Cough during infancy and subsequent childhood asthma.

OBJECTIVES: Wheezing in infancy has been associated with subsequent asthma, but whether cough similarly influences asthma risk has been little studied. We sought to determine whether prolonged cough and cough without cold in the first year of life are associated with childhood asthma. METHODS: Participants in the Infant Immune Study, a non-selected birth cohort, were surveyed 7 times in the first 9 months of life regarding the presence of wheeze and cough. Cough for more than 28 days was defined as prolonged. Parents were asked at 1 year if the child ever coughed without a cold. Asthma was defined as parental report of physician diagnosis of asthma, with symptoms or medication use between 2 and 9 years. Logistic regression was used to assess adjusted odds for asthma associated with cough characteristics. RESULTS: A total of 24% (97) of children experienced prolonged cough and 23% (95) cough without cold in the first 9 months, respectively. Prolonged cough was associated with increased risk of asthma relative to brief cough (OR 3.57, CI: 1.88, 6.76), with the risk being particularly high among children of asthmatic mothers. Cough without cold (OR 3.13, 95% CI: 1.76, 5.57) was also independently associated with risk of childhood asthma. Both relations persisted after adjustment for wheeze and total IgE at age 1. CONCLUSIONS AND CLINICAL RELEVANCE: Prolonged cough in infancy and cough without cold are associated with childhood asthma, independent of infant wheeze. These findings suggest that characteristics of cough in infancy are early markers of asthma susceptibility, particularly among children with maternal asthma.

Relation of early antibiotic use to childhood asthma: confounding by indication?

BACKGROUND: Findings from studies of the relation between early antibiotic use and subsequent asthma have been inconsistent, which may be attributable to methodologic issues. OBJECTIVE: Our objective was to assess the impact of confounding by indication on the relation of early antibiotic use to childhood asthma through age 5 in a non-selected birth cohort (n=424). METHODS: Oral antibiotic use was assessed by frequent nurse interviews in the first 9 months of life. Physician-diagnosed active asthma and eczema were assessed by questionnaire at 1, 2, 3, and 5 years, and were considered as ever asthma or ever eczema if positive at any age. Allergen-specific IgE was assessed in plasma at 1, 2, 3, and 5 years. Confounding by indication was investigated by considering the relation of asthma to antibiotic use while controlling for the number of illness visits to a physician in early life. RESULTS: There was no statistically significant relation of early antibiotic use with physician-diagnosed eczema or allergen-specific IgE. A dose-response relation was evident for antibiotic use with ever asthma (odds ratio [OR]=1.5, P=0.047). Ever asthma also increased significantly with the number of illness visits to a physician (P<0.001). After adjustment for number of illness visits, antibiotic use showed no relation with asthma. CONCLUSIONS: The relation of asthma to antibiotics in this cohort appears to be an artefact of the strong relation of number of physician visits for illness with both antibiotic use and risk for asthma.

Decreased activation of inflammatory networks during acute asthma exacerbations is associated with chronic airflow obstruction.

Asthma exacerbations are associated with subsequent deficits in lung function. Here, we tested the hypothesis that a specific pattern of inflammatory responses during acute exacerbations may be associated with chronic airway obstruction. Gene coexpression networks were characterized in induced sputum obtained during an acute exacerbation, from asthmatic children with or without chronic airflow limitation. The data showed that activation of Th1-like/cytotoxic and interferon signaling pathways during acute exacerbations was decreased in asthmatic children with deficits in baseline lung function. These associations were independent of the identification of picornaviruses in nasal secretions or the use of medications at the time of the exacerbation. Th2-related pathways were also detected in the responses, but variations in these pathways were not related to chronic airways obstruction. Our findings show that decreased activation of Th1-like/cytotoxic and interferon pathways is a hallmark of acute exacerbation responses in asthmatic children with evidence of chronic airways obstruction.

Dynamic changes in sensitization to specific aeroallergens in children raised in a desert environment.

BACKGROUND: Allergen skin test reactivity and total serum IgE are objective measures used to characterize and help diagnose allergic diseases. Cross-sectional studies have shown that overall aeroallergen skin test reactivity increases throughout childhood. However, little attention has been paid to whether individual aeroallergen remittance occurs, which could distort or mask relationships to disease. OBJECTIVE: To access the incidence and remittance of skin test reactions to individual allergens in children aged 6-11 years. METHODS: Longitudinal sensitization to six aeroallergens and total IgE were assessed in 828 children raised in the semi-arid US southwest at ages 6 and 11 years. RESULTS: New sensitization (to any allergen) between 6 and 11 years occurred in 30.2% of children compared with 39.7% before age 6 years. The rate of complete remittance from positive to negative between ages 6 and 11 years was 8.2%, and total IgE at age 6 years was not predictive. Remittance rates for individual allergens were high and variable (19-49%). The perennial allergens Bermuda and Alternaria were early sensitizers and had low remittance rates. Early sensitization to the four seasonal allergens was less common and more subject to remittance with the bulk of sensitization occurring between 6 and 11 years. CONCLUSION: This study shows that sensitization to individual aeroallergens in childhood is dynamic and indicates the limitation of single point assessment of skin test reactivity.

