[On general practitioners' care of patients with asthma]. / HausärztlicheVersorgung von Patienten mit Asthma.

UNLABELLED: This review offers readers new aspects for the guideline-compliant care of asthma patients. Here, attention is focused on illustrating the bottlenecks in the administration of good and practicable therapeutic care and listing these as "major challenges for GPs". The interdisciplinary team of authors - consisting of three hospital-based pulmonologists, one pulmonologist in private practice, one internist in general practice, one pharmacist and one health economist discussed aspects of asthma therapy relevant in clinical practice. RESULTS AND CONCLUSIONS: Practicable results for the reader included an asthma pentagram, a graphic depicting the links and interactions between diagnosis, symptom management, communication, application and costs. From this emerged a consensus on four recommendations that can help GPs improve their care of their patients: (1) Whenever possible, have a specialist verifythe diagnosis. (2) Practice inhalation techniques with the patient and check up on their technique at regular intervals. (3) Monitor and fine-tune the therapeutic goals set down together with the patient. (4) Clearly define the (patient's) responsibilities and who is organizing care (communication between GP-specialist-patient-pharmacist-family members).

P2 purinergic receptors of human eosinophils: characterization and coupling to oxygen radical production.

Extracellular nucleotides elicit multiple responses in eosinophils but no information on expression of purinergic receptors in these cells is available so far. In the present study we show that human eosinophils express the following P2Y and P2X subtypes: P2Y(1), P2Y(2), P2Y(4), P2Y(6), P2Y(11), and P2X(1), P2X(4), P2X(7), whose stimulation results in intracellular Ca(2+) increase and production of large amounts of reactive oxygen intermediates. These events are stimulated or inhibited, respectively, by P2 receptor agonists or antagonists.

Adenosine triphosphate-induced oxygen radical production and CD11b up-regulation: Ca(++) mobilization and actin reorganization in human eosinophils.

Eosinophils are major effector cells in cellular inflammatory conditions such as parasitic infections, atopic diseases, bullous dermatoses, and vasculitis. Biological activities of adenosine triphosphate (ATP) were characterized in human eosinophils and compared with those of other eosinophil activators such as complement fragment product C5a, platelet-activating factor (PAF), and eotaxin. ATP initiated production of reactive oxygen metabolites, as demonstrated by lucigenin-dependent chemiluminescence. Furthermore, ATP caused up-regulation of the integrin CD11b. In addition, fluorescence microscope measurements labeled with fura-2 (1-[2-(5-carboxy-oxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2' -amino-5' -methyl-phenoxy)-ethane-N, N, N, N'-tetraacetic acid, pentaacetoxymethyl ester) eosinophils in the presence or absence of ethyleneglycotetraacetic acid (EGTA) indicated that there was Ca(++) mobilization from intracellular stores by ATP. Flow cytometric studies showed transient actin polymerization upon stimulation with ATP and its stable analogues adenosine 5'-0-(3-thiotriphosphate) and 2-methylthioadenosine triphosphate tetrasodium (met-ATP). The reactions induced by ATP were comparable to those obtained by C5a, PAF, and eotaxin. Production of reactive oxygen metabolites and actin polymerization after stimulation with ATP was inhibited by pertussis toxin, which indicated involvement of receptor-coupled guanine nucleotide-binding proteins (G(i) proteins). In addition, experiments with oxidized ATP also suggest involvement of P2X receptors in this activation process. The results show that ATP is a strong activator of eosinophils and has biological activity comparable to those of the eosinophil chemotaxins C5a, PAF, and eotaxin. The findings strongly suggest a role of ATP in the pathogenesis of eosinophilic inflammation as an activator of proinflammatory effector functions.

Specific serum immunopatterns in clinical phases of allergic bronchopulmonary aspergillosis.

