Evaluation of a large set of patients with Autoimmune Polyglandular Syndrome from a single reference centre in context of different classifications.

PURPOSE: To characterize patients with APS and to propose a new approach for their follow-up. Query ID="Q1" Text="Please check the given names and familynames." METHODS: Monocentric observational retrospective study enrolling patients referred to the Outpatients clinic of the Units of Endocrinology, Diabetology, Gastroenterology, Rheumatology and Clinical Immunology of our Hospital for Autoimmune diseases. RESULTS: Among 9852 patients, 1174 (11.9%) [869 (73.9%) female] were diagnosed with APS. In 254 subjects, the diagnosis was made at first clinical evaluation (Group 1), all the other patients were diagnosed with a mean latency of 11.3 ± 10.6 years (Group 2). Group 1 and 2 were comparable for age at diagnosis (35.7 ± 16.3 vs. 40.4 ± 16.6 yrs, p = .698), but different in male/female ratio (81/173 vs 226/696, p = .019). In Group 2, 50% of patients developed the syndrome within 8 years of follow-up. A significant difference was found after subdividing the first clinical manifestation into the different outpatient clinic to which they referred (8.7 ± 8.0 vs. 13.4 ± 11.6 vs. 19.8 ± 8.7 vs. 7.4 ± 8.1 for endocrine, diabetic, rheumatologic, and gastroenterological diseases, respectively, p < .001). CONCLUSIONS: We described a large series of patients affected by APS according to splitters and lumpers. We propose a flowchart tailored for each specialist outpatient clinic taking care of the patients. Finally, we recommend regular reproductive system assessment due to the non-negligible risk of developing premature ovarian failure.

Autoantibodies' titre modulation by anti-BlyS treatment in systemic lupus erythematosus.

OBJECTIVE: The objective of this study was to analyse autoantibodies' titres modulation during belimumab treatment in 50 patients with systemic lupus erythematosus (SLE). METHODS: Sera were collected at belimumab start (T0) and every six months until the 24th month. Disease activity index (SLEDAI-2K) was analysed at every timepoint. High avidity anti-dsDNA was detected by radioimmunological method, anti-ENA, anti-cardiolipin antibodies (aCL), anti-ß2 glycoprotein I (anti-ß2GPI) were analysed by ELISA. RESULTS: Fifty patients with SLE (mean SLEDAI-2K: 7.18 ± :3), mean age of 39 ± 11 years and mean follow-up of 13 ± 7.8 years were enrolled. A significant decrease of anti-dsDNA and anti-ß2GPI IgM titres was observed at all timepoints. IgG aCL titre showed significant decrease only at T18. Anti-dsDNA negativization was detected in 21%, anti-ß2GPI IgG in 33% and aCL IgG in 30% of sera, mostly at T6. Anti-ribosomal showed a significant titre decrease at T6 and T12, with negative seroconversion at T18. Anti-Sm titre significantly dropped down at T6, then remained stable during the time. Significant correlations were found between anti-dsDNA and anti-ribosomal titre and between SLEDAI ratio (SLEDAI value/SLEDAI T0) and anti-ribosomal titre ratio (value/value T0). CONCLUSIONS: Belimumab treatment induced a significant reduction of SLE-specific autoantibodies titre and IgM anti-ß2GPI. Anti-ribosomal titre decrease correlates with anti-dsDNA titre and disease activity improvement.

Relationship between endothelial dysfunction, videocapillaroscopy and circulating CD3+CD31+CXCR4+ lymphocytes in systemic lupus erythematosus without cardiovascular risk factors.