Relation between infantile colic and asthma/atopy: a prospective study in an unselected population.

OBJECTIVE: To assess whether children with history of infantile colic may be at increased risk of subsequently developing asthma and/or atopy. METHODS: We used data collected in a large, prospective study from an unselected population. Infantile colic and concurrent feeding method were determined from the 2-month well-infant visit form completed by the physician for 983 children who were enrolled at birth. Markers of atopy (total serum immunoglobulin E and allergy skin prick test), allergic rhinitis, asthma, wheezing, and peak flow variability were the main outcome measures studied at different ages between infancy and 11 years. RESULTS: Ninety (9.2%) children had infantile colic. Prevalence of colic was similar among children fed either breast milk or formula. There was no association between infantile colic and markers of atopy, asthma, allergic rhinitis, wheezing, or peak flow variability at any age. CONCLUSION: Our data cannot support the hypothesis that infantile colic provides increased risk for subsequent allergic disease or atopy.

The association of allergic sensitization in mother and child in breast-fed and formula-fed infants.

Human milk contains immunologically active substances potentially capable of altering infant immune response. As part of the prospective Children's Respiratory Study, we assessed whether the association between maternal allergic status and allergic status of the child was altered by breast-feeding. Skin-prick tests for 7 common allergens were administered to 702 6-year-old children and their mothers. The percentage of children sensitized to specific allergens, maternal skin test response to that allergen, and whether or not the child was ever breast-fed was determined. Findings indicated that specific sensitization in the mother was associated with specific sensitization in the child only if the child was breast-fed. This indirectly supports the hypothesis that contents of milk differ with maternal allergic status, and appear to affect allergic status in the child. These results suggest that milk from allergic mothers either promotes a Th2 type immune response or suppresses Th1 immune response in the child.

Two subphenotypes of childhood asthma that differ in maternal and paternal influences on asthma risk.

Asthma is a phenotypically heterogeneous disease. Two subgroups are defined here based initially on skin test reactivity to the allergen Alternaria at age 6 from among a large population of children born and raised in the Southwestern desert environment of Tucson, Arizona. When compared with asthma among Alternaria-positive subjects, asthma among Alternaria-negative subjects was associated with lower levels of total serum IgE, no relation to local aeroallergen skin tests, a younger age at diagnosis, greater remittance by age 11, and more frequent wheezing lower respiratory illnesses (LRIs) in the first year of life. Despite the difference in total serum IgE, however, IgE concentrations were significantly higher in each asthma group compared with its respective control group. Asthma in each parent contributed approximately equivalent risk for Alternaria-positive asthma in the child. However, neither parental skin test sensitization nor total serum IgE levels provided risk for asthma in the child. Inheritance patterns for Alternaria-negative asthma revealed a contribution from maternal but not paternal asthma. Thus, dividing asthma in children at age 6 into Alternaria-positive and Alternaria-negative groups identifies subphenotypes that are further distinguished by differences in phenotypic markers and parental influences.

Differential immune responses to acute lower respiratory illness in early life and subsequent development of persistent wheezing and asthma.

BACKGROUND: Recent epidemiologic evidence suggests that 2 wheezing syndromes coexist in early life: transient wheezing, limited to early childhood, and persistent wheezing, which starts in early childhood and persists beyond that age. OBJECTIVE: Whether the nature of the immune response occurring during acute lower respiratory illnesses (LRIs) in infancy differs between these 2 groups of wheezers has yet to be determined. METHODS: We compared total serum IgE levels and peripheral blood eosinophil counts obtained during the acute phase of the first LRI with those obtained during the convalescent phase or with well-baby samples in persistent (n = 49) and transient early wheezers (n = 88), as well as in children who had only nonwheezing LRIs (n = 43) during the first 3 years of life. RESULTS: Total serum IgE levels were significantly higher (P =.008) during the acute phase compared with the convalescent phase of the LRI in persistent wheezers, a response not observed in transient early wheezers (P =.7). Peripheral blood eosinophil counts were significantly reduced during the acute phase of the LRI (P =.009) in transient early wheezers, a response not observed among persistent wheezers (P =.7). Acute responses in children who had nonwheezing LRIs only were similar to those seen in transient early wheezers. CONCLUSION: Alterations in acute immune response to viral infection may be detected at the time of the first wheezing episode in subjects who will go on to have persistent wheezing symptoms.

