Alessandro Milani

Clinical usefulness of patch and challenge tests in the diagnosis of cell-mediated allergy to betalactams

BACKGROUND Literature reports dealing with cell-mediated allergy to betalactams have appeared with increasing frequency in the last years. OBJECTIVE To evaluate patients with such reactions and to identify cross-reactivities among betalactams in order to provide safe guidelines for their further clinical management. METHODS Thirty consecutive subjects with cell-mediated allergy to betalactams (history of adverse reactions to these antibiotics; serum total IgE within the normal range; absence of serum specific IgE antibodies to penicillin G and V, amoxicillin, and ampicillin; negative skin tests with a wide pattern of betalactam preparations; and positive patch-test to at least one betalactam antigenic determinant) were investigated. The subjects admitted to the study were patch tested with a wide variety of betalactam preparations in order to identify alternative molecules tolerated by the patient. To better evaluate the cross-reactivity pattern, tolerance challenges with patch-negative betalactams were also performed in each subject. RESULTS Both specific IgE and skin tests were negative in all patients. The skin biopsies performed on the positive patch-tested area in four patients showed a clear T-lymphocyte, CD4+-type infiltrate, thus definitely proving the occurrence of a cell-mediated response. A total of 44 adverse reactions (mean: 1.47 episodes for each patient) were reported in history, with a mean interval of 15 hours after betalactam administration. The reported symptoms were mainly cutaneous (maculo-papular rash and urticaria) and the responsible drugs were chiefly aminopenicillins (86.4% of cases) and penicillin G (9.1%). We were able to identify three separate groups of patients on the basis of clinical history, patch-test, and tolerance challenge pattern: allergy to the side chain of aminopenicillins in 16 patients (53.3%); allergy to the thiazolidine ring in 3 patients (10.0%); undetermined specificity in the remainder 11 patients (36.7%). Cross-reactivity among different betalactam molecules (revealed by positive tolerance tests performed with patch-negative betalactams) was found in 4.8% of cases only (23.3% of all investigated patients). This fact demonstrates a very high (95.2%) predictive value of a negative patch-test in excluding the occurrence of a cross-reactivity. The mis-match between patch and tolerance tests was observed in 3 out of 178 cases only (1.7% of cases, 10.5% of patients) in groups A and B, and in as much as 12.2% of cases (45.5% of subjects) in group C (P < .05). CONCLUSIONS Delayed allergy to betalactams (mainly to aminopenicillins) may be exerted by a cell-mediated response. Patch tests and tolerance challenges are extremely useful and safe for diagnosis and further clinical treatment of these patients, helping to identify safe alternative betalactam molecules that could be successfully tolerated by the allergic subjects.

Effects of lysine-acetylsalicylate (LAS) treatment in nasal polyposis: two controlled long term prospective follow up studies

Nasal polyposis is a multifactorial disease with a complex and still not completely understood pathogenesis. In more than one third of cases it is associated with intolerance to acetylsalicylic acid (aspirin, ASA) or to other non-steroidal anti-inflammatory drugs (NSAIDs).1 In as many as 20% of cases nasal polyposis is also associated with the presence of bronchial asthma and/or rhinitis, configuring the so-called ASA triad or aspirin disease.2 Nasal polyps may benefit from medical treatment (corticosteroids) and surgery,3 but they frequently relapse soon after surgery4-9 with significant morbidity and high social and medical costs. Unfortunately, the effect of treatment with steroids is also often temporary.3 10-16 In the last two decades it has been observed that, in aspirin sensitive patients, oral aspirin desensitisation (followed by long term aspirin treatment) often results in an improvement in the clinical course of nasal polyposis.17-21 We have shown that aspirin sensitive patients with nasal polyposis have a higher rate of positive nasal provocation tests (rhinomanometric measure of nasal airflow reduction after exposure to the drug) with lysine-acetylsalicylate (LAS) than aspirin sensitive patients without nasal polyps.22-24 Moreover, LAS has been found to have an in vitro non-specific antiproliferative, dose dependent effect on the growth of fibroblasts of both nasal polyps and normal skin.23 We have shown that long term topical (endonasal) treatment with LAS prevents the recurrence of nasal polyps after polypectomy with satisfactory results.24 In this paper we present and discuss the definitive results obtained in two controlled long term prospective follow up studies dealing with the evaluation of relapse rates in nasal polyposis. The first is a six year follow up study of patients with nasal polyps who underwent long term intranasal LAS treatment after surgical polypectomy in comparison with matched controls (patients who underwent …

Oral desensitisation in cow milk allergy: immunological findings.

