The effect of BCG vaccine at birth on the development of atopy or allergic disease in young children.

BACKGROUND: Exposure to infectious diseases may reduce the development of asthma or allergy. In particular, the role of the BCG vaccine in modulating asthma or allergy has been a source of speculation. OBJECTIVE: To study newborns from 3 international sites to evaluate the prospective effect of BCG vaccine on allergic diseases or atopic development. METHODS: Infants were enrolled from newborn and well-infant clinics in Thailand, Argentina, and Turkey. The standard BCG vaccine for each country was given at birth. Parents who consented to have their infant included in the protocol completed an allergy family questionnaire. Infants underwent a standard purified protein derivative (PPD) test at 9 to 12 months of age, and the reaction size was measured. At the age of 2 years, the children returned to be studied. Allergy skin tests to common allergens appropriate to location and age were performed, and the parents completed the International Study of Allergy and Asthma in Childhood questionnaire. The PPD reaction size was compared with the presence of atopy and allergy questionnaire responses. RESULTS: A total of 1,704 infants were studied. Statistical significance was found between a negative PPD response vs any positive PPD response and the risk of having an allergic history at the age of 2 years in Turkey (relative risk, 2.11; 95% confidence interval, 1.25-3.55; P = .005) and Thailand (relative risk, 2.16; 95% confidence interval, 1.18-3.94; P = .02) but not Argentina (relative risk, 1.09; 95% confidence interval, 0.70-1.68; P = .70). CONCLUSIONS: This study further supports the role of infectious agents in modulating asthma and allergy development.

Mycobacterial antigens attenuate late phase response, airway hyperresponsiveness, and bronchoalveolar lavage eosinophilia in a mouse model of bronchial asthma.

Allergens, in combination with genetic predisposition, drive undifferentiated T cells towards the type 2 T cells. Some childhood infections may activate the production of a type 1 T cell profile. It is reasonable to speculate that a decrease in childhood infections may increase the incidence of allergy by allowing the immune balance to shift towards the type 2 T cells. We hypothesized that pre-exposure of mycobacterial antigens in sensitized mice would prevent the development of asthma-like conditions. Specifically, we examined the effect of mycobacterial antigens, Bacillus Calmette-Guerin (BCG) vaccine and Mycobacterium vaccae, on antigen-induced bronchoconstriction, airway hyperresponsiveness to methacholine, bronchoalveolar lavage eosinophilia, and plasma IL-4 and IL-12 levels in ovalbumin (OVA)-sensitized and challenged Balb/c mice. Challenge with OVA produced a 2-3-fold increase in bronchoconstriction within 3-5 min, followed by a delayed response after 60 min, the latter of which was significantly attenuated by both BCG and M. vaccae. Airway hyperresponsiveness to methacholine 24 h after OVA challenge was prevented by BCG and M. vaccae. Airway eosinophilia was also prevented by BCG and M. vaccae. The plasma IL-12 levels were significantly increased and plasma IL-4 levels were significantly decreased following BCG or M. vaccae administration in OVA-sensitized and challenged mice. Interestingly, a significant increase in plasma IL-12 was observed with BCG as compared to M. vaccae administration, suggesting a stronger type 1 response to BCG. These data support our hypothesis and suggest that BCG and M. vaccae may prevent the underlying pathophysiological changes in asthma.

The protective effect of brachial plexus palsy in purpura fulminans.

Acute infectious purpura fulminans is reported in a 16-month-old male with a history of posttraumatic asplenia and complete left brachial plexus palsy. This patient developed peripheral necrosis of both lower extremities and the right upper extremity, whereas the left upper extremity was completely spared from ischemia and tissue damage. Amputation of four digits on the right hand and debridement of both lower extremities were required. This patient demonstrated the protective effect of a traumatic sympathectomy, which suggests the requirement of an intact sympathetic reflex in the development of purpura fulminans.

Apoptosis in the murine rd1 retinal degeneration is predominantly p53-independent.

PURPOSE: To determine if p53 mediates apoptosis in photoreceptors of retinal degeneration, rd1, mice. METHODS: The rd1/rd1 mice were interbred with p53 null mice to generate p53-/- rd1/rd1 and p53+/+ rd1/rd1 mice. Rates of loss and incidence of apoptosis in rod photoreceptors were analyzed at appropriate ages (postnatal days 12, 14 and 16). RESULTS: The extent and kinetics of photoreceptor cell loss in rd1 mice were nearly indistinguishable in the p53+/+ and p53 null mice. CONCLUSIONS: Photoreceptor cell apoptosis in the rd1 mouse model occurs by a predominantly p53-independent molecular pathway.

