Francesco Mori

Long-term safety and efficacy of topical cyclosporine in 156 children with vernal keratoconjunctivitis

Vernal keratoconjunctivitis (VKC) is a chronic and potentially sight-threatening disease. Topical corticosteroids (Cs) seem to be the only effective treatment for this condition, although severe side effects may occur owing to their prolonged use. More recently, cyclosporine (Cyc) eye drops have been reported as a valid alternative, but so far such treatment has only been successfully experimented for a short time and in small numbers of patients. The aim of our study is to evaluate the long term safety and efficacy of topical cyclosporine eye drops in children suffering from VKC. Over a period of 7 years we followed a large group of children suffering from severe VKC. They were selected to start cyclosporine eye drop treatment, because of the prompt relapse of their disease as soon as they stopped topical corticosteroids administration. All patients were followed-up in an ambulatory care assessment. A total of 156 children with VKC were treated with topical cyclosporine eye drops over a period ranging from two to seven years [mean time 3.8±1.09 years] during the seasonal relapse [range 9–66 months; mean time 24.7±10.4 months]. Two formulations, at 1% and 2% (82% and 18% respectively) concentrations, of cyclosporine eye drops were made. The dosage administered was one drop in each eye from two to four times a day, depending on the severity of the disease and the season. The ocular objective scores were determined and compared every year, at the beginning and at the end of each treatment period. Blood samples were collected once a year in order to check both kidney and liver functions, as well as cyclosporine serum levels. We enrolled 156 patients (mean age 8.31±2.79 years; 116 males and 40 females) who were followed-up over a period of 7 years [156 (100%) children during the first and the second year; 138 (88.5%) patients until the third year; 90 (57.7%) until the fourth year; 32 (20.5%) until the fifth year; 10 (6.4%) until the sixth year and 2 (1.3%) until the seventh year]. The ocular objective scores significantly improved (p<.001) over the years when comparing them at the beginning and the end of each seasonal treatment period, except for the last year. Over the treatment period, non-significant changes were recorded in terms of kidney and liver enzymatic activities and also in terms of cyclosporine serum levels. Cyclosporine eye drops, either at 1% or 2% concentrations, resulted safe and effective for long-term treatment of VKC in 156 children. The lack of significance of the score results during the seventh year can be explained by the small number of subjects treated for such a long period. A systematic ocular examination and both liver and kidney functional investigations allowed us to exclude the possibility of local or systemic side effects due to cyclosporine. If either transient or long-lasting, the occurrence of burning was referred by some of the patients treated, but none of them required to discontinue the drug. In conclusion, this is the first study showing that topical cyclosporine is easily handled even by children, with safe and effective results even when it is used over a long period of time. Our findings, though encouraging, need to be confirmed by further studies.

Cytokine Expression in CD3+ Cells in an Infant with Food Protein-Induced Enterocolitis Syndrome (FPIES): Case Report

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by severe vomiting, diarrhea, and often failure to thrive in infants. Symptoms typically resolve after the triggering food-derived protein is removed from the diet and recur within few hours after the re-exposure to the causal protein. The diagnosis is based on clinical symptoms and a positive food challenge. In this study, we report a case of FPIES to rice in an 8-month-old boy. We performed a double-blind placebo-controlled food challenge (DBPCFC) to rice and we measured the intracellular T cell expression of interleukin-4 (IL-4); IL-10, and interferon γ (IFN-γ) pre-and post-challenge during an acute FPIES reaction and when tolerance to rice had been achieved. For the first time we describe an increase in T cell IL-4 and decrease in IFN-γ expression after a positive challenge with rice (i.e. rice triggered a FPIES attack) and an increase in T cell IL-10 expression after rice challenge 6 months later after a negative challenge (i.e., the child had acquired tolerance to rice) in an 8 month old with documented FPIES to rice. A Th2 activation associated with high IL-4 levels may contribute to the pathophysiology of the disease. On the other hand, T cell-derived IL-10 may play a role in the acquisition of immunotolerance by regulating the Th1 and Th2 responses.