Selective expansion of Vgamma2-Vdelta7 TCR gammadelta cells in C57BL/6 mice is postnatal and extrathymic.

Previous studies have shown that TCR-gammadelta cells expressing Vgamma2 region elements are selectively expanded in vivo in C57BL/6 (B6), but not DBA/2, mice. Genetic analysis demonstrated that the expansion of Vgamma2+ was linked to the TCR alphadelta loci, suggesting that a particular Vgamma-Vdelta pair may be necessary for the expansion. In the studies presented here, we find that the expanding TCR gammadelta cells in B6 mice express a Vgamma2+/Vdelta7+ TCR. The Vgamma2-Jgamma and Vdelta7-Ddelta-Jdelta junctional amino acid sequences of these cells display wide variation in length, suggesting that expansion is based on variable region usage and not junctional diversity. The kinetics and dynamics of Vgamma2+/Vdelta7+ T cell expression were studied to determine the biological basis of clonal expansion. Although expression of the Vgamma2+ cells in B6 and DBA/2 neonates was similar, Vgamma2+ cells in the B6 mice expanded fourfold by 4 wk of age, while the expression in DBA/2 mice remained constant. In addition, expansion of the Vgamma2+ cells occurred in athymic nude mice, suggesting that expansion was driven by extrathymic stimuli. Finally, B6 mice housed under germfree conditions expressed expanded levels of Vgamma2+ gammadelta T cells similar to their normally housed counterparts. Thus, expansion and diversification of Vgamma2+/Vdelta7+ T cells are postnatal extrathymic events that do not require microbial antigenic exposure.

Alternaria as a major allergen for asthma in children raised in a desert environment.

The relationships of asthma and allergic rhinitis with individual immediate skin test responses were examined for preferential associations and for changes with age in children raised in a semiarid environment. Prevalence of physician-diagnosed asthma was 9.8% at age 6 (n = 948) and 15.5% at age 11 (n = 895). Immediate skin test responses to Bermuda grass were the most prevalent among children with allergic rhinitis and control subjects, whereas responses to the mold, Altenaria alternata, were the most prevalent among asthmatics. Skin test responses for crude house dust, Dermatophagoides farinae, and cat had low prevalences in all groups. By logistic regression, Alternaria was the only allergen independently associated with increased risk for asthma at both ages 6 and 11. Allergic rhinitis showed independent association with sensitization to Bermuda grass and mulberry tree pollen at age 11 but did not show an independent relation to any single allergen at age 6. Logistic regression further revealed that persistent asthma (diagnosed before age 6) was independently associated with Alternaria skin tests at both ages 6 and 11, whereas new asthma (diagnosed after age 6) was associated with Alternaria skin tests at age 6 but not at age 11. We conclude that Alternaria is the major allergen associated with the development of asthma in children raised in a semiarid environment and that skin test responses at age 6 are more closely linked to asthma than those at age 11.

Serum levels of the soluble low affinity receptor for IgE and soluble interleukin-2 receptor in childhood, and their relation to age, gender, atopy and allergic disease.

Identifying immune factors associated with the development of atopy can enhance our understanding of the in vivo mechanisms involved and may have utility in paradigms designed to prevent disease. Two candidates suggested for such roles are the soluble low affinity receptor for IgE (sCD23) and the soluble interleukin-2 receptor (sCD25). To assess serum levels of these factors blood samples were collected at birth and at age 6 in a large nonselected population from Tucson, AZ. Log mean sCD23 and sCD25 levels decreased from birth to age 6, (for sCD23 0.60 ffi 0.26pg/l, n = 340 and 0.53 + 0.28pg/l, n = 333 and for sCD25 1.95 i 0.14pM, n = 304 and 1.86 ffi 0.20pM, n = 327, for the two ages respectively. Anglo children had lower sCD23 levels at birth compared to Hispanic children (p < 0.01); no effect of gender was observed. Skin test reactivity at age 6 was directly related to sCD25 levels at age 6 (p = 0.007) and even levels at birth showed a similar trend (p = 0.06). These relations were distinct from any relation to total serum IgE. No relation was observed with sCD23 levels for either skin test reactivity or serum IgE. The prevalences of asthma, rhinitis and eczema by age 6 were unrelated to sCD25 or sCD23 levels. The results indicate that soluble CD23 and CD25 have higher levels at birth than later in childhood and that the development of skin test reactivity may be associated with regulatory mechanisms involving sCD25, whereas sCD23 was not similarly implicated.