In the literature there are several reports dealing with the possibility of a desensitising treatment in food allergy, but there are very few studies concerning the immunological mechanisms of or al desensitisation. We studied the immunological modifications in four children who underwent oral desensitisation with cow milk. Four children with cow milk allergy underwent oral desensitisation according to a standardized protocol. Total IgE, eosinophilic cationic protein in serum, and specific IgE and IgG4 to α-lactalbumin, to β-lactoglobulin and to casein were determined at the beginning of the treatment and after 6, 12 and 18 months in the 4 children treated. All the 4 treated patients successfully completed the treatment. Specific IgE to casein showed a significant reduction (p<0.01), while specific IgG4 to α-lactalbumin (p<0.02), to β-lactoglobulin (p<0.01) and to casein (p<0.01) showed a significant increase. Total IgE, eosinophilic cationic protein, and specific IgE to a-lactalbumin and to β-Iactoglobulin did not show any significant modification. Control patients did not show any immunological modification and still had a positive double-blind, placebo-controlled food challenge. These results make us think that oral desensitisation in food allergy occurs with the same mechanisms of traditional desensitising treatments for respiratory and insect sting allergies.

Latex allergy desensitization by exposure protocol: Five case reports

Two clinical reports dealing with subcutaneous desensitization to latex are available, but these treatments were reported to have significant side effects. To investigate an alternative method for latex desensitization, we present five cases of immunoglobulin E-mediated latex allergy in which a specific desensitization was successfully performed by means of an original exposure protocol. Five female patients with proven latex allergy underwent an original contact desensitization by wearing latex gloves daily, progressively increasing exposure to latex. All patients reached a final latex exposure time of 60 min in both hands. The desensitization protocol was completely successful in all patients. Twelve months after the beginning of the desensitization program, all the treated subjects were able to wear latex gloves daily without any clinical manifestations. This study provides evidence that a successful contact desensitization to latex is possible with no side effects. The adopted exposure protocol seems to be completely safe and effective. However, further studies in larger groups of subjects are necessary to fully confirm these preliminary results.

The aspirin disease

Aspirin or acetylsalicylic acid (ASA) is still one of the most widely sold drugs in the world and its side effects are well known. Among these, hypersensitivity reactions represent one of the most frequently described since the first report of urticaria and angio-oedema by Hirshberg in 1902.1 The hypersensitivity reactions to aspirin may be divided into two major categories2: type A characterised by respiratory symptoms (bronchial asthma, rhinitis) which account for about 15% of cases, and type B with urticaria and angio-oedema which occur in more than 75% of cases.3 A third category (type C) which includes any other peculiar clinical presentation (such as multiform erythema, fixed exanthema, Stevens-Johnsons syndrome, Lyells syndrome) occurs in a small number of cases. Females are more affected than males, except in childhood in which the asthmatic type A reactions are rare. A familial (and sometimes a personal) history of allergic disease is reported in about one third of cases.3 An extra-immunological (“pseudo-allergic”) mechanism is involved in the pathogenesis of nearly all aspirin hypersensitivity reactions. The most accepted pathogenetic theory4 5 postulates that the cyclo-oxygenase (COX) block (COX-1 and COX-2) induced by aspirin leads to an increase in arachidonic acid metabolism by an alternative pathway represented by lipoxygenase. This in turn increases the synthesis of leukotrienes C4, D4, and E4 which are able to exert a powerful bronchospastic action.6 7 An increasing number of reports concerning the existence of a relationship between bronchial asthma and the presence of nasal polyposis in the clinical picture of hypersensitivity reactions to aspirin has been accumulating in the literature since the late 1920s. The association of bronchial asthma and nasal polyposis in aspirin intolerant patients was first described by Widal in 19228and confirmed by several …

Reduced serum levels of immunoreactive erythropoietin in patients with cirrhosis and chronic anemia

