Pholcodine, perioperative anaphylaxis, and the European Medicines Agency: finally the decision to remove pholcodine from the market in the European Union.

Two recent case-control studies, both published in the British Journal of Anaesthesia, have shown that intake of pholcodine-containing cough medicines during the year preceding general anaesthesia significantly increased the risk of anaphylaxis caused by neuromuscular blocking agents. Both a French multicentre study and a single-centre study from Western Australia offer strong support to the pholcodine hypothesis for IgE-sensitisation to neuromuscular blocking agents. The European Medicines Agency, criticised for not taking preventive action at its first assessment of pholcodine in 2011, finally recommended a stop to sales of all pholcodine-containing medicines throughout the EU on December 1, 2022. Time will tell whether this reduces the incidence of perioperative anaphylaxis in the EU, as in Scandinavia.

Functional Gastrointestinal Symptoms Are Associated with Higher Serum Total IgE Levels, but Less Atopic Sensitization.

BACKGROUND: The relation of gastrointestinal (GI) complaints to IgE-mediated allergy is not well understood. Increased numbers of "IgE-armed" mast cells have been observed in duodenal mucosa of patients with functional GI complaints. AIMS: To explore whether total IgE and atopic sensitization were associated with functional GI complaints. METHODS: Levels of serum total and specific IgE and GI complaints were measured in 161 patients and in a general population sample of 478 persons. Standard inhalant allergens were measured in the patient group, and selected inhalant allergens in the general population. GI complaints were assessed by two standardized questionnaires. The associations between GI complaints and total IgE were analyzed in multiple regression models. RESULTS: GI complaints were positively associated with higher total IgE levels (all: b = 0.028, p = 0.012; patient group: b = 0.038, p = 0.072; general population: b = 0.038, p = 0.005), but negatively associated with atopic sensitization (all: b = -11.256, p = 0.181; patient group: b = -85.667, p < 0.001; general population: b = -14.394, p = 0.083). The relationship between total IgE and GI complaints was consistent among sensitized and non-sensitized persons, among men and women, and across age groups. CONCLUSION: Serum total IgE was positively associated with GI complaints, while atopic sensitization was inversely associated with GI complaints. This suggests that IgE-mediated immunology plays a role in the pathophysiology of functional GI complaints. The biological mechanisms reflected in higher total IgE levels, but less atopic sensitization, warrant further studies.

Pholcodine consumption and immunoglobulin E-sensitization in atopics from Australia, Korea, and Japan.

BACKGROUND: Accumulating data indicates that pholcodine (PHO)-consuming countries have higher sero-prevalences of immunoglobulin E (IgE)-antibodies to PHO and suxamethonium (SUX) and increased frequencies of IgE-mediated anaphylaxis to neuromuscular blocking agents (NMBAs) than nonconsuming. Withdrawing PHO-containing cough syrups resulted in a significant decrease of cases with anaphylaxis in Scandinavia. Nevertheless, the European Medicines Agency in 2011 advised to continue the unrestricted use throughout the European Union. OBJECTIVE: To extend studies on PHO consumption and prevalence of IgE-sensitization to morphine (MOR), PHO, and SUX to countries representing high (Australia), and low (Korea and Japan), consumers, respectively. METHODS: IgE-antibodies to SUX, MOR, and PHO in atopic subjects were determined by immunoassay and compared with official figures for PHO consumption and reported anaphylaxis to NMBA. RESULTS: The prevalences of IgE-antibodies to PHO, MOR, and SUX were 10%, 8.6%, and 4.3%, respectively, in Australia. The corresponding figures for Japan were 0.8%, 0.8%, and 1.5%, and for Korea 1.0% to PHO and 0.5% to MOR and SUX. Of the SUX-positive sera, 100% were positive to PHO or MOR in Australia and 0% in Japan and Korea. CONCLUSION: The study supports previous findings; exposure to PHO may induce IgE-antibodies to the substituted ammonium ion epitope of NMBAs, thus increasing risk of NMBA-induced anaphylaxis considerably. However, other, still unknown factors occasionally might induce IgE-antibodies to SUX.

Perceived food hypersensitivity: a review of 10 years of interdisciplinary research at a reference center.