Association of interleukin-2 and interferon-gamma production by blood mononuclear cells in infancy with parental allergy skin tests and with subsequent development of atopy.

The mechanisms regulating the onset of atopic sensitization in human beings are not yet fully clarified. We assessed the capacity of mitogen-stimulated umbilical and peripheral blood mononuclear cells to produce interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) at birth and at 9 months of age in 159 infants. Mononuclear cell production of both IFN-gamma and IL-2 at 9 months, but not at birth, was found to be inversely related to parental immediate skin test reactivity to seven local aeroallergens. Skin test reactivity at the age of 6 years was also inversely related to IFN-gamma and IL-2 production at 9 months of age. However, no relationship was evident between total serum IgE levels at 6 years and production of these cytokines at 9 months. The proportions of circulating lymphocytes and CD4+ or CD8+ cells were also unrelated to skin test reactivity at the age of 6 years. These data suggest that mechanisms regulating skin test reactivity to inhaled allergens may involve deficient IFN-gamma production, deficient IL-2 production, or both during or preceding the time of initial sensitization and that additional mechanisms are involved in regulating total serum IgE level.

Association of non-wheezing lower respiratory tract illnesses in early life with persistently diminished serum IgE levels. Group Health Medical Associates.

BACKGROUND: The role of lower respiratory tract illnesses (LRIs) in the development of allergies is not well understood. The relation of wheezing and non-wheezing LRIs to serum IgE levels and atopy was studied in 888 children. METHODS: Total serum IgE levels were measured at birth, nine months and six years of age; and interferon gamma production by blood mononuclear cells was measured at birth and nine months. Atopy was determined by skin prick tests at age six. Wheezing and non-wheezing LRIs up to age three were diagnosed by a physician. RESULTS: Cord serum IgE levels were similar between all LRI groups and the no LRI group. Children who had wheezing LRIs until the age of three had IgE levels at nine months and at six years within normal ranges for age. In contrast, children who had a non-wheezing LRI before the nine month IgE sample had lower IgE levels at nine months and six years (geometric mean 1.8 IU/ml and 9.9 IU/ml, respectively) compared with children who had no LRIs (3.9 IU/ml and 38.3 IU/ml, respectively). Children who had non-wheezing LRIs after the nine month IgE sample had normal nine month IgE levels (3.2 IU/ml) but decreased IgE levels at six years of age (15.7 IU/ml). Children with more than one non-wheezing LRI before the age of three were less likely to be atopic than those with no LRI (odds radio 0.2). Interferon gamma production was higher in the non-wheezing LRI group at nine months than in the no LRI or wheezing LRI groups. CONCLUSIONS: Non-wheezing LRIs are associated with subsequent depression of IgE levels and reduced skin test reactivity.

A new low-frequency red cell antigen, 'SARAH'.

There are more than 100 low-frequency antigens (LFAs) which have been given International Society of Blood Transfusion (ISBT) numbers as members of systems, collections or the 700 series. In addition, there are a number of well-known (to reference laboratories) unpublished LFAs. The presence of an LFA was suspected when 2 sera were found to react with a single example of K homozygous cells. Anti-K reacting with K homozygotes was eliminated on testing with other KK cells. Testing of the reactive cell with antibodies to known LFAs and the reactive sera with cells known to carry LFAs failed to identify the specificity. A study on the family of the cell donor showed inheritance of the antigen in two generations. Further testing, which included immunoblotting and RFLPs, was carried out in Australia, the UK, Canada and the USA. By March 1993 all published LFAs had been excluded, and an application was made to the ISBT to have the antigen, SARAH, assigned a 700 series number. In April the number 700.052 was provisionally designated for this new antigen.

Pure anti-Doa stimulated by pregnancy.

Pure anti-Doa stimulated by pregnancy was detected in 2 non-transfused females during routine antenatal screening. Anti-Doa occurs rarely and has generally been reported in combination with other antibodies. The first, and only report to date, of pure anti-Doa was also stimulated by pregnancy. We believe these instances to be only the second and third reported cases of pure anti-Doa.

Peripheral T cell receptor gamma delta variable gene repertoire maps to the T cell receptor loci and is influenced by positive selection.