Immunoblotting, radioallergosorbent test (RAST), and enzyme-linked immunosorbent assay (ELISA) were performed to determine specific IgE and IgG responses to Aspergillus fumigatus (Af) allergens (IgE-Af; IgG-Af). Serology results were compared in patients with allergic bronchopulmonary aspergillosis (ABPA) (n = 43), patients with Aspergillus fumigatus-associated asthma (Af-asthma) (n = 26), and healthy individuals (n = 3). In patients with different clinical phases of ABPA, three specific immunopatterns were found by immunoblotting. It is proposed to classify ABPA into the active, intermediate, and remission phase with respect to the specific immunoresponse to Af-allergens and asthma symptoms. First, the active phase of ABPA is characterized by a fully developed specific immunoresponse to Af-allergens and severe asthma. Second, the intermediate phase includes patients with elevated specific immunologic findings without asthma symptoms. Third, the remission phase is characterized by a weak specific immunoresponse to Af-allergens after a long-term asymptomatic period. No correlation occurred between specific immunopatterns and irreversible brochopulmonary lesions. The IgE-Af RAST and IgG-Af ELISA titers of patients with ABPA in the active and intermediate phase were significantly higher compared with patients with ABPA in remission phase and with patients with Af-asthma. In particular, the demonstration of positive IgG-Af ELISA titer generally allows the serologic discrimination of patients with asthma and ABPA from patients with Af-asthma in clinical practice. The present study revealed that immunoblots of most patients with Af-asthma were negative. Immunoblotting demonstrated an IgG reactivity exclusively to low molecular weight (MW) Af-allergens in 8 out of 26 patients with Af-asthma and in the three healthy individuals, and this IgG response may reflect naturally occurring antibodies.

A prospective trial using salivary-theophylline levels to guide asthma therapy.

In three prospectively designed studies, first saliva (SA) samples were collected simultaneously with serum (SE) from 86 children who received slow-release theophylline (Th) b.i.d. for treatment of bronchial asthma. SA was collected with a standardized sampling procedure. Regression analysis revealed a close correlation between SE and SA-Th levels (r = 0.959; SE = 1.87 x SA + 0.05) and yielded a "therapeutic SA-Th range" of 5.8 to 10.7 mg/L. In 16 children the diurnal variation was then assessed by measuring 6 SA-Th levels within 24 hr, using the same sampling method. At 0, 9, and 24 hr SE-Th levels were also measured. The levels of SE-Th and SA-Th were again closely correlated (0.914 less than or equal to r less than or equal to 0.949) and both remained constant over the 24-hr period. In the third prospective trial only SA levels were used to monitor Th therapy in 50 asthmatic children. Seven days after starting therapy SA-Th levels were measured and then the Th dose was increased weekly until SA-Th levels above 5.8 mg/L were reached. The following day SE and SA samples were collected simultaneously and their Th levels compared. In 36 of the 47 children who completed the study therapeutic SE-Th levels (greater than or equal to 10 and less than or equal to 20 mg/L) were measured; in one patient it was greater than or equal to 20 mg/L, in 6 it was between 8.0 and 10 mg/L, and only 4 had SE levels less than 8.0 mg/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Sputum ECP levels correlate with parameters of airflow obstruction.

Growing evidence suggests that eosinophils play an important role as proinflammatory cells in asthma, possibly by releasing toxic cationic proteins. In this study concentrations of serum and sputum eosinophil cationic protein (ECP) from 134 patients with productive cough and a history suggestive of airflow obstruction were measured by radioimmunoassay. Small sputum volumes were suspended in saline, vortexed, and centrifuged and ECP measured in the supernatant. Serum ECP levels ranged from 0.002 to 0.095 mg/L (0.016 +/- 0.0014), whereas sputum ECP concentrations were between 0.024 and 5.66 mg/L ECP per g sputum (0.878 +/- 0.092). Only 17 of the 134 patients (14 asthma, one cystic fibrosis, one bronchiectasis, and one bronchitis) had not been pretreated with corticosteroids. Sputum but not serum ECP levels of the 14 patients with asthma were inversely correlated with impairment of FEV1 (r = -0.73). Airway resistance (Raw) (r = 0.71) as well as the change in FEV1 (r = 0.79) and Raw (r = 0.84) after inhalation of 0.2 mg albuterol were positively correlated. This relationship was not observed in the remaining 117 patients on topical and/or systemic corticosteroids, suggesting that corticosteroid treatment influences sputum ECP levels. Also, sputum ECP levels and the degree of sputum eosinophilia were not correlated in any of the patient groups. Neither did serum ECP levels predict sputum ECP concentrations. We conclude that sputum ECP concentrations serve as a marker of eosinophil degranulation in the sputum, and this marker correlates with airflow obstruction. Sputum ECP levels are more closely related to lung function parameters than serum ECP concentrations and/or microscopic sputum analysis.

