Giuliano Ciappi

Effects of environment on atopic status and respiratory disorders in children

BACKGROUND We investigated whether living in areas with higher air pollution levels increases the prevalence of positive skin reactivity in children and the possible synergic effect of air pollution exposure and atopy on respiratory disorders. METHODS This cross-sectional study was conducted in an urban area, in an industrialized area, and in a rural control area in the Latium region of Italy. A total of 2226 subjects, aged 7 to 11 years, were studied. RESULTS The prevalence of children with positive skin test results did not vary significantly over the areas (urban area = 21.0%, industrialized area = 22.0%, rural area = 20.2%). Children living in polluted areas experienced significantly more cough and phlegm (odds ratio [OR] = 1.5), rhinitis (OR = 1.7), pneumonia (OR = 1.7), and early respiratory infections (OR = 1.4) than control subjects. The pattern of the odds ratios for atopy and air pollution suggested that the two factors were probably additive in affecting asthma and early respiratory infections (synergy index [SI] = 1.04 and 1.27, respectively), whereas they seemed to act synergically in regard to cough and phlegm (SI = 1.59), rhinitis (SI = 3.01), and pneumonia (SI = 2.75). CONCLUSION Environmental air pollution seems not to increase the prevalence of atopic status; it seems, however, to enhance the development of clinical symptoms among already sensitized subjects.

Validation of leukotriene B4 measurements in exhaled breath condensate.

Abstract:Objective: To qualitatively validate an enzyme immunoassay to measure leukotriene B4 in exhaled breath condensate. Exhaled breath condensate is a new non-invasive method to monitor airway inflammation.¶Subjects: Twenty-two subjects with different lung diseases attended the outpatient clinic on one occasion for exhaled breath condensate collection.¶Methods: Samples were pooled together and purified by reverse-phase high-performance liquid chromatography. The fractions eluted were assayed for leukotriene B4 by enzyme immunoassay.¶Results: A single peak of leukotriene B4-like immunoreactivity co-eluting with leukotriene B4 standard (retention time: 24 min) was identified by enzyme immunoassay. Reverse phase-high performance liquid chromatography peak of leukotriene B4 was clearly separated from those of 6-trans- leukotriene B4 (retention time: 14 min) and leukotriene B5 (retention time: 18 min) for which the antiserum used in the enzyme immunoassay had the highest cross-reactivity. Leukotriene B4 recovery was 64%.¶Conclusions: This study provides evidence for the presence of leukotriene B4 in the exhaled breath condensate and the specificity of the enzyme immunoassay used.

Validation of 8-isoprostane and prostaglandin E2 measurements in exhaled breath condensate

AbstractObjective:To qualitatively validate radioimmunoassays for 8-isoprostane and prostaglandin (PG) E2 in exhaled breath condensate. Subjects:Twenty-two subjects with different lung diseases attended the outpatient clinic on one occasion for exhaled breath condensate collection. Methods:Samples were pooled together and purified by reverse phase high performance liquid chromatography (RP-HPLC). The eluted fractions were assayed for 8-isoprostane-like immunoreactivity and PGE2-like immunoreactivity by radioimmunoassays. In addition, simultaneous measurements of exhaled breath condensate unextracted samples with two anti-8-isoprostane and anti-PGE2 sera with different cross-reactivity were performed. Results:A single peak of 8-isoprostane-like immunoreactivity and PGE2-like immunoreactivity co-eluting with 8-isoprostane (retention time: 13 min) and PGE2 (retention time: 21 min) standards, respectively, was identified by radioimmunoassays. Testing with two different antisera showed similar results for both 8-isoprostane-like immunoreactivity (limits of agreement = 4.5 pg/ml and – 4.1 pg/ml, n = 12) and PGE2-like immunoreactivity (limits of agreement = 6.1 pg/ ml and – 6.1 pg/ml, n = 12). Conclusion: This study provides evidence for the specificity of the radioimmunoassays for 8-isoprostane and PGE2 in exhaled breath condensate. This is critical for proposing these markers as a non-invasive way for monitoring airway inflammation.