Perceived food hypersensitivity is a prevalent, but poorly understood condition. In this review article, we summarize narratively recent literature including results of our 10 years' interdisciplinary research program dealing with such patients. The patients (more than 400) included in our studies were all adults referred to a university hospital because of gastrointestinal complaints self-attributed to food hypersensitivity. Despite extensive examinations, food allergy was seldom diagnosed. The majority of the patients fulfilled the diagnostic criteria for irritable bowel syndrome. In addition, most suffered from several extra-intestinal health complaints and had considerably impaired quality of life. However, psychological factors could explain only approximately 10% of the variance in the patients' symptom severity and 90% of the variance thus remained unexplained. Intolerance to low-digestible carbohydrates was a common problem and abdominal symptoms were replicated by carbohydrate ingestion. A considerable number of patients showed evidence of immune activation by analyses of B-cell activating factor, dendritic cells and "IgE-armed" mast cells. Multiple factors such as immune activation, disturbed intestinal fermentation, enteric dysmotility, post-infectious changes and "local" allergy in the gut as well as psychological disturbances may play a role in the pathophysiology of perceived food hypersensitivity. Hence, our results support the view that management of these patients should be interdisciplinary.

Clinical characteristics of patients with drug hypersensitivity in Norway: a single-centre study.

BACKGROUND: Drug hypersensitivity reactions (DHRs) represent an important public health problem. Knowledge of their clinical characteristics will provide improved diagnostic approaches to this topic. OBJECTIVES: The aim of the present study was to describe the clinical characteristics of patients with suspected DHRs. METHODS: The medical records of 206 outpatients with suspected DHRs, who consulted a Norwegian allergy centre from January 2005 to December 2009, were investigated in a retrospective study. RESULTS: Mean age (range) was 44.3 (11-84) years, and 72% of the patients were women. The most common underlying diseases justifying the use of drugs were infections (49%) and pain-related diseases (23%). Antibiotics (53%), non-steroidal anti-inflammatory drugs (NSAIDs) (32%), paracetamol (15%) and other drugs (46%), used as monotherapy or combinations, were the most often suspected drugs. Cutaneous symptoms were the most frequently reported symptoms (83%). Hospitalisation or prolonged hospitalisation was needed in 38% of the cases, and anaphylaxis was reported in 28% of all the patients. Skin prick tests were performed in 185 patients, of which 14 patients had positive test results. Drug provocation tests (DPTs) were performed in only 86 patients, six of which had positive reactions. DHRs were confirmed in 24 and rejected in 81 patients. Unsettled cases (39%) were mainly due to not performing DPTs. CONCLUSIONS: Suspected DHRs occur predominantly in women. The most common manifestations are cutaneous symptoms, but life-threatening reactions justifying hospitalisation may occur. Antibiotics and NSAIDs are the two drug families most frequently suspected. DPTs need to be included in diagnostic protocols in order to evaluate suspected DHRs.

[Anaphylaxis during anaesthesia]. / Anafylaksi under anestesi.

BACKGROUND: Anaphylaxis is a serious life-threatening generalized or systemic hypersensitivity reaction. The aim of this paper is to provide knowledge on how to diagnose, treat and follow up patients with suspected anaphylaxis during general and local anaesthesia. MATERIAL AND METHODS: The article is based on literature identified through a non-systematic search in PubMed, the Scandinavian Guidelines on anaphylaxis during anaesthesia and on own research. RESULTS: Anaphylactic symptoms during anaesthesia vary with respect to severity. Manifestations from skin and the cardiovascular and respiratory systems are present simultaneously in approximately 70 % of patients. Early treatment with adrenaline, fluid and extra oxygen may be vital for survival without sequelae. The following patients should be assessed before anaesthesia: those with moderate or serious reactions or with reactions that raise suspicion of allergy which may cause problems in connection with future treatment. Neuromuscular blocking agents are the main cause of IgE-mediated anaphylaxis during anaesthesia in Norway. New research has shown that allergy towards neuromuscular blocking agents can develop after ingestion of cough syrup containing pholcodine (stimulates asymptomatic production of antibodies). These antibodies cause cross-sensibilisation with neuromuscular blocking agents. The cough syrup Tuxi was withdrawn from the Norwegian market during spring 2007. INTERPRETATION: Allergic reactions during anaesthesia are rare and potentially life-threatening; patients should be followed up and treated in a standardized way.