OBJECTIVE: The objective of this paper is to analyse whether digital capillary morphology, analysed by nailfold videocapillaroscopy (NVC), and the number of circulating CD3 + CD31 + CXCR4 + lymphocytes (angiogenic T cells) could be markers of endothelial dysfunction (ED) in systemic lupus erythematosus (SLE) without cardiovascular disease (CVD) and CV risk factors. METHODS: Nineteen consecutive SLE patients, according to Systemic Lupus International Collaborating Clinics Classification Criteria, with a disease duration less than five years, low disease activity, without CVD and CV risk factors (diabetes, chronic renal disease, uncontrolled systemic arterial hypertension, smoking, hypercholesterolemia, obesity), statin or beta-blocker use were enrolled. Each patient and sex- and age-matched healthy control (HC) underwent Doppler echocardiogram, an endothelial function study by peripheral arterial tonometry technique, NVC and peripheral blood immunophenotyping. RESULTS: SLE ED+ more frequently showed NVC abnormalities compared with HCs ( p < 0.0001) in terms of minor alterations ( p = 0.017), lower capillary numbers ( p = 0.0035) and major alterations. SLE ED + showed a higher rate of CD3 + CD31 + CXCR4 + lymphocytes compared with SLE ED- and with HCs. NVC + SLE showed a significantly reduced rate of total CD3 + cells, but a higher rate and absolute number of CD3 + CD31 + CXCR4 + , compared with NVC- SLE. CONCLUSION: NVC alterations are frequent in SLE without any CV risk factors and CVD. They are associated with ED and increased circulating CD3 + CD31 + CXCR4 + lymphocytes. These findings demonstrate a clear microvascular perturbation in patients with short disease duration, low disease activity and no CV risk factors.

Cooking influence in tolerance acquisition in egg-induced acute food protein enterocolitis syndrome.

BACKGROUND: Few studies on the age of resolution of Food Protein Induced Enterocolitis Syndrome (FPIES) induced by solid foods are available. In particular, for FPIES induced by egg, the mean age of tolerance acquisition reported in the literature ranges from 42 to 63 months. OBJECTIVE: We have assessed whether the age of tolerance acquisition in acute egg FPIES varies depending on whether the egg is cooked or raw. METHODS: We conducted a retrospective and multicentric study of children with diagnosis of acute egg FPIES seen in 10 Italian allergy units between July 2003 and October 2017. The collected data regarded sex, presence of other allergic diseases, age of onset of symptoms, kind and severity of symptoms, cooking technique of the ingested egg, outcome of the allergy test, age of tolerance acquisition. RESULTS: Sixty-one children with acute egg FPIES were enrolled, 34 (56%) males and 27 (44%) females. Tolerance to cooked egg has been demonstrated by 47/61 (77%) children at a mean age of 30.2 months. For 32 of them, tolerance to raw egg has been demonstrated at a mean age of 43.9 months. No episodes of severe adverse reaction after baked egg ingestion have been recorded. CONCLUSIONS: It is possible to perform an OFC with baked egg, to verify the possible acquisition of tolerance, at about 30 months of life in children with acute egg FPIES.

True and false contraindications to vaccines.

Nowadays, the awareness of risks related to infectious diseases has decreased, whereas THE perception of risks related to vaccination is growing. Therefore, it may be difficult for health care providers to convince people of the importance of vaccination and adherence to the immunisation schedule. Selected situations that might raise uncertainties about vaccine recommendations are discussed in order to help health care providers to identify real and perceived contraindications to vaccines, and cases to be referred to specialised pre-vaccination consultation due to an increased risk of adverse events to vaccines.

Macrophage activation syndrome in adult systemic lupus erythematosus: report of seven adult cases from a single Italian rheumatology center.

The aim was to describe the macrophage activation syndrome (MAS), a life-threatening syndrome characterized by excessive immune activation that can be triggered by conditions affecting immune homeostasis, in a cohort of adult Italian patients with systemic lupus erythematosus (SLE). This was a monocentric retrospective evaluation. The utility of the H-score, developed to estimate the individual risk of having reactive MAS in adult patients, was assessed. Among 511 patients with SLE, 7 cases (1.4%) of MAS (all females) were identified and their medical records reviewed. In all cases, MAS was simultaneous to the onset of SLE. All patients had fever, lymphadenopathy, hematological involvement, and high titer of anti-dsDNA antibodies. Workup for infections and malignancies was negative. In all cases, the H-score was higher than the cut-off suggested for the classification of reactive MAS. All cases required hospital admission, and 2 patients were admitted to the intensive care unit. Most patients were treated successfully with high doses of corticosteroids and with immunosuppressive drugs, whereas the full therapeutic regimen developed for primary hemophagocytic lymphohistiocytosis HLH was used only in one case. No death from MAS was observed. MAS is a rare and severe disorder that complicated the onset of SLE in our cohort. The H-score may be useful in the classification of these patients.

Organ damage accrual and distribution in systemic lupus erythematosus patients followed-up for more than 10 years.