Cloning and expression of recombinant Aspergillus fumigatus allergen I/a (rAsp f I/a) with IgE binding and type I skin test activity.

Aspergillus fumigatus secretes an 18-kDa nonglycosylated IgE-binding protein. This protein was previously shown to be a ribotoxin, like alpha-sarcin and mitogillin. A 686-bp long A. fumigatus cDNA encoding an 18-kDa ribotoxin was cloned and expressed in Escherichia coli as a fusion protein with six adjacent histidines (rAsp f I/a). rAsp f I/a was purified to homogeneity by Ni(2+)-chelate affinity chromatography and refolded. The recombinant protein was enzymatically active resulting in the cleavage of 28S rRNA within a universally conserved region. rAsp f I/a was cytotoxic for EBV immortalized or PHA stimulated human PBMC. Furthermore, rAsp f I/a was recognized by murine mAb made against an 18-kDa ribotoxin. IgE of individuals allergic to A. fumigatus bound to rAsp f I/a as shown by ELISA, dot blots, and Western blots. rAsp f I/a elicited positive immediate type I skin reactions in individuals allergic to A. fumigatus but not in healthy control individuals. The results show that rAsp f I/a has similar functional characteristics when compared to the native 18-kDa ribotoxin. rAsp f I/a expressed in E. coli can therefore be used as a standardized Ag/allergen for serologic and clinical diagnosis of A. fumigatus-associated diseases.

Altered distribution of IgG subclasses in aspirin-induced asthma: high IgG4, low IgG1.

We have determined IgG subclass concentrations in 100 patients with aspirin-induced asthma and 80 healthy controls. Patients on chronic corticotherapy (n = 64) had significantly lower total IgG levels than patients not receiving steroids (n = 36) or controls. Corticotherapy was not associated with changes in the subclass distributions. In patients, the most striking finding was elevation of IgG4. It was not related to corticotherapy or serum IgE levels. The rise in IgG4 was accompanied by a modest, though statistically significant, depression of IgG1. No changes of IgG2 and IgG3 concentrations were observed. Thus, aspirin-induced asthma is characterized by a distinct pattern of distributions of IgG subclasses. It is suggested that in aspirin-induced asthma elevation of IgG4 might result from chronic antigenic stimulation, of viral origin, and that determination of IgG subclass distribution might be of clinical interest.

Sputum eosinophils from asthmatics express ICAM-1 and HLA-DR.

Sputum from symptomatic asthmatics is a rich source of eosinophils from the respiratory tract. Following liquefaction of sputum with dithioerythritol (DTE), a cell suspension for indirect double immunofluorescence with flow cytometry was obtained. Eosinophils were identified using anti-CD9 fluorescein conjugate, and particular surface markers measured with the relevant mouse MoAb followed by goat anti-mouse immunoglobulin phycoerythrin conjugate. Blood and sputum eosinophil surface markers were determined in parallel from asthmatics not receiving steroid therapy. Sputum eosinophils were found to have considerably elevated levels of CD11b, a reflection of eosinophil activation. Sputum but not blood eosinophils were found to express ICAM-1 (nine out of 11 cases) and HLA-DR (eight out of 11 cases). Furthermore, following culture of normal blood eosinophils with pooled T cell supernatants, ICAM-1 and HLA-DR could be induced in vitro. The induction of eosinophil adhesion molecules such as ICAM-1 and HLA-DR may influence eosinophil localization and function in asthma.