Anxiety and depression in patients with self-reported food hypersensitivity.

OBJECTIVE: Self-reported food hypersensitivity (SFH) is common. Psychological factors are assumed to be associated. We assessed anxiety and depression in SFH patients, using both questionnaires and interview. METHODS: Consecutive patients (n=130) and randomly selected healthy volunteers (n=75) completed the Hospital Anxiety and Depression Scale (HADS), the neuroticism scale of the Eysenck Personality Questionnaire (EPQ-N) and the General Health Questionnaire (GHQ). Seventy-six of the patients were also interviewed by use of the Mini International Neuropsychiatric Interview and the Montgomery-Aasberg Depression Rating Scale. All patients underwent extensive allergological, gastroenterological and dietary examinations. RESULTS: According to interviews, 57% of patients fulfilled the DSM-IV criteria for at least one psychiatric disorder. Anxiety disorders (34%) and depression (16%) predominated. According to questionnaires, patients scored significantly higher than controls on all psychometric scales except for depression (HADS). We also found an underreporting of depression in HADS compared with interviews (2.5% vs. 16%, P=.001). Food hypersensitivity was rarely confirmed by provocation tests (8%). Eighty-nine percent of the patients had irritable bowel syndrome. CONCLUSIONS: Anxiety and depression are common in patients with IBS-like complaints self-attributed to food hypersensitivity. Anxiety disorders predominate. In this setting, depression may be underreported by HADS.

Effects of industrial processing on the immunogenicity of commonly ingested fish species.

BACKGROUND: Food-processing techniques may induce changes in fish protein immunogenicity. Allergens from >100 fish species have been identified, but little is known on the effects of processing on fish protein immunogenicity. METHODS: IgE binding of sera of patients allergic to fresh and processed (smoked, salted/sugar-cured, canned, lye-treated and fermented) cod, haddock, salmon, trout, tuna, mackerel and herring and of hydrolysates based on salmon and whiting was investigated using immunoblot and inhibition ELISA. RESULTS: Parvalbumin oligomers were identified using monoclonal and polyclonal antibodies. IgE binding was seen in most sera at 12-14 kDa (parvalbumin), and at 17-60 kDa for all fish except tuna. Changes in IgE binding appeared to reflect altered parvalbumin monomers and oligomers. Smoked haddock, salmon and mackerel had increased IgE binding and novel bands at 30 kDa. Chemically processed cod, salmon, trout and pickled herring had reduced or abolished IgE binding. The serum of 1 subject, however, had increased IgE binding to these products and also inhibition of binding by both fish hydrolysates to their constituent fish species. CONCLUSION: Process-induced changes in fish protein immunogenicity were more dependent on process rather than species, although individual responses varied. Changes in the allergenicity of a product may depend on the net effect of processing on parvalbumin oligomerization patterns, which may also vary in different species. Chemical processes generally caused loss in IgE-binding activity, though sensitization may occur to modified or degraded rather than intact peptides as shown by increased binding by chemically processed fish and hydrolysates in 1 subject. The clinical significance of these findings remains to be established.

Occupational allergy to Artemia fish fry feed in aquaculture.

BACKGROUND: Artemia (brine shrimp) is used as feed for fish fry and shrimp in aquaculture. Two employees in a Norwegian aquaculture research farm reported having chest symptoms when working in an Artemia hatch room. AIMS: To determine the presence and prevalence of Artemia sensitization at the farm and the extent of any Artemia-related respiratory and hand skin symptoms and to identify the allergens involved. METHODS: Participants completed a questionnaire and structured interview. Skin prick tests (SPTs) were performed, and immunoglobulin E (IgE) antibodies to Artemia, shrimp and recombinant tropomyosin were determined. Gel electrophoresis and immunoblots of Artemia extracts were also carried out. RESULTS: Thirty of 42 employees (71%) participated. Among the 24 subjects exposed to Artemia, four (17%) reported chest and/or hand skin symptoms during exposure and three of them were IgE sensitized to Artemia. Five (21%) of those exposed demonstrated IgE antibodies to Artemia and four (17%) had immediate-positive SPTs. A serum pool from these subjects exhibited IgE binding to a protein of approximately 97 kDa in the Artemia extract. CONCLUSIONS: Occupational exposure to the Artemia fish fry feed can cause IgE sensitization and allergic symptoms affecting airways and skin.