Induction of immune tolerance in a 7-year-old hemophiliac with an anaphylactoid inhibitor.

BACKGROUND: Anaphylactic reactions were a rare complication of low purity VIII concentrates, but not with high purity VIII concentrates. CASE: 7 y/o WM with severe hemophilia A, received only cryoprecipitate and monoclonally purified VIII concentrates; developed post-infusional urticaria. A 2-Bethesda-unit inhibitor was detected. Generalized urticaria and bronchospasm following factor developed as the titer increased. Skin tests demonstrated reactivity to plasma derived VIII, but not recombinant VIII (rhVIII). Attempts at desensitization using rhVIII failed. ELISA revealed an anti-VIII IgE antibody. He was treated with a modified tolerance regimen using rhVIII starting at 500 U/day with aggressive premedication. The dosage increased by 200 U weekly as tolerated to a maximum of 100 U/kg/d without symptoms. RESULTS: His antibody titer decreased rapidly once he started 100 U/kg/d. Six months later, the inhibitor was < 1 Bethesda unit. CONCLUSION: Immune tolerance induction using a graduated dosage of rhVIII was successful.

Cross-sectional study of bone density in asthmatic children.

The emphasis in treatment of asthma in children has shifted from bronchodilators to inhaled anti-inflammatory medications, including inhaled corticosteroids (ICS). Children with chronic asthma and moderate to severe symptoms have been targeted as particularly deserving of maintenance therapy with ICS. We have previously reported a cross-sectional study of bone density in children treated with ICS. There was no significant difference between the total bone density of asthmatic patients and controls. We sought to extend the information available on bone density in asthmatic children by evaluating 15 asthmatic subjects taking daily ICS (beclomethasone dipropionate) and comparing them with age- and sex-matched controls. We compared total and regional bone density, bone age, and calcium intakes in these subjects. Asthmatic subjects were on ICS for 4-60 months, with doses ranging from 200 to 450 micrograms/day. There was no significant difference between asthmatics and matched controls for height, weight, % RDA Ca2+, or bone age. The asthmatic subjects had bone density (total and regional measurements) equivalent to their controls. These results provide additional support for the safety of low-dose ICS on bone density in asthmatic children.

Longitudinal assessment of bone mineral density in children with chronic asthma.

BACKGROUND: With the emphasis on asthma as a chronic inflammatory process, the management of moderate to severe asthma, even in the pediatric population, has shifted to the regular use of inhaled anti-inflammatory agents, including inhaled corticosteroids. Accompanying the use of these agents has been the precaution that long-term use may have subtle or potential side effects, including growth suppression or decreased bone mineral deposition. OBJECTIVE: We sought to study the effects of inhaled anti-inflammatory agents on bone mineral density accumulation in growing asthmatic children. Included in this report is the longitudinal acquisition of bone mineral density in children with moderate to severe asthma. METHODS: Bone mineral density in normal and asthmatic children was measured longitudinally by dual-energy absorptiometry. Bone densitometry was determined twice over a 7- to 16-month period in 21 asthmatic children and a 13- to 60-month period in 14 normals. These children with two longitudinal visits were compared with a group of 107 normal children who had a single bone mineral density measurement. RESULTS: Nineteen of 21 asthmatic children used regular inhaled corticosteroids during the interval visits. The majority of the asthmatic boys had bone mineral density measurements, at both visits, that were at a higher percentile than normal boys with two visits. Asthmatic girls had bone density measurements at percentiles not significantly different than normal girls with two visits. CONCLUSIONS: The advancement of bone mineral density in asthmatic children provides support for the safety of inhaled anti-inflammatory medications on bone mineral density in children with significant asthma.

The usefulness of questionnaire-derived information to predict the degree of nonspecific bronchial hyperresponsiveness.

Nonspecific bronchial hyperresponsiveness (BHR) is a hallmark of clinical asthma, but can be present in nonasthmatics as well. The diagnosis of asthma is based on clinical grounds, and no laboratory procedure can definitely establish its presence. This poses a problem in studies of asthma. If epidemiological studies are to provide valid information, the tools used must have a relative degree of predictive or diagnostic ability. This report determined whether the American Thoracic Society-Division of Lung Disease (ATS-DLD) respiratory questionnaire has the ability to predict different degrees of non-specific BHR. In the years 1983-1990, when the ATS-DLD questionnaire was used in our Natural History of Asthma study, 192 subjects completed the ATS-DLD questionnaire and underwent a standardized methacholine challenge. A recursive partitioning analysis of the ATS-DLD questionnaire was able to predict which questions would likely be answered if the subject had nonspecific bronchial reactivity to inhaled methacholine of 100 and 200 breath units. Positive responses for questions concerning treatment for asthma, wheezing, or shortness of breath, and emergency treatment for asthma predicted the presence of increased bronchial reactivity.

