Search

Background: beta-Lactam (BL) antibiotics can induce non-immediate skin reactions, frequently manifested as exanthema or urticaria. The time between drug intake and the reaction appearance is generally 24-48 h. Because the mechanisms involved are not completely understood, diagnostic tests for these reactions have still to be fully validated., Objective: To evaluate the role of skin and drug provocation tests (DPTs) in the diagnosis of patients with non-immediate reactions to BL., Methods: We evaluated a group of 22 patients who developed maculopapular exanthema or urticarial exanthema after BL intake. Diagnosis was confirmed by DPT with BL. Intradermal/patch testing was performed with benzylpenicilloyl, minor determinant mixture, amoxicillin (AX), ampicillin (AMP) and the culprit drug in patients and in 22 negative controls. Immunohistochemical studies were done in the affected skin at the acute phase of the reaction and after a delayed positive skin test/DPT. IFN-gamma and IL-4 were quantified in peripheral mononuclear cells, obtained during the positive response to DPT and after resolution of the symptoms., Results: From the total number of cases, 12 patients developed urticarial exanthema and 10 maculopapular exanthema after DPT. Only two of the 22 patients (9%) had a positive delayed intradermal skin test: one to AX/AMP and the other to cloxacillin. Biopsies showed a mononuclear CD4, CD8 infiltrate and activated and memory cells. The cytokine expression showed a Th1 pattern in patients, in contrast with the Th0 pattern in controls., Conclusion: In patients with non-immediate reactions to BLs (maculopapular exathema or urticarial exanthema), the sensitivity of skin testing is low and DPT may be required to establish the diagnosis. The reproducibility of the reactions and the cytokine pattern expressed during the acute episode support a T cell-induced non-immediate response.

Background: Cysteinyl leukotrienes are capable of inducing chemotaxis of eosinophils in vitro and within the airways of animals and humans in vivo., Objective: We hypothesized that montelukast (MK-0476), a potent cysLT1 receptor antagonist, would protect against allergen-induced early (EAR) and late (LAR) asthmatic responses by virtue of anti-inflammatory properties. Hence, we studied the effect of pretreatment with oral montelukast on allergen-induced airway responses. As an exploratory endpoint, changes in inflammatory cell differentials and eosinophil cationic protein (ECP) were evaluated in hypertonic saline-induced sputum., Methods: Twelve asthmatic men (20-34 years, FEV1 79-109% predicted, histamine PC20FEV1 <4 mg/mL) with dual responses to inhaled house dust mite extract participated in a two-period, double-blind, placebo-controlled, crossover study. Three oral doses of montelukast (10 mg) or matching placebo were administered 36 and 12 h before, and 12 h post-allergen. The airway response to allergen was measured by FEV1, and the EAR and LAR were expressed as the corresponding areas under the time-response curves (AUC0-3 h and AUC3-8h, respectively). During each study period, sputum was induced with 4.5% NaCl 24 h before and 24 h after a standardized allergen challenge. Processed whole sputum cytospins were stained with Giemsa, and cell counts expressed as percentage nonsquamous cells. ECP was measured by FEIA in sputum supernatants., Results: All subjects completed the study. The changes in baseline FEV1 were not significantly different between the two pretreatments (P = 0.183). Montelukast significantly inhibited the EAR and LAR, reducing the AUC0-3h by 75.4% (P<0.001) and the AUC3-8h by 56.9% (P = 0.003) as compared with placebo. Sputa of nine subjects could be included in the analysis (<80% squamous cells). Allergen challenge significantly increased sputum eosinophils after placebo (mean change +/- SD: 4.8 +/- 5.8%, P = 0.038), with a similar trend after montelukast (mean change +/- SD: 4.1 +/- 5.4%; P = 0.056). The allergen-induced changes in sputum eosinophils and ECP, however, were not significantly different between the two pretreatments (P = 0.652 and P = 0.506, respectively)., Conclusion: We conclude that oral montelukast protects against allergen-induced early and late airway responses in asthma. However, using the present dosing and sample size, this protection was not accompanied with changes in sputum eosinophil percentage or activity, which may require more prolonged pretreatment with cysLT1 receptor antagonists.