Although the mechanisms that determine TCR-alpha beta V gene repertoire are well studied, the genetic influences involved in TCR-gamma delta repertoire development are unclear. Unlike the TCR-gamma delta populations that localize in epithelial tissues, the circulating peripheral TCR-gamma delta V region repertoire is quite diverse. Previous studies have shown that three TCR-gamma chains and at least six TCR-V delta genes are expressed by splenic TCR-gamma delta cells. However, the relative frequency of individual gamma delta subsets among genetically diverse mice has not been determined. Therefore, the repertoire of TCR-gamma delta cells was examined using anti-TCR V region specific mAb against V gamma 2 and V delta 4 on TCR-gamma delta + cells from total splenocytes. We found that there was a strain-specific variation in TCR-gamma delta usage. The frequency of V gamma 2 expression in different strains varied from 54 to 12%, and the frequency of V delta 4 expression in different strains varied from 38 to 10%. However, the level of V delta 4 and V gamma 2 expression for an individual strain was highly consistent from experiment to experiment. F1 analysis between parental strains that differed in relative frequency of either V gamma 2+ or V delta 4+ cells revealed that high expression was genetically dominant, suggesting that positive selection events play a major role in the peripheral gamma delta repertoire. Variations in the levels of V gamma 2+ cells and V delta 4+ cells was not associated with Mls or MHC haplotype. Analysis of recombinant inbred strains revealed that high V delta 4 expression mapped to the TCR-gamma locus, while high V gamma 2 expression was influenced by the TCR-delta locus. Back-cross analysis confirmed that the TCR loci dominantly influenced the level of V delta 4+ cells and V gamma 2+ cells; however, there was clear evidence that multiple genes affect the TCR-gamma delta repertoire.

Lymphocyte subpopulation number and function in infancy.

Normal values for percentages of lymphocyte subpopulations and functional responses to mitogen stimulation in infancy are not well established. In the present study, lymphocyte subpopulations were examined in umbilical cord blood samples and in peripheral blood samples drawn before 7 and 24 months of age (mean age 10.4 months) from a healthy population of infants born in Tucson, Arizona. Results indicate significant increases occurred from birth to later infancy in the percentages of total T cells (CD3), T-cell subsets (CD4, CD8) and B cells (CD20). The CD4/CD8 ratio and the functional responses to ConA and PWM mitogens significantly decreased from birth to later infancy. PHA responsiveness did not show a significant change. Results from cross-sectional analyses (n = 271) were supported in a smaller longitudinal subset (n = 37). There were no detectable ethnic- or gender-related differences in cord blood or samples obtained in later infancy. The normal values established in this study will be useful in studies of immune-system maturation and in the clinical evaluation of newborns, infants, and toddlers suspected of either acquired or congenital immune-deficiency states.

Haemolytic disease of the newborn probably due to anti-ELO, an antibody to a low frequency red cell antigen.

Investigation of mild bilirubinaemia and a positive direct antiglobulin test in a 2 day old baby revealed that the mother's serum contained an antibody against the low frequency antigen ELO, which was present on the father's red cells. Family studies showed that the ELO antigen segregates from Rh, Gc, ADA and PGM1. The ELO antigen is enzyme resistant and therefore not likely to be part of the MNS or Duffy systems. No abnormalities were detected in immunoblotting studies. Although insufficient samples were available to attempt elution of the antibody from the cord cells, it is probable that this case represents the first reported haemolytic disease of the newborn due to anti-ELO.

From coercion to collaboration: two weeks in the life of a therapeutic community.

The purpose of this paper is to describe an aspect of the functioning of a therapeutic community conceptualized in terms of a sociotherapy framework as adumbrated, for example, by Edelson (1970), Rapoport (1960), and White et al. (1964). This approach, as distinct from group therapy, is concerned with the social system and social conditions that form the fabric of any given behavior. In the hospital context it is the therapeutic community that provides the fabric in which interpersonal and intergroup tensions can be addressed and clarified. We will illustrate this approach by detailing a discussion between therapy and nursing staff members who consult to, and participate in, the various group meetings of the Therapeutic Community Program (TCP), which together provide the framework of this particular community. Specifically, the discussion was about the evolving nature of the engagement between the community and a borderline patient, who attempted to alter the structure and functioning of an aspect of the community program in order to meet her own needs and avoid inner conflict. The discussion will focus on the way in which the community members adhered to existing structures and functioning, and were able to utilize staff consultation to this end, despite the patient's strong pressure on them to alter it. In describing this particular case we hope to illustrate how a well-functioning therapeutic community can "hold" one of its members in a manner that allows change to take place, and also serves as an important adjunct and facilitator to individual therapy.