Respiratory function during pregnancy

We studied the respiratory mechanics, acid-base status, alveolar ventilation and ventilatory response to hypercapnia in pregnant women at the first and third trimesters and postpartum. We found alveolar hyperventilation and hypersensitivity of the respiratory centers to carbon dioxide with no significant differences between the first and third trimesters. After delivery we found a sudden decrease in these parameters. The changes seem to be due to a direct primary (probably hormonal) stimulation on the medulla oblongata and cannot be correlated to the metabolic needs of the fetus and are aimed at favoring placental gas exchanges, especially at the beginning of the pregnancy, when the fetal cardiovascular system is not yet developed.

Effects of two doses of cromolyn on allergen-induced late asthmatic response and increased responsiveness.

We selected five atopic children with asthma with previously documented late asthmatic response (LAR) associated with increased hyperresponsiveness to methacholine after the inhalation of Dermatophagoides pteronyssinus. The children had four allergen inhalation tests on 4 different days, at least 14 days apart. On days 1 and 4, saline placebo was inhaled 1 hour before the expected onset of LAR, and FEV1 was measured hourly until FEV1 returned within 10% of baseline value; then methacholine challenge was performed. On days 2 and 3, 20 and 40 mg of cromolyn was inhaled double blind 1 hour before the expected onset of LAR. FEV1 and methacholine responsiveness were measured as on days 1 and 4. The two doses of cromolyn significantly delayed the LAR onset without altering the overall LAR magnitude and prevented the allergen-induced increase in methacholine responsiveness. Both these effects were greater at the maximal dose used. We conclude that cromolyn can prevent the allergen-induced increase in methacholine responsiveness and that this effect is not due to alteration in the magnitude of LAR. Our findings reveal a possible explanation of the effectiveness of this drug in the treatment of allergic asthma.

Late bronchial response and increase in methacholine hyperresponsiveness after exercise and distilled water challenge in atopic subjects with asthma with dual asthmatic response to allergen inhalation

We investigated the occurrence of late asthmatic response and increased methacholine responsiveness after exercise and ultrasonically nebulized distilled water (UNDW) inhalation in 12 subjects with asthma with dual asthmatic response and increased responsiveness after allergen challenge. On 3 separate days, allergen, exercise, and UNDW challenges were performed 2 hours after methacholine. FEV1 was measured for 8 hours to detect any delayed change in airway caliber. If there were a further significant reduction in FEV1 after the recovery from the immediate bronchoconstriction, methacholine challenge was performed again when FEV1 had returned to baseline. Reproducibility of any observed late response to exercise and UNDW was also investigated by repeating these challenges on 2 subsequent days. After allergen inhalation only nine subjects had an early asthmatic response, whereas all the tested subjects demonstrated a late reaction and increased methacholine responsiveness. Ten subjects had an immediate response to exercise, and this was followed by a late response in only four patients. Nine subjects demonstrated early response to UNDW inhalation, and five subjects also had a late reaction. These late responses were associated with an increase in methacholine responsiveness in a subset of the tested subjects. Late-phase reactions to exercise and UNDW were not reproducible.

The effect of indomethacin on the refractory period occurring after the inhalation of ultrasonically nebulized distilled water

We examined the involvement of inhibitory prostaglandins in refractoriness induced by repeated ultrasonically nebulized distilled water (UNDW) challenge. Six male subjects with asthma who developed both UNDW-induced bronchoconstriction and refractoriness after UNDW were studied on 3 separate days, 1 week apart. On each study day, subjects had an initial UNDW challenge. UNDW responsiveness was assessed with dose-response curves of UNDW volume output versus the percent fall in FEV1. The output provoking a 20% fall in FEV1 (PO20 UNDW) was calculated. FEV1 was measured again at 5-minute intervals until it returned to within 5% of baseline value. UNDW challenge was then repeated. On day 1, the two successive UNDW challenges were performed in absence of any treatment (control day). Before days 2 and 3, subjects received placebo capsules or indomethacin, 100 mg per day, in a double-blind, randomized fashion for 3 days. On both the control and placebo days, repeated UNDW inhalation provoked a significant increase in PO20 UNDW (p less than 0.01), indicating refractoriness. On the indomethacin day, the mean PO20 UNDW during the second UNDW challenge was not significantly different from that obtained during the initial test on that day (p greater than 0.05), indicating that refractoriness did not occur. We suggest that inhibitory prostaglandins are involved in the development of refractoriness after UNDW inhalation.