Evaluation of growth hormone secretion in children with juvenile rheumatoid arthritis and short stature.

Children with juvenile rheumatoid arthritis (JRA) often exhibit delayed skeletal development. Previous evaluations of growth hormone (hGH) levels in these children have used single-value blood determinations. We sought to extend information on possible hGH deficiency in children with short stature and JRA by measuring 24-hour hGH pulsatile secretion. Five children with JRA were identified as having a height less than the 3rd percentile, and one child with a height at the 25th percentile. Three of these had abnormally low 24-hour serum hGH secretion. Two underwent a 24-month trial of human recombinant hGH; both exhibited only marginally accelerated growth. These results suggest that children with JRA and persistent short stature may have low hGH secretion without an adequate physiologic response to exogenous hGH administration.

Eosinophil accumulation and activation in antigen-induced late asthmatic response in guinea pigs.

The purpose of this study was to investigate the participation of airway eosinophils in the antigen-induced late asthmatic response (LAR) and increased airway responsiveness in the guinea pig model of asthma. After antigen challenge, guinea pigs sensitized with aerosolized ovalbumin showed a late-phase decrease in specific airway conductance, which was accompanied by airway hyperresponsiveness to histamine, eosinophilia in the bronchoalveolar lavage fluid (BALF), decreased BALF eosinophil density, and increased generation of superoxide anions from purified BALF eosinophils. We demonstrated an association of the LAR with eosinophil accumulation and activation in the airway.

The effect of RP 59227, a platelet-activating factor antagonist, against antigen challenge and eosinophil and neutrophil chemotaxis in asthmatics.

STUDY OBJECTIVES: Platelet-activating factor (PAF), an inflammatory mediator, induces microvascular leak, eosinophil chemotaxis, and possibly increases non-specific bronchial hyperresponsiveness in humans. PAF antagonists may have clinical benefits in asthma. DESIGN: We determined the safety and efficacy of a 240 mg oral dose of RP-59227 in attenuating the early and late phase antigen challenge in eight asthmatics, using a double-blind, placebo-controlled, crossover design. Also determined was the effect of the ex vivo addition of PAF following placebo or drug and the level of neutrophil (NCA) and eosinophil chemotactic activity (ECA) in the serum immediately, and 4 h after antigen challenge with either drug or placebo. RESULTS: There was not a significant difference in the maximum percent fall in FEV1 during the early and late phase on screening or placebo days or drug RP-59227 days. There was a significant inhibitory effect (p < 0.05) in peak ECA and NCA in blood after RP-59227. The addition of PAF to ex vivo serum was less effective in inducing chemotaxis to eosinophils following RP-59227 (p < 0.05). CONCLUSIONS: RP-59227 attenuated the release of NCA and ECA after antigen challenge, and reduced the effect of exogenously added PAF in inducing eosinophil chemotaxis but did not protect against the antigen-induced early or late phase response.

Bone mineral density in normal and asthmatic children.

BACKGROUND: The largest increase in bone mass occurs during childhood and adolescence. A subnormal bone mass is associated with increased risk of fracture. Bone mass is influenced by height, age, race, exercise, and stage of puberty. It is adversely affected by chronic disease states and corticosteroid use. We performed a cross-sectional study of bone density in children with moderate to severe asthma who were treated with inhaled corticosteroids, inhaled cromolyn, oral corticosteroids, or a combination of these, and we compared them with normal children. METHODS: A cross-sectional study of bone density, measured either by dual-photon or dual-energy absorptiometry, was performed on 97 normal white and 30 asthmatic white children, aged 5 to 18. Average daily calcium intake, height, weight, and Tanner stage were determined. The total daily and lifetime doses of inhaled corticosteroids in children with asthma were calculated. T tests, multiple regression, chi square analysis, and analysis of covariance were performed. RESULTS: No significant difference in bone density was demonstrated between children with asthma and normal control subjects. No measure (including calcium intake, Tanner stage, daily or lifetime inhaled corticosteroid dose, or duration of illness), except for height and age, provided a significant contribution to the explanation of bone density in children with asthma. CONCLUSION: Children and adolescents with moderate to severe asthma, including those treated with inhaled corticosteroids, do not appear to have adversely affected bone mass. There was, however, the possibility of a type II error in this study because of the sample size.

Effect of terfenadine on human eosinophil and neutrophil chemotactic response and generation of superoxide.

