Michael Makris

The role of interleukin-1 in allergy-related disorders.

Purpose of reviewInterleukin-1&bgr; (IL-1&bgr;) is a potent proinflammatory cytokine, which is involved in many inflammatory conditions including autoinflammatory and allergic disorders. This review provides insights into recent advances of our understanding of the pathogenesis of IL-1&bgr;-associated allergy-related disorders. Recent findingsIn autoinflammatory as well as allergic diseases such as contact hypersensitivity, atopic dermatitis and bronchial asthma, dysfunctional inflammasome processing has been demonstrated to account for IL-1&bgr;-induced inflammation. IL-1-neutralizing drugs have been shown to completely suppress or markedly reduce inflammatory responses in clinical studies and experimental models of urticarial autoinflammatory diseases as well as common allergic disorders. SummaryThe recent findings support a crucial role for IL-1&bgr; and inflammasome components in a variety of allergy-related disorders.

Fish and shellfish allergy in children: review of a persistent food allergy.

The increased consumption of fish and shellfish has resulted in more frequent reports of adverse reactions to seafood, emphasizing the need for more specific diagnosis and treatment of this condition and exploring reasons for the persistence of this allergy. This review discusses interesting and new findings in the area of fish and shellfish allergy. New allergens and important potential cross‐reacting allergens have been identified within the fish family and between shellfish, arachnids, and insects. The diagnostic approach may require prick to‐prick tests using crude extracts of both raw and cooked forms of seafood for screening seafood sensitization before a food challenge or where food challenge is not feasible. Allergen‐specific immunotherapy can be important; mutated less allergenic seafood proteins have been developed for this purpose. The persistence of allergy because of seafood proteins’ resistance after rigorous treatment like cooking and extreme pH is well documented. Additionally, IgE antibodies from individuals with persistent allergy may be directed against different epitopes than those in patients with transient allergy. For a topic as important as this one, new areas of technological developments will likely have a significant impact, to provide more accurate methods of diagnosing useful information to patients about the likely course of their seafood allergy over the course of their childhood and beyond.

Anaphylaxis to Gadobenate Dimeglumine (Multihance®): A Case Report

Background: Gadolinium chelates are relatively safe contrast media used in MRI. Immediate severe adverse effects are exceptionally rare and mostly concern mild anaphylactoid reactions. We report a case of anaphylaxis to gadobenate dimeglumine (Gd-BOPTA, Multihance®), a gadolinium-based contrast agent. Methods: A 32-year-old female patient with a personal history of multiple sclerosis, while undergoing an MRI scan, developed bronchospasm and acute urticaria with diffuse giant pruritic plaques in the first minute of Gd-BOPTA infusion. The procedure was cancelled and acute treatment of the reaction took place. The patient reported 2 additional MRI scans with definite use of unknown contrast media in the past 2 years without any adverse effect. Blood samples were obtained 2 and 48 h after the reaction for measurement of serum tryptase concentration (Pharmacia Diagnostics, Uppsala, Sweden). Skin prick tests and intradermal tests were performed using 1:1,000, 1:100 and 1:10 dilution of the offending agent and alternative gadolinium-based agents [gadodiamide (Omniscan®) and gadoteric acid (Dotarem®)]. A group of 10 nonatopic individuals who underwent the same skin testing comprised the control group. Results: Tryptase concentration was highly elevated 2 h after the reaction (21 µg/l) compared with that at 48 h (3 µg/l). Skin prick tests in our patient were all negative, while intradermal testing with 0.03 ml of 1:100 and 1:10 preparations of Multihance showed a definite positive wheal-and-flare reaction. Skin tests to the alternative agents showed no response. In the control group, all performed tests were negative. Conclusion: We report the first case of an allergic reaction to gadobenate dimeglumine. Besides, skin testing seems to be a precious diagnostic tool which, if positive, strongly suggests a mast cell-mediated underlying mechanism.