There is uncertainty about the relative contributions of bronchial smooth muscle contraction, mucosal oedema and mucus plugging to airflow obstruction in the allergen-induced late asthmatic response (LAR). We systematically studied the ability of the inhaled beta 2-agonist salbutamol to reverse the LAR in eight subjects after allergen bronchoprovocation. Salbutamol reversed the LAR by restoring FEV1 to a level similar to the initial value measured at the same time of day (18.00 h) on the previous evening. For the eight subjects studied, this initial FEV1 value, measured after abstaining from beta-agonists for 8 h, was a mean +/- SEM 90.7 +/- 5.6% of predicted, which suggests further bronchodilation may have been possible at this time. We then studied six of the eight subjects in an identical protocol with saline challenge substituted for allergen bronchoprovocation to answer the question whether further bronchodilation was possible at that time after salbutamol in the absence of an LAR. After salbutamol on the allergen challenge day the FEV1 for the six subjects was 84.1 +/- 7.0% of predicted, compared with 94.0 +/- 3.7% of predicted at the same point on the saline challenge day (P < 0.05). We conclude that, although the LAR may be effectively reversed by beta 2-agonists, there is evidence for some residual airway narrowing, presumably related to mucosal oedema, exudate and mucus plugging.

Dendritic cells within the dermis in the later stages of delayed-type contact hypersensitivity were examined ultrastructurally and immunohistochemically. The immunohistochemical observations were done using monoclonal antibody M1-8, which reacts specifically with murine Langerhans cells and interdigitating cells. Seventeen hours after challenge, infiltrating cells in the dermis included dendritic cells, possibly so-called indeterminate cells, monocytoid cells and Langerhans cells. Immunohistochemically, the indeterminate cells and some monocytoid cells were M1-8-positive. These findings suggest that indeterminate cells are intimately related to Langerhans cells, and that they belong to the mononuclear phagocyte system. M1-8 is a very useful marker for studies on the kinetics of Langerhans cells or indeterminate cells.

The response of six healthy young adults to tuberculin skin testing was studied. Five subjects developed a typical delayed-type hypersensitivity reaction to PPD with a local rise in skin temperature, and the sixth showed a less intense response; a considerable increase in blood flow velocity was seen in all reactions. All subjects showed a fall in pH in the dermis during the course of the reaction: in four subjects the pH minimum occurred at the time when the changes of erythema and induration were most prominent, in one subject the pH fall preceded the maximal clinical changes, and in the remaining subject a substantial fall in pH occurred with only transient erythema. It was concluded that the local tissue acidosis had resulted from the greatly increased metabolic demand of the lymphocytes and monocytes attracted into the dermis as part of the type IV delayed-type hypersensitivity reaction, and that the concurrent reactive hyperaemia was insufficient to clear the acidic metabolic products of the greatly increased cell population.

In this paper we report that treatment with 17 beta-oestradiol depresses cutaneous delayed-type hypersensitivity (DTH) to oxazolone (OXA) in female oophorectomized NZB/W mice. Analysis of the parental strains revealed that this oestrogen-induced inhibition of DTH mice is a trait inherited from the healthy NZW and not from the autoimmune NZB strain. The down-regulating effect of oestradiol on DTH in female NZB/W mice was found both in the sensitization and effector phase of the DTH response. Decreased DTH reactivity to OXA was demonstrated in oophorectomized NZB/W and NZW mice after administration of both low, physiological doses (s.c. injections) and high, pharmacological doses (siliac tube implantation) of oestradiol. In addition, s.c. implantation of testosterone containing siliac tubes suppressed DTH reactivity to OXA in castrated male NZW mice. This down-regulating effect was not found in male NZB or NZB/W mice similarly treated. Serological analysis revealed that high doses of oestradiol increased whereas testosterone depressed the IgG anti-OXA antibody responses in female NZB/W mice. Our results indicate that one possible contribution of the NZW parental strain to the lupus disease in NZB/W mice is a trait of oestrogen sensitivity leading to the acceleration of the autoimmune disease, the latter feature being inherited from NZB mice.