Second generation antihistamines have been reported to have anti-inflammatory properties in addition to their potency as H1 antagonists. In this in-vitro study, we evaluated the effect of terfenadine on platelet activating factor-(PAF)-induced or N-formyl-methionyl-leucyl-phenylamine-(FMLP)-induced human eosinophil and neutrophil chemotactic responses; and on superoxide anion generation from human eosinophils and neutrophils activated by either PAF, calcium ionophore (A23187) or phorbol myristate acetate. Since eosinophil degranulation is also associated with tissue inflammation, we further examined the effect of terfenadine on the PAF-induced release of eosinophil cationic protein. The peak concentration of terfenadine-related materials in serum of adult individuals after 60 mg of oral administration has been reported to be 351 +/- 0.4 ng/mL. We therefore used 100 to 1000 ng/mL concentrations of terfenadine. Purified normodense-eosinophils and neutrophils were obtained by discontinuous gradient from allergic subjects. We observed that terfenadine had greater inhibitory effects on eosinophils than neutrophils in both chemotactic response and superoxide generation. Terfenadine, at concentrations of 500 and 1000 ng/mL, significantly inhibited PAF-induced and FMLP-induced eosinophil chemotaxis, whereas 1000 ng/mL of terfenadine was necessary to suppress neutrophil chemotaxis. Terfenadine, at concentrations achievable at standard dosing regimens, has anti-inflammatory properties in vitro.

Longitudinal measurement of airway hyperresponsiveness in selected subjects with persisting pulmonary symptoms.

The relationship between airway hyperresponsiveness and pulmonary symptoms was examined longitudinally in 52 subjects. Subjects were part of a larger study, the Natural History of Asthma, and had repeated measures of airway hyperresponsiveness using methacholine. Atopy was determined using skin tests and serum IgE levels. The subjects completed a standardized respiratory questionnaire. Each subject reported respiratory and pulmonary symptoms at either their initial or follow-up visit. The subjects did not, however, have a physician-confirmed diagnosis of asthma. Subjects were divided into groups according to the current status of their respiratory symptoms. The four groups included subjects who were initially normal but developed respiratory symptoms at follow-up; subjects who had symptoms at all visits; subjects with respiratory symptoms at their initial visit but who had no symptoms at follow-up; and subjects who had respiratory symptoms prior to their initial visit and who did not have a recurrence during follow-up. There was no statistical difference in airway hyperresponsiveness, IgE, or skin test scores at the initial visits. Subjects who had airway responsiveness were significantly more atopic than subjects who did not have airway responsiveness. Subjects were classified as "consistently positive," "variable," or "consistently negative" responders according to the pattern of methacholine-induced airway hyperresponsiveness. Overall, among the four groups, 33% were consistently positive at all visits, 43% were variable, and 22% were consistently negative. Airway hyperresponsiveness was statistically associated with atopy, but not necessarily associated with questionnaire-based respiratory symptomatology. These factors need to be considered in epidemiological studies of asthma utilizing respiratory questionnaires.

Effect of cetirizine on human eosinophil superoxide generation, eosinophil chemotaxis and eosinophil peroxidase in vitro.

Cetirizine, a potent H1-antagonist, has been reported to inhibit eosinophil migration into human skin. We, therefore, further evaluated the effect of cetirizine on eosinophil function, including superoxide anion generation, chemotaxis, and eosinophil peroxidase (EP) release. In allergic subjects, superoxide anion generation 60 min after platelet-activating factor (PAF) activation was inhibited by concentrations of cetirizine ranging from 0.01 to 1 microgram/ml (2.612 x 10(-8) to 2.612 x 10(-6) M). No significant inhibition was observed in normal subjects. PAF (10(-6) M)-induced eosinophil chemotaxis was also inhibited by cetirizine. In allergic subjects, percent inhibitions were 47.5 +/- 6.1% at 0.01 microgram/ml, 50.8 +/- 5.1% at 0.1 microgram/ml and 58.9 +/- 6.4% at 1 microgram/ml of cetirizine. In allergic subjects, N-formyl-methionyl-lencyl-phenylalanine induced eosinophil chemotaxis was inhibited by cetirizine, although EP release was not. These results suggest cetirizine has effects on eosinophils which can not be explained by H1-blockade alone.

Importance of interleukin-3 on histamine release from human basophils.

We investigated the effects of interleukin-3 (IL-3) on histamine release (direct releasing and indirect enhancing effects) from basophils in allergic asthmatic subjects. Interleukin-3 caused direct histamine release (HR) in selected donors (IL-3 responders) and enhanced anti-IgE-induced HR in other IL-3 nonresponders, although both direct releasing and indirect enhancing activities of IL-3 on HR did not coexist with each other. There was a significant correlation between IL-3-induced HR and spontaneous histamine release (r = .8532, P < .0001).