Deaths from asthma in Italy (1974–1988): Is there a relationship with changing pharmacological approaches?

In this article we consider the relationship between asthma mortality rates, obtained from the Italian National Institute of Statistics (ISTAT), and the doses of all antiasthmatic drugs except systemic steroids sold in Italy in the years 1974-1988. The total asthma mortality rate showed three different trends: it decreased slowly until 1978 (period A); increased 10-fold from 1979 to 1985, rising from 0.30 to 4.17/100,000 (period B); and remained stable until 1988 (period C). More than half of the deaths in 1988 occurred in people 75 years of age or more. Men died more in the older age groups, while the mortality of women prevailed in the 35- to 54-year age group. In the 5- to 34-year age group the rate rose from 0.01 in 1978 to 0.21 /100,000 in 1986. Coding changes due to the 9th revision of the International Classification of Disease, adopted in Italy in 1979, probably increased the number of deaths being attributed to asthma in case of contemporary mention of bronchitis, a common diagnosis in older men, which showed the greatest increase in mortality. Increased prevalence and awareness of asthma may also have played a role. Although international comparisons strongly suggest undertreatment of asthma in Italy, the doses of anti-asthma drugs sold in Italy grew from 276 to 1,080 million from 1974 to 1985. During period B xanthine sales rose sevenfold and grew from 6.5 to 23.3% of the total doses, along with a twofold increase in beta 2-agonist and cromolyn sales. Period C was characterized by stable total doses (1155 million in 1988), with increases only in antiinflammatory and preventive drug sales. The increase in asthma deaths in Italy has been striking despite the contemporary rise in sales of all antiasthma drugs, particularly of beta 2-agonist metered aerosols and xanthine tablets. The increase in antiinflammatory and preventive drug sales may have contributed to the stabilization of asthma deaths during period C.

Probit analysis applied to the allergen dose-response curve: A method for epidemiologic surveys

The degree of skin sensitivity to five common allergens (grass, Dermatophagoides pteronyssinus, mugwort, birch, and Parietaria) was determined by the threshold dilution technique in all the skin test reactors of a random sample of 295 schoolchildren (142 male and 153 female subjects, age range 11 to 14 years), and the frequency distribution of responders at each concentration was analyzed by probit analysis. The potency of each allergen was presented in terms of median effective dose (ED50), and comparison between different allergens and between symptomatic and asymptomatic subjects was made by computing the relative potency. The ED50 of the allergens was found to be nearly identical (grass, 13.5; D. pteronyssinus, 12.3; mugwort, 9.6 activity units by RAST (AUR)/ml) with the exception of birch (22 AUR/ml). Grass and D. pteronyssinus demonstrated a lower ED50 in symptomatic subjects (3.3 and 2.8 AUR/ml, respectively) than in asymptomatic subjects (85 and 27 AUR/ml, respectively). The lower fiducial limits of ED50 in symptomatic subjects demonstrated to be a cutoff point, since they included only 5% and 12% of asymptomatic reactors to grass and D. pteronyssinus, respectively. We conclude that probit analysis applied to the distribution of threshold doses of allergen extracts is a useful method to evaluate skin sensitivity in epidemiologic surveys. We believe that the ED50 is a practical and reliable allergy index.

Comparison of the performance of two mini peak flow meters

Two mini peak flow meters commonly used to monitorize the peak expiratory flow rate (PEFR) are compared to assess their agreement, precision and, with respect to a standard pneumotachygraph, accuracy. Precision of the mini-Wright peak flow meter is greater, possibly as result of a systematic overestimation of PEFR values. The Assess peak-flow meter is more accurate, but its ability to reproduce the actual well-known PEFR variability is dependent from the absolute level of air flow. The agreement between two instruments is very poor, both in asthmatics and in normals, so that it is mandatory to use always the same mini peak flow meter in population studies and during the follow-up of asthmatic patients.