Objective The aim of this study was to determine the prevalence, predictors and progression of organ damage in a monocentric cohort of systemic lupus erythematosus patients with a long follow-up. Organ damage was assessed by the Systemic Lupus International Collaborating Clinics Damage Index one year after diagnosis and every five years. Disease activity was measured by the systemic lupus erythematosus disease activity index (SLEDAI)-2K at the beginning of the follow-up. Univariate and multivariable analyses were used to detect items associated with damage. A total of 511 systemic lupus erythematosus patients (92% females, 95% Caucasian), prospectively followed from 1972 to 2014, were included. Results After a mean disease duration of 16 years (SD: 9.5) and a mean follow-up of 12.9 years (SD: 8.8), 354 patients (69.3%) had accrued some damage: 49.7% developed mild/moderate damage, while 19.5% showed severe damage. Damage was evident in 40% of 511 patients one year after diagnosis, and its prevalence linearly increased over time. Longer disease duration, higher SLEDAI, severe Raynaud's, chronic alopecia and cerebral ischaemia were significantly associated with organ damage. No associations between damage and autoantibodies, including anti-dsDNA, anti-Sm or antiphospholipid antibodies, were observed. Anyway, antiphospholipid syndrome and anticardiolipin antibodies predicted the development of neuropsychiatric damage. The ocular, musculoskeletal and neuropsychiatric systems were the most frequently damaged organs, with a linear increase during follow-up. Conclusion A high rate of moderate and severe damage has been detected early in a wide cohort of young lupus patients, with a linear trend of increase over time. Disease activity and long duration of disease predict damage, while antiphospholipid antibodies play a role in determining neuropsychiatric damage.

The contribution of antiphospholipid antibodies to organ damage in systemic lupus erythematosus.

OBJECTIVES: The objective of this study was to assess the contribution of clinically significant antiphospholipid antibodies (aPL) to organ damage in systemic lupus erythematosus (SLE). METHODS: Patients with disease duration of less than 10 years and at least 5 years of follow-up were identified from two SLE registries. A clinically significant antiphospholipid antibody (aPL) profile was defined as: positive lupus anticoagulant, anticardiolipin IgG/M ≥ 40 G phospholipid units (GPL)/M phospholipid units (MPL), and/or anti-ß2-glycoprotein-I IgG/M ≥ 99th percentile on two or more occasions, at least 12 weeks apart. Organ damage was assessed by the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Univariate and multivariate analysis compared SLE patients with and without SDI increase during a 15-year follow-up. RESULTS: Among 262 SLE patients, 33% had a clinically significant aPL profile, which was associated with an increased risk of organ damage accrual during a 5-year follow-up in univariate analysis, and during a 15-year follow-up in the multivariate analysis adjusting for age, gender, race, disease duration at registry entry, and time. In the multivariate analysis, older age at diagnosis and male gender were also associated with SDI increase at each time point. CONCLUSION: A clinically significant aPL profile is associated with an increased risk of organ damage accrual during a 15-year follow-up in SLE patients.

The role of clinically significant antiphospholipid antibodies in systemic lupus erythematosus.

The objective is to investigate the role of clinically significant antiphospholipid antibodies (aPL) in a cohort of systemic lupus erythematosus (SLE) patients. All SLE patients followed for at least 5 years and with available aPL profile at the beginning of the follow-up in our center were studied. Clinically significant aPL were defined as: positive lupus anticoagulant test, anti-cardiolipin and/or anti- ß2Glycoprotein I IgG/IgM >99th percentile on two or more occasions at least 12 weeks apart. Patients with and without clinically significant aPL were compared by univariate (Chi square or Fisher's exact test for categorical variables and Student's t or Mann-Whitney test for continuous variables) and multivariate analysis (logistic regression analysis). P values <0.05 were considered significant. Among 317 SLE patients studied, 117 (37%) had a clinically significant aPL profile at baseline. Such patients showed at univariate analysis an increased prevalence of deep venous thrombosis, pulmonary embolism, cardiac valvular disease, cognitive dysfunction and antiphospholipid syndrome (APS), but a reduced prevalence of acute cutaneous lupus and anti-extractable nuclear antigens (ENA) when compared with patients without clinically significant aPL. Multivariate analysis confirmed the association between clinically significant aPL and reduced risk of acute cutaneous lupus [p=0.003, odds ratio (OR) 0.43] and ENA positivity (p<0.001, OR 0.37), with increased risk of cardiac valvular disease (p=0.024, OR 3.1) and APS (p<0.0001, OR 51.12). Triple positivity was the most frequent profile and was significantly associated to APS (p<0.0001, OR 28.43). Our study showed that one third of SLE patients had clinically significant aPL, and that this is associated with an increased risk, especially for triple positive, of APS, and to a different clinical and serological pattern of disease even in the absence of APS.