High prevalence of immunoglobulin E (IgE) sensitization among sisal (Agave sisalana) processing workers in Tanzania.

PURPOSE: Allergic sensitization among workers exposed to sisal is scarcely documented. We examined whether sisal processing is associated with IgE sensitization and its relationship to the prevalence of respiratory symptoms among Tanzanian processors. METHODS: 138 sisal exposed workers and 78 non-exposed controls were skin prick tested (SPT) using dry sisal extract and fresh sisal sap. Sera from a subset of 43 participants were analyzed for total and sisal specific IgE. SPT wheal size, prevalence of positive SPTs and adjusted relative risk (RR) for sisal sensitization were determined and compared between exposed and controls. Prevalences for respiratory symptoms were compared between sensitized and non-sensitized sisal workers. RESULTS: Significantly higher prevalence of positive SPTs to sisal was found among 74 % of sisal workers compared to 17 % among controls. Compared to controls, the RR of sensitization to sisal was 4 times higher (95 % CI; 2.4-6.7) among exposed workers. All exposed workers had elevated IgE levels (>100 kU/l) and 27 % of tested sera had elevated sisal specific IgE. A high prevalence of respiratory symptoms was found in both sensitized and non-sensitized sisal workers. CONCLUSION: Sisal processing is associated with increased risk of IgE sensitization, but its clinical implication is not obvious.

Bronchial responsiveness in bakery workers: relation to airway symptoms, IgE sensitization, nasal indices of inflammation, flour dust exposure and smoking.

BACKGROUND: Bronchial hyperresponsiveness (BHR) is common in bakery workers. The relation between bronchial responsiveness measured with a tidal breathing method and smoking, airway symptoms, IgE-sensitization, nasal indices of inflammation and flour dust exposure have been studied with bronchial responsiveness expressed as a continuous outcome. MATERIAL AND METHODS: Bakery workers (n = 197) were subjected to interviews, questionnaires, allergy tests, workplace dust measurements and bronchial metacholine provocation. Eosinophil cationic protein (ECP) and alpha(2)-macroglobulin were measured in nasal lavage. Bronchial responsiveness was expressed as slope(conc), a measurement based on regressing the per cent reduction in FEV(1) at each provocation step. RESULTS: BHR expressed as slope(conc) was associated with smoking (P = 0.009), asthma symptoms at work (P = 0.001), and occupational IgE sensitization (P = 0.048). After adjusting for baseline lung function the association between BHR and IgE sensitization was no longer present. We demonstrated an association between nasal ECP and BHR (slope(conc) < 3: P = 0.012), but not to alpha(2)-macroglobulin in nasal lavage. No association was seen between BHR and current exposure level of flour dust, number of working years in a bakery or a history of dough-making. CONCLUSION: BHR is related to baseline lung function, work-related asthma symptoms, smoking and nasal eosinophil activity, but not to occupational IgE sensitization and current flour dust exposure when measured with metacholine provocation. The slope(conc) expression seems to be a useful continuous outcome in bronchial responsiveness testing.

Nasal indices of eosinophilic and exudative inflammation in bakery-workers.

AIMS: Rhinitis symptoms frequently occur in bakery-workers. Yet, little is known about the pathophysiology of this condition. The objective of the present study was to examine nasal indices of inflammation in relation to occupational dust exposure, occupational rhinitis according to defined criteria, rhinitis symptoms associated to the workplace, and occupational sensitization in bakery-workers. METHODS: Bakery-workers (n = 197) were subjected to interviews, questionnaires, workplace dust measurements, allergy tests, and nasal lavages with and without histamine. alpha(2)-Macroglobulin and eosinophil cationic protein (ECP) were measured in saline lavages as indices of plasma exudation and eosinophilic activity, respectively. Histamine lavages were employed to explore the nasal exudative responsiveness. RESULTS: alpha(2)-Macroglobulin and ECP increased significantly by increased workplace dust exposure (P< or =0.035). Furthermore, the exudative responsiveness to histamine increased significantly by such exposure (P< or =0.016). Similar patterns were seen in workers with occupational rhinitis and in subjects with rhinitis symptoms associated to the workplace, but not in workers with occupational sensitization. CONCLUSIONS: We conclude that occupational dust exposure in bakery-workers is associated with nasal eosinophilic exudative inflammation. In contrast, occupational sensitization is not a discriminating factor with regard to indices of eosinophilic, exudative inflammation in the present material.