Rupatadine Inhibits Proinflammatory Mediator Secretion from Human Mast Cells Triggered by Different Stimuli

Background: Mast cells are involved in allergy and inflammation by secreting multiple mediators including histamine, cytokines and platelet-activating factor. Certain histamine 1 receptor antagonists have been reported to inhibit histamine secretion, but the effect on cytokine release from human mast cells triggered by allergic and other stimuli is not well known. We investigated the ability of rupatadine, a potent histamine 1 receptor antagonist that also blocks platelet-activating factor actions, to also inhibit mast cell mediator release. Methods: Rupatadine (1–50 μM) was used before stimulation by: (1) interleukin (IL)-1 to induce IL-6 from human leukemic mast cells (HMC-1 cells), (2) substance P for histamine, IL-8 and vascular endothelial growth factor release from LAD2 cells, and (3) IgE/anti-IgE for cytokine release from human cord blood-derived cultured mast cells. Mediators were measured in the supernatant fluid by ELISA or by Milliplex microbead arrays. Results: Rupatadine (10–50 μM) inhibited IL-6 release (80% at 50 μM) from HMC-1 cells, whether added 10 min or 24 h prior to stimulation. Rupatadine (10–50 μM for 10 min) inhibited IL-8 (80%), vascular endothelial growth factor (73%) and histamine (88%) release from LAD2 cells, as well as IL-6, IL-8, IL-10, IL-13 and tumor necrosis factor release from human cord blood-derived cultured mast cells. Conclusion: Rupatadine can inhibit histamine and cytokine secretion from human mast cells in response to allergic, immune and neuropeptide triggers. These actions endow rupatadine with unique properties in treating allergic inflammation, especially perennial rhinitis and idiopathic urticaria.

Pediatric Allergic Rhinitis and Asthma: Can the March be Halted?

The strong epidemiologic and pathophysiologic link between allergic rhinitis (AR) and asthma has led to the concept of ‘united airways disease’ or ‘respiratory allergy’, implying that allergy, in its widest sense, underlies this clinical syndrome. Progression from AR to asthma is frequent and part of the ‘atopic march’. Since pediatric immune responses are more adaptable and therefore may be more amenable to treatment, interventions at early childhood are characterized by a higher chance to affect the natural history of respiratory allergy. Although current treatments are quite effective in alleviating respiratory allergy symptoms, it has proven much more difficult to confirm any influence on the progression of the disease. Much more promising is the field of specific allergen immunotherapy, where current evidence, although not yet of ideal robustness, points towards a disease-modifying effect. In addition, newer or emerging, possibly more effective or more targeted interventions are promising in the preventive sense.

Acute Generalized Exanthematous Pustulosis (AGEP) Triggered by a Spider Bite

BACKGROUND Acute generalized exanthematous pustulosis (AGEP) is a rare and severe cutaneous reaction usually triggered by drugs. Other causative factors such as viral infections are rarely involved. In this study, we report a case of AGEP caused by a spider bite. CASE SUMMARY A 56-year-old woman was referred to the allergy unit after a spider bite at the left popliteal fossa, while gardening, 5 days earlier. The offending spider was captured and identified by an entomologist as belonging to the Loxosceles rufescens species. No acute reaction was observed; however, after 24 hours, due to the occurrence of typical dermonecrotic skin lesions associated with erythema and edema, Cefuroxime and Clindamycin were administered intramuscularly after medical advice was given. Almost 72 hours after the spider bite, an erythematous and partly edematous eruption appeared locally in the gluteus area bilaterally, which progressively expanded to the trunk, arms and femors. Within 24 hours dozens of small, pinhead sized, non-follicular pustules were present, mainly in the folds. The patient complained of a burning sensation of the skin in addition to pruritus; and simultaneously had a fever of 38-39 degrees C as the eruption expanded. DISCUSSION A spider bite may represent a possible causative factor of AGEP. A spiders venom contains sphingomyelinase that stimulates the release of IL8 and GM-CSF, which are involved in AGEP pathogenesis. Whether or not the con-current use of antibiotics has an effect in AGEP appearance when combined with a spiders venom, cannot be excluded.

Nasal provocation of patients with allergic rhinitis and the hypothalamic-pituitary-adrenal axis.