Patients with longstanding primary antiphospholipid syndrome: retrospective analysis of organ damage and mortality.

OBJECTIVE: To assess the prevalence of disease- and therapy-related complications and of the organ damage after a follow-up of 15 years or more in patients with primary antiphospholipid syndrome (PAPS). METHODS: Medical records of patients prospectively followed in our centre for at least 15 years were retrospectively reviewed. RESULTS: Thirty-five Caucasian patients (33 female, two male) with diagnosis of PAPS followed from 1984 to 2013 with a mean age at onset of 32 years (SD 8.17) and a median follow-up of 20.5 years (range 15-30) were included. The occurrence of systemic autoimmune disease was observed in 14% of patients. Haemorrhagic, infective and neoplastic events were recorded in 34%, 6% and 9% respectively. Organ damage was present in 20% of patients at the end of the follow-up (17% neurological and 3% renal) and was significantly associated with the occurrence of thrombotic events (p: 0.027), particularly arterial (p<0.001). A 48-year-old patient died from sepsis. CONCLUSION: During long-term follow-up of PAPS systemic autoimmunity is not unexpected. Organ damage progresses in a significant proportion of patients especially if they have suffered previous arterial events. Our study clearly shows the possible evolution of the disease and of organ damage, suggesting that optimal therapy and optimal prophylaxis of each PAPS patient should be carefully identified and strictly applied.

Rare autoantibodies to cellular antigens in systemic lupus erythematosus.

OBJECTIVE: A high number of antinuclear antibody specificities can be detected in systemic lupus erythematosus (SLE). Some of them are related to a distinct clinical subset of disease, independently of their frequency. The aim of our study was to investigate, in a cohort of SLE patients, the prevalence and the clinical relevance of autoantibodies to cellular antigens less frequently found in SLE. METHODS: Antinuclear antibodies were detected by indirect immunofluorescence on HEp-2 cells while counterimmunoelectrophoresis was used to detect anti-ENA antibodies in 540 patients with SLE, classified according to ACR and SLICC criteria. Clinical and serological features were collected from clinical charts. RESULTS: A total of 319 (58.9%) out of 540 sera were positive for anti-ENA antibodies. Anti-Ro/SSA was found in 235 sera, 50 of which also contained anti-La/SSB. Anti-U1RNP were detected in 67, anti-Sm in 46 and anti-ribosomal P protein in 13 sera. In a multivariate analysis anti-Sm was associated with discoid lupus (p = 0.045) and photosensitivity (p = 0.037), anti-U1RNP with malar rash and Raynaud's phenomenon (p = 0.01 and p = 0.0004, respectively) and anti-Ro/SSA with malar rash, oral ulcers, xerostomia, xerophthalmia and rheumatoid factor (p = 0.029, p = 0.01, p = 0.031, p = 0.002 and p = 0.028, respectively). Other anti-ENA antibodies were found in 50 positive sera (15.6%). Anti-Ki antibodies were detected in 31, anti-Ku in 8, anti-centromere in 5, isolated anti-La/SSB, anti-PCNA and anti-Topo I in 3 each and anti-Jo-1 in 2 sera. About half of these antibodies (27 out of 50) were detected as the single anti-ENA specificity in serum. At multivariate analysis anti-Ki was significantly associated with male gender while anti-Ku with African ethnicity (p = 0.017 and p < 0.0001, respectively). No sign of muscular or pulmonary involvement was found in anti-Jo-1-positive patients whilst features of systemic sclerosis were detectable in two out of three anti-Topo I. CONCLUSIONS: Our study shows that antibodies to cellular antigens more rarely found in SLE are detectable in more than 15% of patients with anti-ENA antibodies. Most of them are found as single anti-ENA specificity. Anti-Ki and anti-Ku are found in a subset of disease, characterized by male gender and African origin, respectively. Clinical features of scleroderma were found only in patients with anti-Topo I.