Delayed generation of thrombin in clotting blood of atopic patients with hayfever and asthma.

There have been several reports on alterations of platelet function and raised plasma heparin levels in symptom-free atopic subjects. Either of these can affect formation of thrombin in vivo. In 25 symptom-free atopic patients and 32 healthy volunteers we studied the generation of thrombin in blood emerging from a standardized skin microvasculature injury, which also served to determine bleeding time. Generation of thrombin was delayed in atopics. They produced significantly less thrombin (P less than 0.01) during the early and central phase of haemostasis. The amount of thrombin generated was inversely correlated to bleeding time, which in atopics was on average 50 sec longer than in controls (P = 0.055). Two hours after ingestion of 500 mg aspirin, this difference increased up to 150 sec, although the individual responses varied markedly (P = 0.08), while the generation of thrombin became strongly depressed in both groups. The possible clinical relevance of the delayed formation of thrombin in atopy awaits further studies.

[Neopterin in phases of exacerbation of bronchial asthma and in experimental asthma conditions]. / Neopterin in Exazerbationsphasen des Asthma bronchiale und unter den Bedingungen des experimentellen Asthmas.

In conditions associated with stimulation of cellular immunity and enhanced macrophage activity, for example, in viral infections, neopterin is elevated. Acute exacerbations of bronchial asthma--in particular in the case of intrinsic asthma--are frequently precipitated by viral infections of the upper airways. In both extrinsic and intrinsic asthma, neopterin is normal in the stable phases. In the exacerbation phase with signs of infection of the upper airways, however, neopterin in significantly elevated both in the serum and in the urine. In contrast, during and following positive inhalative provocation testing with histamine, allergens and aspirin, no increase in neopterin is to be observed.

[Experiences with a combination therapy of methylprednisolone and troleandomycin in severe bronchial asthma requiring high-dose corticoids]. / Erfahrungen mit einer Kombinationstherapie von Methylprednisolon und Troleandomycin (TAO) bei schwerem, hochkortikoidbedürftigem Asthma bronchiale.

Although treatment comprising a combination of methylprednisolone (MP) and troleandomycin (TAO) has been employed to treat cases of severe bronchial asthma requiring high doses of corticosteroids, for about 20 years, now, it has always been associated with major adverse reactions (1). A new protocol avoids these adverse effects by a rapid reduction in the dose of MP to alternating administrations and low TAO dosage (250 mg). Nineteen patients were treated using this protocol, 16 of whom for more than two months (maximum 21, minimum 4 months). Three patients were taken out of the study as early non-responders in the initial phase. Five patients must be considered to be late non-responders, or were discharged from the study on account of pathological liver parameters. In 8 patients who showed good tolerance, an appreciable reduction in the dose of steroids, with stabilisation of the asthma, was observed.

[Comparison of salivary with serum levels of retard theophylline under steady-state conditions]. / Vergleich von Saliva- mit Serumspiegeln bei Retardtheophyllin unter Steady-State-Bedingungen.

In 86 asthmatic children, the theophylline levels in the serum and saliva were compared. A pronounced (r = 0.95) and statistically highly significant (p less than 0.001) relationship was observed to exist between the theophylline concentrations in serum and saliva.

[Is sodium salicylate suitable as a protective agent in the analgesic-induced asthma syndrome?]. / Eignet sich Natriumsalizylat (NaS) als Protektivum beim Analgetika-Asthma-Syndrom (AIA)?

The protective effect of NaS in analgetic-induced asthma (AIA) was investigated in patients with AIA. In none of the patients was the asthmatic reaction to acetylsalicylic acid (ASS) completely inhibited by the oral administration of NaS. In a single patient, an intolerance reaction occurred after oral ingestion of the substance. In several patients, induction of tolerance towards acetylsalicyclic acid was facilitated after prior ingestion of NaS.