Cefaclor anaphylaxis in children.

tin and rifapentin was still present; total IgE was 102 kU/l. Our findings confirm previous reports showing IgE-mediated reactions to rifamycin SV (5); moreover, we demonstrated serum-specific IgE to rifaximin, by means of the inhibition test, and crossreactivity among rifamycins. The time course of the reactions could suggest that the scarce quantity of rifaximin absorbed, not only provoked the first, relatively mild systemic reaction, but could have induced a booster effect on the IgE synthesis to rifamycins (probably present since the first reaction, 4 years earlier), which enhanced the subsequent, very severe, reaction to rifamycin SV. Indeed, the worsening onset of the allergic disease, due to the short time interval between two subsequent contacts with the same allergen has already been documented (6). In conclusion, the presence of IgEmediated cross-reactivity among rifamycins is a recommendation for the avoidance of rifaximin as well, despite its poor absorption. The authors wish to thank Paul Bowerbank for his help in reviewing the English of the manuscript.

Surgical debridement plus topical cyclosporine A in the treatment of vernal shield ulcers.

Vernal Keratoconjunctivitis (VKC) is a severe chronic bilateral inflammation of the ocular surface characterized by seasonal exacerbations. Long-term prognosis is generally good; however, 6% develop sequelae responsible for permanent visual impairment. Corneal involvement is almost always present, consisting of punctate keratitis, shield ulcers (3–11%) and late corneal neovascularization. In recent years, topical cyclosporine A preparations at 2% in oil or at 1% in polyvinyl alcohol, have been successfully proposed for long term VKC treatments. It has been previously proven that medical treatment is not always sufficient, especially when it is employed to treat shield ulcer plaques. In such conditions, surgery may be effective for avoiding long term complications such as amblyopia, strabismus, infections and corneal perforation. In this paper, we show the efficacy of surgical debridement by means of simple scraping associated with topical cyclosporine treatment for the management of vernal shield ulcers complicated with plaques.

Diagnostic value of three different latex extracts.

The diagnosis of latex allergy is made on clinical history, but a confirmatory skin prick test (SPT) or a serological assay based on a commercial latex extract is always recommendable. Different raw materials can be used in the preparation of commercial latex extracts. Such extracts can consequently show both different qualitative profiles and a different diagnostic potential. Therefore, the selection of a proper latex extract is essential for in vitro and in vivo diagnosis of latex allergy. In the present study three different latex extracts, prepared from different raw materials (ammoniated -AL-, serum -SL-, or rubber particles -RPE- latex), are compared by in vitro techniques using sera from twenty patients with latex allergy. SDS-PAGE technique was used to compare the antigenic profile of the three latex extracts. Subsequently, their allergenic profiles were evaluated by immunoblotting technique using the individual sera from the twenty latex allergic patients. The diagnostic potential of the three latex extracts was also evaluated using direct Radio-Allergo-Sorbent Test (RAST) as well as skin prick tests (SPTs). In order to establish the more appropriate latex extract in a perspective of in vivo diagnosis of latex sensitization, the same latex extracts were subsequently compared by an in vivo SPT involving ten of the above subjects. The SDS-PAGE profiles of the three latex extracts examined were quite different. SL extract showed numerous bands comprised between 10–100 kDa. RPE extract was characterized by two intense bands at 14 and 20 kDa while AL extract showed the poorer antigenic composition. Analogously, immunoblotting analysis evidenced a different profile in relation to both different patients and extracts. For only two out of the twenty sera, direct RAST results showed a same positive class in relation to the different latex extracts used. SPT with SL extract showed, in respect to the other extracts (AL, RPE), a significantly higher wheal. This study showed that SL extract is able to express the best in vitro and in vivo diagnostic potential. Thus, its use should be preferred for the diagnosis of patients affected by latex allergy.

Biphasic anaphylactic reaction to Ketorolac tromethamine.

Ketorolac tromethamine is a recent injectable non-steroidal anti-inflammatory drug (NSAID) with analgesic properties approved for short-term pain management. In spite of its increasing use both in adults and children (1-2), relatively few allergic-like reactions have been reported (3–5). Reactions are often severe, and a death occurred following an intramuscular injection of ketorolac (6).