Anti-cyclic citrullinated peptide antibodies in systemic lupus erythematosus patients with articular involvement: a predictive marker for erosive disease?

A small number of systemic lupus erythematosus (SLE) patients develop an erosive disease. Some studies have suggested an association between anti-cyclic citrullinated (anti-CCP) antibodies and this pattern of arthritis, but their exact significance in SLE patients remains unclear. The aim of this study was to evaluate the prevalence of anti-CCP antibodies in SLE patients with different subsets of articular disease. Among 521 SLE patients followed in this center from 1976 to 2011, those with articular involvement (n=298) were selected to take part in the study. We searched for anti-CCP2 IgG antibodies in 198 patients using a commercial enzyme linked immunosorbent assay (Immunoscan RA, Eurodiagnostica). In 174 patients the results for rheumatoid factor (RF) by nephelometry were retrospectively collected. C reactive protein (CRP) was obtained from clinical records. Patients were classified into 3 groups: erosive, non-erosive deforming, non-erosive non-deforming arthritis. Results of the different tests were compared among the groups. P<0.05 was considered statistically significant. Anti-CCP antibodies were significantly associated with erosive disease. We also found that RF positivity and increased CRP were more frequent in erosive arthritis and erosive or non-deforming arthritis, respectively, than in non-erosive non-deforming arthritis. This study supports the evidence that anti-CCP antibodies could be a useful marker of erosive disease in SLE patients. Increase in RF and CRP could be an additional means of identifying lupus patients with arthritis at risk of a worse prognosis.

Systematic Review and Meta-analysis on the Association of Occupational Exposure to Free Crystalline Silica and Rheumatoid Arthritis.

KEY MESSAGES: • Occupational exposure to free crystalline silica and tobacco smoking are associated with an increased risk rheumatoid arthritis, with the evidence of an interaction in seropositive subjects. • Further studies in the field are needed to support such association We carried out a systematic search for all published epidemiological studies concerning the association between occupational exposure to free crystalline silica (FCS) and subsequent development of rheumatoid arthritis (RA). A meta-analysis was conducted on relevant studies. We searched PubMed and Embase, search engines, for original articles published (from 1960 to November 2019) in any language. In addition, we also searched reference lists of included studies manually for additional relevant articles. Finally, twelve studies were included in the meta-analysis (seven case-control cases and five cohort studies). The odds risks and 95% confidence interval (CI) were calculated using a random effect meta-analysis. A primary meta-analysis (using a random effect model)-regarding RA risk in subjects exposed to FCS-yelled to an overall OR of 1.94 (95% CI 1.46-2.58). We also conducted three further meta-analysis, taking into account the presence of autoantibodies (anti-RF or anti-ACPA) and smoking habits and found a significant association between FCS and RA in both seropositive and seronegative subjects (OR 1.74, 95% CI 1.35-2.25 and OR 1.23, 95% CI 1.06-1.4, respectively) and in seropositive subjects which were smokers (OR 3.30, 95% CI 2.40-4.54). The studies that have investigated the association between RA and occupatational exposure to FCS are still scarce and the heterogeneity between the studies remains high. Some critical limitations have been identified within studies, among which, the methods for assessing exposure stand out. Although with due caution, our results confirm the hypothesis of an association between occupational exposure to FCS and RA development. There was an interaction between FCS and tobacco smoking in RA seropositive workers.

Antibiotic allergy.

Antibiotics are commonly injected during the perioperative period and are responsible of 15 percent of the anaphylactic reactions. Anaphylaxis triggered by antibiotics primarily involves penicillin and cephalosporin. The management of patients with histories of allergic reactions to antibiotics is a common situation in clinical practice. The confirmation or invalidation of the allergic nature of the reported reaction is not based on in vitro tests, but on a rigorous allergological work-up based on detailed analysis of clinical history, skin tests and drug provocation test. Considering a possible cross-reactivity between penicillins, once an immediate penicillin allergy has been diagnosed, skin testing with the alternative molecule (cephalosporin, carbapenem, aztreonam) is mandatory and, if negative, the relevant drug should be given in an appropriate setting at increasing doses.

Perioperative latex allergy.