Chronic anemia is frequently observed in patients affected by cirrhosis. To investigate the possible role of erythropoietin (Epo) in the pathogenesis of anemia in cirrhosis, we measured the immunoreactive Epo levels and the respective hemoglobin (Hb) concentrations in 48 anemic and nonanemic cirrhotic patients and in a control group of healthy subjects and patients with iron‐deficiency anemia. Epo concentrations were determined in serum using a sensitive enzyme immunoassay. The regression curve between Epo values and Hb concentrations showed a significant inverse exponential trend both in cirrhotic patients (r = −.55; P < .0001) and controls (r = −.92; P < .0001). In a semilogarithmic plot, the line slope obtained in cirrhotic patients was significantly lower (P < .005) than that of controls, suggesting a blunt Epo response to anemia in cirrhosis. Moreover, covariance analysis showed that the Epo levels for a given degree of anemia were furtherly reduced in the patients with a more severe disease, suggesting a close relation between cirrhosis and the mechanisms involved in the derangement of the Epo feedback system. Finally, the Epo concentrations measured in the cirrhotic patients without anemia did not significantly differ from Epo values obtained in healthy subjects. An impaired Epo response may play a role in maintaining low Hb concentrations in cirrhotic patients with anemia. However, the evidence of a residual Epo response to anemia in cirrhosis and the presence of normal basal Epo levels in nonanemic cirrhotic patients do not support an inadequate Epo secretion as one of the primary causes of anemia in cirrhosis. (HEPATOLOGY 1995;22:1132–1135.).

Ascites dynamics in cirrhosis: Proposal and validation of a methylene blue dilution test

In order to investigate ascites dynamics, we examined a simple compartmental model based on the analysis of the peritoneal clearance rate of methylene blue in 58 patients with cirrhosis and ascites. After abdominal injection of 10-50 mg methylene blue, the ascitic concentration of the dye progressively decreased, following an exponential trend. The dye distribution volume (7.1 + 0.61, mean + SE) and its peritoneal clearance (87.6 + 5.0 ml/min) were determined by mathematical analysis. The accuracy of volume determinations was controlled in 5 subjects by total paracenteses. In 6 patients, methylene blue clearances were also compared with free-water peritoneal clearances, estimated by a deuterium oxide dilution technique. The decrease in the ascitic concentrations of both tracers followed a corresponding exponential decay in all patients, and the parameters of ascites dynamics determined by the two techniques (peritoneal volumes and clearance values) showed no statistical difference. We therefore suggest the use of the methylene blue dilution test to estimate free-water transperitoneal dynamics, which may be useful in the evaluation and control of cirrhotic patients with ascites.

Treatment of genotype-1 hepatitis C recurrence after liver transplant improves survival in both sustained responders and relapsers

The aim of this study was to evaluate the factors affecting the response to treatment and how it could affect survival in a large series of genotype‐1 HCV‐transplanted patients. Three‐hundred and twenty six genotype‐1 HCV patients were enrolled. One hundred and ninety‐six patients (60.1%) were nonresponders and 130 (39.9%) showed negative HCV‐RNA at the end of treatment. Eighty‐four of them (25.8%) achieved sustained virological response, while 46 (14.1%) showed viral relapse. Five‐year cumulative survival was significantly worse in nonresponders (76.4%) compared with sustained viral response (93.2) or relapsers (94.9%). Sustained responders and relapsers were therefore considered as a single ‘response group’ in further analysis. Pretreatment variables significantly associated with virological response at multivariate regression analysis were the absence of ineffective pretransplant antiviral therapy, the recurrence of HCV‐hepatitis more than 1 year after transplant, an histological grading ≥4 at pretreatment liver biopsy, a pretreatment HCV‐RNA level <1.2 × 106 IU/ml, and the absence of diabetes. As expected, also on‐treatment variables (rapid and early virological response) were significantly associated to the response to antiviral treatment. In conclusion, this study shows that postliver transplant antiviral treatment results in beneficial effect on survival not only in sustained responders but also in relapsers.