Food hypersensitivity reactions visualised by ultrasonography and magnetic resonance imaging in a patient lacking systemic food-specific IgE.

BACKGROUND: Abdominal complaints related to food intake might be due to hypersensitivity. A firm diagnosis of food allergy is often difficult to establish, particularly in the absence of systemic food-specific IgE. Using ultrasonography and magnetic resonance imaging (MRI) we were able to visualise the intestinal response in one such case. METHODS: A 24-year-old female presented with self-reported food hypersensitivity, particularly related to the intake of egg. Nausea and diarrhoea were predominant symptoms. Double-blind placebo-controlled food challenge with raw egg was positive, but all other conventional tests of food hypersensitivity, including skin prick test, total and food-specific IgE in serum, were negative. A thorough investigation programme could not reveal any organic disease of the gastrointestinal tract. We extended the evaluation to include two new provocation tests, where intestinal wall thickening and the amount of luminal liquid were monitored by external abdominal ultrasound and MRI. RESULTS: Both ultrasound and MRI investigations indicated intestinal wall thickening and influx of large amounts of fluid into the proximal small intestines within 10 min of duodenal challenge with egg. The response was associated with abdominal pain and bloating. CONCLUSIONS: The response to provocation was typical of an immediate allergic reaction. Our results indicate that local food-induced hypersensitivity reactions can occur in the gut in the absence of systemic indications of IgE-mediated allergy. Abdominal ultrasonography and MRI might become valuable tools for documenting such responses.

Allergy to fish parvalbumins: studies on the cross-reactivity of allergens from 9 commonly consumed fish.

BACKGROUND: Fish-hypersensitive patients can probably tolerate some fish species while being allergic to others. OBJECTIVE: To determine the allergenic cross-reactivity between 9 commonly edible fish: cod, salmon, pollack, mackerel, tuna, herring, wolffish, halibut, and flounder. METHODS: Sera from 10 patients allergic to fish and rabbit antisera against 3 parvalbumins (Gad c 1, Sal s 1, and The c 1) were used. Cross-reactivity was investigated by SDS/PAGE and IgE immunoblotting, IgG ELISA, IgE ELISA inhibition, and skin prick test (SPT). RESULTS: Cod (Gad c 1), salmon (Sal s 1), pollack (The c 1), herring, and wolffish share antigenic and allergenic determinants as shown by immunoblots and IgE ELISA, whereas halibut, flounder, tuna, and mackerel displayed lowest cross-reactivities. The highest mean IgE ELISA inhibition percent of 10 sera was obtained by Gad c 1, followed by The c 1, herring, Sal s 1, wolffish, halibut, flounder, tuna, and mackerel with the least inhibition. Nine of the 10 patients showed positive SPT to cod, salmon, and pollack; 8 patients reacted to recombinant (r) Sal s 1. Positive SPTs to rGad c 1 and rThe c 1 were demonstrated in 1 patient. CONCLUSION: Gad c 1, Sal s 1, The c 1, herring, and wolffish contained the most potent cross-reacting allergens, whereas halibut, flounder, tuna, and mackerel were the least allergenic in the current study. The latter could probably be tolerated by some of the tested patients.

Occupational rhinitis: diagnostic criteria, relation to lower airway symptoms and IgE sensitization in bakery workers.

CONCLUSIONS: The use of different diagnostic criteria has considerable consequences for the prevalence estimates of occupational rhinitis. There is a strong relationship between occupational rhinitis and lower airway symptoms. Storage mites appear to be important occupational allergens in Norwegian bakeries. OBJECTIVES: To study the consequences of various diagnostic criteria on the prevalence of occupational rhinitis, assess the prevalence of IgE sensitization and explore the relationships between upper and lower airway symptoms and between symptoms and IgE sensitization. MATERIAL AND METHODS: A total of 197 employees in 6 bakeries were interviewed and completed a questionnaire. A skin prick test was performed, total and specific IgE were determined and a histamine release test was performed for relevant allergens. The criteria for the diagnosis of occupational rhinitis were based on the 1994 International Consensus Report on Rhinitis. RESULTS: The prevalence of occupational rhinitis varied between 23% and 50%, depending on the criteria used. The occurrence of nasal symptoms was found to precede the development of lower airway symptoms. Occupational rhinitis, both IgE- and non-IgE-mediated, was associated with asthma symptoms. The most frequent causes of sensitization (20%) were different species of storage mites. Storage mite sensitization was related to occupational rhinitis and work exposure.