The prevalence of latex allergy varies greatly depending on the population studied and the methods used to detect sensitization. Subjects considered to be at high risk for latex allergy are rubber industry workers, children with spina bifida and urological abnormalities, children undergoing multiple surgical procedures and with urinary catheterization, health care workers and people with food allergy (latex fruit syndrome). In this paper we report a review of latex proteins, the symptoms of latex allergy, diagnosis and management in subjects with latex allergy.

Perioperative allergy: risk factors.

Perioperative anaphylactic as well as anaphylactoid reactions can be elicited by drugs, diagnostic agents, antiseptics, disinfectants and latex. In some individuals, allergic reactions occur in the absence of any evident risk factor. Previous history of specific safe exposure to a product does not permit to exclude the risk of having a reaction. We have systematically reviewed characteristics in the patient's history or clinical parameters that affect the risk of developing reactions during anesthesia. Evidence shows that patients with previous unexplained reaction during anesthesia are at risk for perioperative allergic reactions. An allergic reaction to an agent is associated with previous reaction to a product that is related with the culprit agent. Multiple surgery procedures, professional exposure to latex and allergy to fruit are associated with an increased frequency of latex allergy. It has been shown that in some instances, allergic perioperative reactions may be more common in atopic patients and in females.

Perioperative allergy: clinical manifestations.

Adverse drug reactions or side effects are usually expected, dose dependent, and occur at therapeutic doses. Anaphylactic and anaphylactoid reactions are unexpected and dose independent and can occur at the first exposure to drugs used during anesthesia. Perioperative anaphylaxis is a severe and rapid clinical condition that can be lethal even in previously healthy patients. The initial diagnosis of anaphylaxis is presumptive. A precise identification of the drug responsible for the adverse reaction is more difficult to establish in the case of anaphylactoid reaction because the adverse reaction could result from additive side effects of different drugs injected simultaneously. The timing of the reaction in relation to events, e.g. induction, start of surgery, administration of other drugs, i.v. fluids, is essential for the diagnosis. Generally, reactions are predominant in the induction and recovery phases, and manifested mainly as cutaneous symptoms. Reactions to drugs coincide with the phases when they are administered. Reactions to antibiotics are more frequent in the induction phase, to neuromuscular agents in the initiation and maintenance phases and to non-steroidal anti-inflammatory agents in the recovery phase. The differential diagnosis of any adverse reaction during or following anesthesia should include the possibility of anaphylaxis.

Perioperative period: immunological modifications.

Surgical stress induces complex modifications in the hemodynamic, metabolic, neuro-hormonal and immune response of the individual. The magnitude of these alterations depends on preoperative events leading to surgery, the severity of surgical trauma, and also on post-operative/post-traumatic complications (multiple hit hypothesis). As in other conditions of tissue damage, surgery trauma is followed by an immune-inflammatory response, initiated at the site of injury by the innate immune system, followed by a compensatory anti-inflammatory (or immunosuppressive) response (CARS), involving mainly cells of the adaptive immune system, which predispose the host to septic complications. The up-regulated inflammatory response, together with a profound impairment of macrophage and cell-mediated immunity, appear to be the cause for patients' increased susceptibility in developing subsequent sepsis after major surgery.

Muscle relaxants allergy.

The most common agents that are responsible for intraoperative anaphylaxis are muscle relaxants. In fact, neuromuscular blocking agents (NMBAs) contribute to 50-70 percent of allergic reactions during anaesthesia. The main mechanism of hypersensitivity reactions to NMBAs is represented by acute type I allergic reactions and the most severe form is anaphylaxis. The rate of non IgE mediated immediate hypersensitivity reactions usually varies between 20 percent and 35 percent of the reported cases in most large series. In a recent report, non allergic suspected reactions to NMBAs occurred with almost the same frequency as did those with an allergic component. Although the precise mechanisms of these reactions remain difficult to ascertain, they usually result from direct non specific mast cell and basophil activation. After diagnostic procedures, regardless of the specific IgE results, NMBAs are contraindicated if the skin tests were positive. In view of the constantly evolving anesthesiologic practices, and of the complexity of allergy investigation, an active policy to identify patients at risk and to provide any necessary support to anaesthetists and allergologists should be promoted. The high frequency of IgE anaphylactic reactions and the feasibility of skin tests in children justify systematic allergy testing whenever hypersensitivity reaction occurs during general anaesthesia.