Scrotal dartos-fascio-myo-cutaneous flaps for penis elongation after catastrophic iatrogenic skin shaft sub-amputation: A case of recovery using an extremely adaptable flap

Introduction Genitalia are linked to self-esteem and male sexual identity, especially among young men, who sometimes require a surgical procedure to acquire more confidence. Among the surgical procedures requested for aesthetical purposes, circumcision is one of the most popular. Although it can be considered to be a simple surgical practice, it may cause severe complications such as penile skin necrosis. Presentation of case We report a case of a catastrophic situation after a circumcision performed on a 27-year-old HIV positive man resulted in a drastic reduction in the length of the penile shaft due to extensive skin loss; this was subsequently restored using dartos-fascio-myo-cutaneous flaps. Primary healing occurred in 10 days. No infection, dehiscence or flap ischemia were reported. Donor site morbidity was minimal. An adequate aesthetical appearance and satisfactory functional results were obtained. Discussion and conclusion Various techniques are available for penile skin covering, such as skin grafts or cutaneous flaps. The skin of the scrotum seems to be the most suitable tissue to be used to reconstruct the skin covering of the shaft as it is the most similar. Dartos-fascio-myo-cutaneous flap is a single stage procedure that is easy and safe to perform. It can provide satisfactory cosmetic and functional results, offering a large amount of tissue, with minimal donor site morbidity.

High intracytoplasmatic levels of Il-4 and Il-5 in a patient with Gleichs syndrome: case report.

Gleichs syndrome is characterized by recurrent localized angioedema, hypereosinophilia, elevated levels of IgM, rapid weight gain, itchy urticaria and fever. Little is known about the pathogenesis of this disease. Increased serum levels for IL5, IL6 and C5a have been reported before and during clinical exacerbations. In order to better understand the role of the T cells in Gleichs syndrome we analyzed the intracellular cytokine expression in CD3+ cells of a patient affected by the disease. As hypereosinophilia was documented, we asked whether IL-4 and IL-5 levels were increased, and the intracytoplasmatic expression of these Th2-cytokines was determined. The percentage of T lymphocytes (CD3-gated cells) of both CD8− and CD8+ phenotype expressing different cytokines showed an unusually high percentage of Th2-related cytokine (IL-4, IL-5 and IL-13) expressing T lymphocytes. The two new variants (myeloproliferative and lymphoproliferative) seem to account for hypereosinophilia in patients with hypereosinophilic syndrome (HES). In the lymphroliferative variant, the presence of a clonal CD3-CD4+ Th2 like lymphocyte secreting IL-4 and IL-5 in peripheral blood, may explain the hypereosinophilia and the hyper-IgE. In our study we show that the patient had a lymphoproliferative variant and her T cell had a Th2 type phenotype. Moreover, we suggest that Th2 lymphocytes may play a role in the pathogenesis of Gleichs syndrome. Further studies are needed to evaluate the possibility that a polyclonal aspecific activation of Th2 type cells can lead to hypereosinophilia, IgE production and the other manifestations typical of Gleichs syndrome.

Comment to “Postero-Inferior Pedicle Surgical Technique for the Treatment of Grade III Gynecomastia”

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Allergy to all mammalian Bovidae proteins but cow's milk in a child