Subjective health complaints and modern health worries in patients with subjective food hypersensitivity.

Perceived food hypersensitivity is much more common than food allergy as medically verified. Unexplained symptoms and wrong attribution are typical in subjective health complaints. We hypothesize that subjective health complaints and worries are abnormally prevalent among patients with subjective food hypersensitivity. Forty-six patients with subjective food hypersensitivity and two control groups, one formed by 50 health care workers and one by 70 sex- and age-matched volunteers from the general population, were included in our study. All filled in two questionnaires: Subjective Health Complaints Inventory and Modern Health Worries Scale. None of the patients had IgE-mediated food allergy. The patients scored significantly higher than the controls on sum scores for four domains of subjective health complaints, including gastrointestinal complaints (P < 0.001), musculoskeletal complaints (P < 0.01), "pseudoneurology" (P < 0.001), and allergy (P < 0.001). Sum scores on modern health worries did not differ significantly between groups. The results support our hypothesis of an association between subjective food hypersensitivity and subjective health complaints, corroborating the view that, in the absence of food allergy, the conditions are sharing pathogenetic mechanisms.

Response to intestinal provocation monitored by transabdominal ultrasound in patients with food hypersensitivity.

OBJECTIVE: Owing to lack of objective measures, the diagnosis of food hypersensitivity may be difficult. The aim of this study was to investigate whether the intestinal response to direct provocation in patients with food hypersensitivity could be recognized by ultrasound. MATERIAL AND METHODS: Thirty-two patients with chronic abdominal complaints, self-attributed to food hypersensitivity/allergy were included in the study. Via a nasoduodenal tube, the duodenal mucosa was challenged with the suspected food item dissolved in 10 ml water or saline. Using external ultrasound, the sonographic features (wall thickness and diameter of the duodenal bulb and jejunum, peristalsis activity and luminal fluid) were recorded before and during one hour after challenge. RESULTS: Sonographic changes were observed after challenge in 14 (44%) of the 32 patients. A positive sonographic response (increased wall thickness, diameter, peristalsis and/or luminal fluid) was significantly related to a positive skin prick test (p = 0.008) and a positive double-blind placebo-controlled food challenge (p = 0.03). A significant correlation was found between provocation-induced symptoms and wall thickness of the duodenal bulb (r = 0.50, p = 0.004) or the jejunum (r = 0.42, p = 0.02). Intra- and interobserver variation of the tracing procedure showed low values. CONCLUSIONS: Responses of the proximal small intestines to direct provocation (swelling of the wall and exudation of fluid into the lumen) could be visualized by transabdominal ultrasound. This new provocation test could be helpful in the evaluation of patients with food hypersensitivity.

Food hypersensitivity-immunologic (peripheral) or cognitive (central) sensitisation?

Patients with food hypersensitivity suffer poor quality of life and several unexplained health complaints, both abdominal and extra-abdominal. Part of the suffering is due to healthcare providers' neglect and poor insight, allowing a strong position for alternative medicine. Distinguishing food allergy from functional and organic disorders can be extremely difficult. We have found examination of faecal calprotectin and gut permeability to be useful for excluding organic disease, whilst conventional provocation tests for positive diagnosis of food hypersensitivity are cumbersome. Our new ultrasound provocation test has been promising, but we acknowledge that much work remains to be done before its sensitivity and specificity can be finally established. The majority of patients with self-reported food hypersensitivity have a non-allergic hypersensitivity disorder. We suggest that cognitive-emotional sensitisation at the brain level, and not peripheral (immunological) sensitisation, is a major pathogenetic mechanism by which the patients' various abdominal and extra-abdominal health complaints are generated. Extensive activation of cognitive networks might be triggered by peripheral sensory mechanisms, often misinterpreted as 'food allergy'. Clearly, the approach to patients with food hypersensitivity should be interdisciplinary.