreement with Dr Kivity and his colleagues, we find that these patients will give positive nasal provocation to Trichophyton [9,10]. However, it is important to distinguish this from patients with fungal sinusitis. Trichophyton is not a nasal pathogen or saprophyte, and repeated attempts to grow this dermatophyte from nasal passages, sinuses or the lungs have been negative [9,11]. Thus, if dermatophyte antigens are contributing to the respiratory tract disease the antigen must either be absorbed or become airborne. It is obviously possible that some patients with severe fungal infection shed sufficient skin scales to create an airborne challenge, and it is known that podiatrists can be sensitized by exposure to Trichophyton antigens presumably while grinding infected toenails [12]. However, we agree with Dr Kivity that this is unlikely to be the primary route of exposure. It is very unusual to induce delayed hypersensitivity by the inhaled route (i.e. with pollens, or mite antigens), thus absorption of antigen is likely to be occurring in some individuals. Similarly, hives is not commonly associated in inhaled allergen but can occur with Trichophyton again suggesting systemic absorption. Finally, our own experience with an immunoassay for Trichophyton allergen {Tri 11) suggests that this allergen is not measurable in dust samples, suggesting again that the airborne route is not important [6]. Trichophyton infection is universal but is probably more common and more severe in hotter climates (e.g. Virginia and Tel Aviv). Indeed, the allergic complications of Trichophyton are widely accepted by allergists practicing in Alabama and Arizona, but are apparently not common in Wisconsin, Maine or the U.K. The real issue is whether the associated allergic disease responds to antifungal treatment. Our own anecdotal experience continues to be good, but it is clearly necessary to carry out double blind placebo controlled trials of antifungal treatment. Controlled trials should be possible using oral Fluconazole, which is very effective against even severe onychomycosis. We certainly continue to see patients with chronic allergic disease whose sole positive skin test

Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis

Background: Long‐term topical treatment is often required for atopic dermatitis (AD), a chronic inflammatory skin disease. Objective: To assess the long‐term safety results from a multicenter, open‐label, 48‐week safety study (AD‐303) of patients (N = 517) ≥2 years of age with mild to moderate AD who continued crisaborole treatment, a topical phosphodiesterase‐4 inhibitor, after completing a 28‐day phase 3 pivotal study (AD‐301, AD‐302). Methods: Global disease severity was assessed in patients every 4 weeks, and if assessed as mild or greater, a 28‐day treatment period with crisaborole applied twice daily was initiated. Adverse events (AEs), including treatment‐emergent AEs (TEAEs), and serious AEs were analyzed. Results: During the pivotal studies and AD‐303, 65% of patients reported ≥1 TEAE, most of which were mild (51.2%) or moderate (44.6%) and considered unrelated to treatment (93.1%). The frequency and severity of TEAEs were consistent. The most frequently reported treatment‐related AEs (overall, 10.2%) were dermatitis atopic (3.1%), application‐site pain (2.3%), and application‐site infection (1.2%). Nine patients (1.7%) discontinued the long‐term study because of TEAEs. Limitations: Long‐term efficacy was not analyzed. Conclusion: Crisaborole ointment had a low frequency of treatment‐related AEs over 48 weeks of treatment of patients with AD.