Effect of pre-treatment with inhaled furosemide on allergen nasal challenge

The inhalation of furosemide has been reported to inhibit the bronchospasm induced by several agents. In the present study, we evaluated the effect of inhaled furosemide on the specific nasal challenge test in patients with allergic rhinitis. A total of 21 consecutive patients with allergic rhinitis (positive skin test and RAST) and a positive based nasal provocation test (NPT) with the specific allergen were investigated. In each patient, we compared the changes in nasal air-flow (anterior rhinomanometry) during NPT after inhalation of placebo and 20 mg furosemide. The previously positive NPT response to the inhalation of the specific allergen became negative after the furosemide pretreatment in 16 patients (76.2%, p < 0.001, chi-square test). The nasal air flows during NPT were significantly increased after furosemide treatment with respect to placebo inhalation (F = 17.2, d.f. = 1 and 3; p < 0.03; covariance analysis). Our results suggest that the pretreatment with inhaled furosemide in atopic subjects is able to exert a protective effect on the nasal mucosa reactivity to the specific allergen. Therefore, the anti-reactive effect of the drug on the airways is not confined to the bronchial asthmatic response.

Moderately Severe Acute Pancreatitis Associated With Riluzole

To the Editor: Compared with other causes, drugs represent a relatively less common cause of acute pancreatitis. However, >500 different drugs have been described by the WHO as able to induce acute pancreatitis as a side effect.1 Riluzole, a tetrodotoxin-sensitive sodium channel blocker, is the only medication approved by the Food and Drug Administration for the treatment of amyotrophic lateral sclerosis (ALS), showing a reduction of mortality in patients affected. Common side effects are nausea, epigastric pain, diarrhea or constipation, and an increase in the level of liver enzymes.2 Riluzole has only been associated with mild acute pancreatic damage in a few studies.3,4 Herein, we report a case of moderately severe acute pancreatitis associated with riluzole treatment. A 79-year-old man was admitted to our hospital because of severe upper abdominal pain and vomiting. He had no history of alcohol consumption, biliary stones, diabetes, trauma, hypercalcemia, hyperlipidemia, previous acute pancreatitis (AP), chronic pancreatitis, or familiarity for pancreatic diseases. He was being treated for years with irbesartan because of arterial hypertension. Three months before the patient started treatment with riluzole (50mg tid) because of a diagnosis of ALS. On physical examination, he showed a normal body weight (body mass index=22.1), with no signs of jaundice. Body temperature was 97.341F, heart rate was 76 bpm, and the blood pressure was 152/94mm Hg. The abdomen was tender, although with no signs of peritoneal irritability. Laboratory analyses showed a deep increase in serum amylase (1298U/L, normal r100U/L) and lipase levels (1650U/L, normal range 13 to 63U/L), moderate leukocytosis (15.750/mm), mild anemia (hemoglobin 12.5 g/dL), and a mild respiratory alkalosis. AP was therefore diagnosed. Total and direct bilirubin, c-glutamyl transpeptidase, alkaline phosphatase, as well as serum lipids and calcium levels, were all within the normal range. Screening for autoantibodies and infectious diseases was negative. Acute Physiology and Chronic Health Evaluation (APACHE II) Score was 9. A computed tomography scan performed 72 hours from the onset of the symptoms showed a mild swelling of the pancreatic body and tail and a focal necrotic area in the distal portion of the tail. AP was classified as moderately severe, according to the revised Atlanta Classification.5 Riluzole treatment was stopped, and symptoms disappeared rapidly. The patient was treated by fasting, parenteral nutrition, carbapenems, and proton pump inhibitors. After 7 days, serum pancreatic enzymes returned to within normal range, as well as peripheral white cell count. According to the Naranjo probability scale, AP was classified as probably caused by riluzole (Naranjo Score 7/13).6 rbesartan has also been described as able to induce pancreatitis approximately 2 weeks after its first administration,7 but the patient had been taking this drug for years before and ameliorated without stopping it. We did not attempt a rechallenge with riluzole; therefore, so the definite evidence for its association with AP is not available. To our knowledge, this is the first described case of moderately severe AP associated with riluzole treatment. As AP can be a life-threatening disease, the possibility of such a side effect, although rare, should be considered in patients treated with riluzole, although this is the main therapeutic option for ALS. Therefore, the management of such cases may be challenging, requiring a close multidisciplinary collaboration between neurologists and gastroenterologists.