Cross reactivity between mammalian proteins (cow, goat, ewe, buffalo) has been previously described in both in vitro and in vivo studies. The highest homologies are observed between the milk proteins from cows and other Bovidae, being on average 96.1% for buffalo, 91.1% for ewe, and 87.6% for goat. Lower sequence similarities are associated with proteins contained in milks from Suidae (pigs and boars, 64.2%), Equidae (horse 62.4% and donkey 62.8%), Camelidae (dromedary 60.0%) and humans (58.4%). Despite the high degree of homology with cow’s milk, allergy to buffalo’s milk is poorly investigated and so far only one case of severe allergy to buffalo’s milk has been shown in a 70-year-old German patient who indeed tolerated cow’s milk and had negative goat milk skin tests. We report the case of a six-year-old boy with a past medical history of atopic dermatitis. At the age of two years, he developed asthma. The skin tests with common inhalants (Alk-Abelló extracts) resulted positive to grass, dust mite, cypressus, cat and mugworth. The child was eating regular cow’s milk proteins from the first year of life. At the age of three years he had vomit immediately after the intake of ewe cheese. Prick-to-prick with ewe’s and goat’s milks resulted positive as well as skin prick tests with goat’s milk and ewe’s milk caseins (Alk-Abello, Milan, Italy). Cow’s milk prick-to-prick and skin prick test (SPT) with purified casein, -lactalbumin and -lactoglobulin (AlkAbello, Milan, Italy) from cow’s milk were negative. He was advised to eat only cow’s milk and cow’s milk products. At the age of four years after the intake of cheese made with cow’s and goat’s milk (the last ingredient was not declared) he developed asthma plus vomit. The in vitro diagnostic test confirmed the presence of specific IgE to goat and ewe milk: >100 KUA/L and 78.9 KuA/L respectively, and the absence of specific IgE to cow’s milk, bovine casein and whey proteins -lactalbumin and -lactoglobulin (ImmunoCAP system, Phadia Diagnostics, Milan Italy). The total IgE level was 100 KUA/L. At the age of five years he had an anaphylactic reaction (asthma, vomit, generalised urticaria) immediately after the intake of buffalo’s mozzarella cheese. At the time of anaphylaxis the child could eat cow’s milk proteins without adverse reactions. Wheal and flare (W/F) reactions by means of prick-to-prick tests with buffalo’s milk, buffalo’s mozzarella and histamine at 10 mg/ml were 10/20, 10/20 and 4/8, respectively. Prick-to-prick with buffalo’s mozzarella was performed in three non-allergic children as controls. Under double-blinded, placebo-controlled oral provocation with buffalo’s fresh untreated milk, the patient developed urticaria and rhinitis (1 mL = single provoking dose). The reaction was treated with oral corticosteroids and anti-histamines. This study was performed with the approval of the ethics committee, and both parents gave written consent. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis with different mammalian milks and with purified proteins from cow’s milk ( e -casein, -lactalbumin, lactoglobulin and bovine serum albumin) was performed. As shown in Fig. 1, different electrophoretic patterns were obtained according to the mammalian species considered. Cow’s milk contains four different bands from top to bottom: and -casein, -lactoglobulin and -lactalbumin. In the goat’s milk sample (both fresh and commercial), the -casein amount is lower than that in cow’s milk according to previous evidence. Ewe’s milk electrophoretic profile is slightly different in terms of electrophoretic mobilities of casein and whey proteins. Buffalo’s milk shows an electrophoretic profile overlapping that of cow’s milk. In the buffalo’s mozzarella both -casein and -casein are easily identified, whereas whey proteins are less clearly visible (only a weak band corresponding to -lactoglobulin). After transfer of proteins from gel to PVDF membrane, incubation with the serum of the allergic patient was performed. The immunoblotting showed specific IgE reactivity against -casein in goat’s milk and ewe’s milk; a lower but still significant reaction was observed versus buffalo’s milk and mozzarella. A marked IgE-mediated reaction with another protein having an electrophoretic run higher than -casein, can be observed in commercial goat’s milk. This is probably due to the presence of -caseins (a fraction of -casein) coming from a partial proteolysis. The same band is also present in fresh goat’s milk but in traces; in fact caseins are fragments due to proteolysis whose abundance increases progressively from fresh milk to cheese. No reactivity with cow’s milk proteins can be detected (Fig. 2). Cross reactivity between goat or ewe’s milk and cow’s milk has been frequently described. Moreover, allergy to milk of goat and ewe, two phylogenetically closely related mammalians, without allergy to cow’s milk has also been reported. Again, despite the close phylogenetic relationship between buffalo and cow, an isolated buffalo’s milk allergy has been described. In this case, specific IgE against two bands were demonstrated and in immunoblot experiments, specific IgE reactivity could be reproduced against non-glycosylated and glycosylated bufaline K-caseins, corresponding to the 17-kDa band.