BACKGROUND Allergic rhinitis is a common problem involving activation of nasal mast cells and irritability. The hypothalamic-pituitary-adrenal (HPA) axis is stimulated in cases of emotional or environmental stress, and mast cells have been implicated in stress-induced immune responses. OBJECTIVE To investigate whether intranasal challenge of patients allergic to a single antigen would stimulate the HPA axis. METHODS Plasma corticotropin and cortisol levels were measured 20, 40, 60, 80, 100, and 120 minutes after intranasal antigen administration in healthy volunteers (n=3) and in patients with rhinitis who are allergic to Parietaria (n=10). RESULTS Mean +/- SD corticotropin levels were 24.43 +/- 14.38 pg/mL in patients compared with 8.83 + 5.02 pg/mL in controls, and this increase was statistically significant (P = .049). Patient cortisol levels also increased to a mean +/- SD of 8.87 +/- 4.90 pg/mL (at 40 minutes) compared with 4.36 +/- 1.72 pg/mL in controls (P = .11 due to 1 outlier). Compared with individual patient prechallenge levels, corticotropin levels increased in 7 patients and cortisol levels increased in 5 at 40 minutes. CONCLUSION These results suggest that allergic rhinitis may activate the HPA axis. A larger study with additional controls is required for definitive conclusions.

Effects of Botulinum Toxin—A Therapy for Palmar Hyperhidrosis in Plantar Sweat Production

BACKGROUND Patients with focal hyperhidrosis in multiple areas often report improvement of plantar hyperhidrosis after botulinum toxin A (BTX‐A) therapy for palmar hyperhidrosis. OBJECTIVE To assess sweat production from the soles in patients receiving BTX‐A treatment for their palmar hyperhidrosis. PATIENTS AND METHODS Thirty‐six patients with both palmar and plantar hyperhidrosis received 100 U of BTX‐A per palm. Sweat production of palms and soles was assessed using a starch iodine test and gravimetry at baseline and 1, 3, and 8 months after treatment. Patients were subjectively assessed using a percentile scale. RESULTS All patients had significant improvement in their palmar hyperhidrosis that lasted for 6.2 ± 1.8 months. Gravimetry revealed marginal improvement of plantar hyperhidrosis in 12 patients (from 39.7 ± 21.3 to 31.5 ± 18.0 mg/min; p=.01) and statistically significant worsening in 24 patients (from 71.6 ± 70.60 to 109.94 ± 82.93 mg/min, p<.001). CONCLUSION Treatment of palmar hyperhidrosis with BTX‐A increased plantar sweating in many patients affected by both palmar and plantar hyperhidrosis in the population under study. Regardless, patients reported satisfaction with the results and were willing to repeat treatment.

Rupatadine inhibits inflammatory mediator release from human laboratory of allergic diseases 2 cultured mast cells stimulated by platelet-activating factor

BACKGROUND Mast cells are involved in allergy and inflammation by the secretion of multiple mediators, including histamine, cytokines, and platelet-activating factor (PAF), in response to different triggers, including emotional stress. PAF has been associated with allergic inflammation, but there are no clinically available PAF inhibitors. OBJECTIVE To investigate whether PAF could stimulate human mast cell mediator release and whether rupatadine (RUP), a dual histamine-1 and PAF receptor antagonist, could inhibit the effect of PAF on human mast cells. METHODS Laboratory of allergic diseases 2 cultured mast cells were stimulated with PAF (0.001, 0.01, and 0.1 μmol/L) and substance P (1 μmol/L) with or without pretreatment with RUP (2.5 and 25 μmol/L), which was added 10 minutes before stimulation. Release of β-hexosaminidase was measured in supernatant fluid by spectrophotoscopy, and histamine, interleukin-8, and tumor necrosis factor were measured by enzyme-linked immunosorbent assay. RESULTS PAF stimulated a statistically significant release of histamine, interleukin-8, and tumor necrosis factor (0.001-0.1 μmol/L) that was comparable to that stimulated by substance P. Pretreatment with RUP (25 μmol/L) for 10 minutes inhibited this effect. In contrast, pretreatment of laboratory of allergic diseases 2 cells with diphenhydramine (25 μmol/L) did not inhibit mediator release, suggesting that the effect of RUP was not due to its antihistaminic effect. CONCLUSION PAF stimulates human mast cell release of proinflammatory mediators that is inhibited by RUP. This action endows RUP with additional properties in treating allergic inflammation.

Allergy skin testing in predicting adverse reactions to fluorescein: a prospective clinical study

Purpose:  To evaluate allergy skin testing as a diagnostic tool of adverse reactions to fluorescein and whether allergy and previous sodium fluorescein angiography (SFA) act as predisposing factors.